Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

Introduction

The metal-catalyzed activation of aromatic carbon–fluorine (C–F) bonds is widely recognized as a challenging task in synthetic organic chemistry owing to their high bond dissociation energy compared to other aromatic C–X (X = Cl, Br, I) bonds [1-7]. This activation is essential for the late-stage functionalization of stable C–F bonds in complex molecules with reactive functional groups, providing an orthogonal approach to complex molecule synthesis. Despite considerable efforts to develop various catalytic systems, the activation of aromatic C–F bonds often requires high temperatures [1-7]. Therefore, methods for activating aromatic C–F bonds at ambient temperature remain underdeveloped.

We have developed efficient metal-mediated methods for activating (i) vinylic [8-13] and (ii) allylic C–F bonds [14-18] using β-fluorine elimination under mild conditions. In these studies, (i) we discovered zirconium-mediated β-fluorine elimination from zirconacyclopropanes A, which are generated by treating 1,1-difluoroethylenes with a zirconocene equivalent (ZrCp₂, Scheme 1a) [8]. The resulting 1-fluorovinylzirconocenes B then undergo palladium-catalyzed coupling with aryl iodides to produce arylated fluoroethylenes. Additionally, (ii) we observed that electron-deficient 2-(trifluoromethyl)-1-alkenes strongly interact with electron-rich zero-valent nickel species to form nickelacyclopropanes C [15-17]. These intermediates enable C–F bond activation through the formation of nickelacyclopentenes D with alkynes, followed by β-fluorine elimination, leading to defluorinative coupling between these components (Scheme 1b).

Among aromatic fluorides, we have targeted 2-fluorobenzofurans 1 for C–F bond activation [19]. These compounds, which we prepared efficiently via 5-endo-trig cyclization of β,β-difluoro-o-hydroxystyrenes [20,21], possess a C–C double bond with an electron-deficient carbon atom owing to the nearby fluorine and oxygen atoms. We expected that 2-fluorobenzofurans 1 could form nickelacyclopropanes E upon treatment with zero-valent nickel species. Subsequent β-fluorine elimination from these intermediates E would facilitate the activation of aromatic C–F bonds (Scheme 1c). In this study, we demonstrate nickel-catalyzed defluorinative cross-coupling [22-37] of 2-fluorobenzofurans 1 with arylboronic acids 2 at ambient temperature, with nickelacyclopropanes E serving as crucial intermediates for the activation of aromatic C–F bonds.

Results and Discussion

First, we explored optimal conditions for nickel-catalyzed defluorinative coupling using 2-fluoronaphtho[2,1-b]furan (1b) and m-tolylboronic acid (2b) as model substrates (Table 1). When 1b was reacted with 2b at 80 °C using Ni(cod)₂ (10 mol %) as a catalyst, PCy₃ (20 mol %) as a ligand, and K₂CO₃ (2.0 equiv) as a base, the desired arylated naphthofuran 3bb was obtained in 75% yield (Table 1, entry 1). Reducing the reaction temperature improved the yield of 3bb, reaching a quantitative yield when the reaction was performed at room temperature (Table 1, entry 3). Reducing the catalyst loading to 5 mol % slightly affected the yield of 3bb, which was 90% (Table 1, entry 4). Next, we evaluated various additives with 5 mol % of Ni(cod)₂ to stabilize regenerated zero-valent nickel species (Table 1, entries 5–8). While phosphine ligands such as triphenyl phosphite were ineffective (Table 1, entry 5), the inclusion of chelating dienes improved the yield of 3bb (Table 1, entries 6–8). Among these, 5 mol % of 1,5-cyclooctadiene (cod) proved to be the most effective additive, affording 3bb in 95% yield (Table 1, entry 8). Additionally, by reducing the equivalents of 2b to 1.0 equiv and K₂CO₃ to 1.2 equiv, we achieved the highest yield of 98% for 3bb (Table 1, entry 9).

Under the optimized conditions, we investigated the substrate scope using 2-fluorobenzofurans 1 and arylboronic acids 2 (Scheme 2). The coupling reaction was efficient with 2-fluorobenzofuran (1a) when reacted with phenylboronic acid (2a) as well as arylboronic acids containing electron-donating groups, such as a methyl group at the 3-position (2b), two methyl groups at the 2- and 5-positions (2c), and a tert-butyl group at the 4-position (2d). The reaction with 3,5-dimethoxyphenylboronic acid (2e), which has electron-withdrawing groups on the aromatic ring, also yielded a satisfactory result of 73%. Additionally, using 2-fluoronaphtho[2,1-b]furan (1b), the reaction with phenylboronic acid (2a) and arylboronic acids with a methyl group at the 3-position (2b) or a tert-butyl group at the 4-position (2d) also produced high yields (94–98%). For arylboronic acid 2f, which has a methoxy group at the 4-position, the use of potassium phosphate as a base resulted in a 94% yield of 3bf. For arylboronic acid 2g, which features a strongly electron-withdrawing trifluoromethyl group, we optimized the coupling reaction using potassium phosphate as a base and increasing the nickel catalyst loading to 20 mol %, achieving a yield of 78% for the desired product 3bg. When 2-naphthylboronic acid (2i) was employed, its solubility was enhanced using a mixed solvent system of toluene, methanol, and water, which effectively promoted the reaction and resulted in a 70% yield of 3bi. Furthermore, when methoxy- and ethoxy-substituted benzofurans 1c and 1d were used, the corresponding coupling products 3ca and 3da were obtained with yields of 67% and 65%, respectively.

Additionally, in the coupling reaction of 2-fluorobenzothiophene (4) with 2a, increasing the amount of Ni(cod)₂ to 20 mol % without adding extra cod yielded 48% of the desired product 5 (Scheme 3). This result indicates that the reaction is applicable to benzothiophenes as well as benzofurans.

Moreover, we successfully introduced two distinct aryl groups onto a benzofuran ring through orthogonal coupling reactions, exploiting the reactivity difference between C–F and C–Br bonds (Scheme 4). Using a palladium catalyst, 5-bromo-2-fluorobenzofuran (1e) was coupled with [4-(trifluoromethyl)phenyl]boronic acid (2g). In this reaction, only the C–Br bond was transformed while the C–F bond remained intact, yielding 2-fluoro-5-[4-(trifluoromethyl)phenyl]benzofuran (1f) in 95% yield. Subsequently, nickel-catalyzed defluorinative arylation of 1f with phenylboronic acid (2a) efficiently produced 2-phenyl-5-[4-(trifluoromethyl)phenyl]benzofuran (3fa) in 81% yield.

Next, we explored the mechanism of the coupling reactions between 2-fluorobenzofurans 1 and arylboronic acids 2. Because these reactions proceed under mild conditions despite involving aromatic C–F bond activation [19], direct oxidative addition of C–F bonds is unlikely (Scheme 5, path a). Instead, the reactions are thought to proceed through a formal oxidative addition involving nickelacyclopropane intermediates E [15-17,38,39], which are generated from 2-fluorobenzofurans 1 and zero-valent nickel species (Scheme 5). Following β-fluorine elimination, this results in a formal oxidative addition to form benzofuranylnickel(II) fluorides F, which then undergo transmetallation with arylboronic acids 2 to produce intermediates G (Scheme 5, path b). Alternatively, a direct transition from E to G via transition state H is also possible (Scheme 5, path c). Ultimately, reductive elimination from G yields the coupling products 3.

The following experiments were performed to elucidate the mechanism. Under the same conditions as the coupling reaction, stoichiometric amounts of Ni(cod)₂, PCy₃, and cod were treated with fluoronaphthofuran 1b at room temperature for 13 h, excluding boronic acid 2a (Scheme 6). The reaction was monitored using ¹⁹F and ³¹P NMR spectroscopy. The ¹⁹F NMR analysis showed that 79% of 1b remained and revealed a new broad double doublet peak at 55.0 ppm (J_FP = 53, 42 Hz) relative to internal C₆F₆ (δ = 0.0 ppm). The ³¹P NMR spectrum depicted broad singlet peaks at 32.0–33.4 ppm and 38.6–40.5 ppm, appearing in a 1:1 ratio. These new peaks were attributed to nickelacyclopropane E_b, which was formed in 19% yield. No peaks corresponding to benzofuranylnickel(II) fluoride F_b, which would arise from the oxidative addition of 1b to nickel(0), were detected [40]. High-resolution mass spectrometry (HRMS) analysis of the reaction mixture also supported the formation of E_b (calcd, 804.4474; found, 804.4449). Additionally, 79% of 1b remained, while the catalytic reaction between 1b and 2a was completed in 13 h, yielding 3ba in 96% (Scheme 2). These findings suggest that nickelacyclopropanes E and 2-fluorobenzofurans 1 are in equilibrium (see Scheme 5). Consequently, in the absence of arylboronic acids 2, the consumption of 1 was suppressed. Upon adding phenylboronic acid (2a, 1.0 equiv) to the above reaction mixture, the coupling proceeded, producing 3ba in 70% yield, with neither complex E_b nor F_b observed (Scheme 6). These results suggest that nickelacyclopropanes E are initially formed and facilitate a formal oxidative addition. Notably, the absence of F in the reaction mixture indicates that fluorine elimination and transmetallation occur simultaneously between E and the arylboronic acids 2, leading to the formation of G (Scheme 5, path c). The intermediates G then undergo reductive elimination to yield 3.

To assess the impact of halogen substituents, we also examined reactions of 2-halogenated benzofurans 1a-X (1a-Cl: X = Cl; 1a-Br: X = Br; 1a-I: X = I) with (3-methylphenyl)boronic acid (2b) (Table 2). Both 2-chlorobenzofuran (1a-Cl) and 2-bromobenzofuran (1a-Br) hardly yielded 3ab under the optimized conditions for 1a (Table 2, entries 2 and 3), while the reaction of 2-iodobenzofuran (1a-I) resulted in a much lower yield (32%) of 2-arylbenzofuran 3ab (Table 2, entry 4) compared to that of 1a (X = F, quant.). The strong interaction between fluorine and boron in H likely facilitates β-fluorine elimination and transmetallation. Thus, the considerably different result observed with 1a is attributed to the distinct mechanistic aspects of the metalacyclopropanation/β-fluorine elimination sequence influenced by the fluorine substituent.

Conclusion

In summary, we have presented a nickel-catalyzed method for synthesizing 2-arylbenzofurans through aromatic C–F bond activation, with the formation of metallacyclopropanes as an essential step. This protocol allows for the late-stage transformation of C–F bonds, as demonstrated by the orthogonal activation of both aromatic C–F and C–Br bonds, thereby facilitating the synthesis of complex 2-arylbenzofurans. Given that natural and synthetic 2-arylbenzofurans often exhibit considerable biological activities and are important in pharmaceuticals and agrochemicals [41-47], we expect that this method will provide a novel and efficient approach for producing these valuable compounds.

Experimental

General: ¹H NMR, ¹³C NMR, ¹⁹F NMR, and ³¹P NMR were recorded on a Bruker Avance 500 or a JEOL ECS-400 spectrometer. Chemical shift values are given in ppm relative to internal Me₄Si (for ¹H NMR: δ = 0.00 ppm), CDCl₃ (for ¹³C NMR: δ = 77.0 ppm), C₆F₆ (for ¹⁹F NMR: δ = 0.0 ppm), and H₃PO₄ (for ³¹P NMR: δ = 0.0 ppm). IR spectra were recorded on a Horiba FT-730 spectrometer. Mass spectra were measured on a JEOL JMS-T100GCV or a JEOL JMS-T200GC spectrometer. All the reactions were conducted under argon or nitrogen.

Materials: Column chromatography was conducted on silica gel (Silica Gel 60 N, Kanto Chemical Co., Inc.). Toluene and N,N-dimethylformamide (DMF) were purified by a solvent-purification system (GlassContour) equipped with columns of activated alumina and supported-copper catalyst (Q-5) before use. 1,4-Dioxane and methanol were distilled from sodium, and stored over 4 Å molecular sieves. Unless otherwise noted, materials were obtained from commercial sources and used directly without further purifications.

Typical procedure for coupling of 2-fluorobenzofurans 1 with arylboronic acids 2: To the mixture of 2-fluoronaphtho[2,1-b]furan (1b, 56 mg, 0.30 mmol), (3-methylphenyl)boronic acid (2b, 41 mg, 0.30 mmol), Ni(cod)₂ (4.2 mg, 0.015 mmol), PCy₃ (8.2 mg, 0.029 mmol), 1,5-cyclooctadiene (1.8 μL, 0.015 mmol), and K₂CO₃ (50 mg, 0.36 mmol) were added toluene (3.0 mL) and H₂O (0.6 mL). After stirring at room temperature for 13 h, the reaction mixture was diluted with H₂O. Organic materials were extracted with diethyl ether three times. The combined extracts were washed with brine and dried over Na₂SO₄. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane/EtOAc = 10:1) to give 3bb (76 mg, 98%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.75–7.67 (m, 4H), 7.58 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.49–7.46 (m, 2H), 7.35 (dd, J = 7.7, 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 2.44 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.6, 152.3, 138.5, 130.5, 130.4, 129.1, 128.8, 128.7, 127.6, 126.2, 125.3, 125.1, 124.6, 124.5, 123.4, 121.9, 112.3, 100.3, 21.5; IR (KBr): 3051, 1606, 1487, 1387, 1280, 1255, 1163, 1053, 991, 935, 789, 690 cm^–1; HREIMS m/z: [M]⁺ calcd for C₁₉H₁₄O, 258.1045; found, 258.1035.