Suzuki Cross-Coupling of [2.2]Paracyclophane Trifluoroborates with Pyridyl and Pyrimidyl Building Blocks

Abstract

We report a new Suzuki cross-coupling protocol for high yielding derivatization of [2.2]paracyclophane with pyridyl and pyrimidyl substituents. The [2.2]paracyclophane trifluoroborate salt presented herein is a bench stable, easily accessible, and convenient substitute to former cross-coupling substrates. This will be of very high interest for future paracyclophane derivatization endeavors.

Introduction

Although it was discovered more than 50 years ago,¹ [2.2]paracyclophane continues to receive attention and is subjected to numerous investigations. Recent advances include multimetallic complexes,² N-heterocyclic carbine (NHC) complexes for enantioselective metal-free silylation,³ and optically active planar-chiral phenylethene dimers.⁴ Because of its electronic and structural peculiarities, the chemistry of [2.2]paracyclophane is considerably more cumbersome than that of the benzene analogue.⁵ Thus, its functionalization remains challenging and often requires a special effort. One of the various uses of [2.2]paracyclophane is that it is used as a rigid and planar-chiral building block. Especially, its application as the bridging backbone for multimetallic complexes with defined metal–metal distances has caught our interest. To furnish metal-binding sites consisting of ligating heteroaromatics,² functionalization can either be done de novo or, more conveniently, by cross-coupling reactions. To this end, our group reported on the modular derivatization of [2.2]paracyclophane via the Stille, Suzuki, Kumada, and Negishi cross-coupling reactions.⁶ However, as found earlier by Canturk et al.,⁷ Suzuki cross-coupling reactions with boronic acid equivalent located on the paracyclophane moiety bear some difficulties.

Because the free boronic acid of [2.2]paracyclophane is unstable, other boron derivatives have to be used. Boronic esters, however, are either unstable (methyl ester) or do not readily undergo the cross-coupling reaction (pinacol ester). To our knowledge, trifluoroborates as boronic acid precursors have never been considered in [2.2]paracyclophane chemistry. Because organotrifluoroborates hydrolyze under basic and acidic aqueous conditions,⁸ it should be possible to generate boronic acid in situ and “capture” it in a one-pot hydrolysis and Suzuki cross-coupling reaction to prevent it from degrading before conversion can take place.

Results and Discussion

Our first attempt to synthesize trifluoroborate from bromide via the pinacol boronic ester route did yield the desired compound but not in satisfying yields. A more direct route was described in the literature by Genêt et al.⁹ and could be applied successfully to 4-bromo[2.2]paracyclophane (1). This one-pot procedure enabled us to synthesize potassium 4-trifluoroborate[2.2]paracyclophane (2) on a multigram scale, which yields up to 85% (Scheme 1).

Scheme 1. Synthesis of Potassium 4-Trifluoroborate[2.2]paracyclophane (2).

Trifluoroborate is a free-flowing, crystalline solid, which can be handled very conveniently. Moreover, it can be stored under air on the benchtop without any special precautions for months without degradation (¹H NMR after 3 months unchanged). This stability makes it stand out in comparison to previous [2.2]paracyclophane coupling methods, which require fresh or even in situ preparation of the coupling nucleophile. Another advantage is the catalyst system, which is the air-stable palladium(II) acetate without the necessity of ligands or additives. Our initial testing showed that palladium(II) acetate led to superior yields than other common palladium(II) or palladium(0) sources.¹⁰ Because of solubility issues, we had to substitute the solvents of choice in the literature (often methanol or ethanol).¹¹ In earlier studies, we found benzene to be the best solvent for the Suzuki cross-coupling of [2.2]paracyclophane trifluoroborates. However, here it could be substituted by less hazardous toluene with a negligible decrease in yield (<3%). An optimization process was conducted with 2-bromopyridine, its boryl derivative being a challenging coupling substrate.¹² The initial yield of 27% (Table 1, entry 1) was increased to 42% by changing the base to cesium carbonate and lowering the temperature to 70 °C with a reaction time of 24 h (entry 15). The addition of commonly used phosphine ligands such as SPhos and XPhos led to a decrease in yield. Also not beneficial were higher temperatures (entry 5) and longer reaction times (entry 10). The trifluoroborate starting material undergoes hydrodeboronation¹³ under cross-coupling conditions, leading to defunctionalized [2.2]paracyclophane as a side product. The percentage of the side product is up to 52% in relation to the used starting material 2 (the most hindered substrate, entry 7). When using less than 5 mol % of the catalyst, the yields started to decrease (entries 13 and 14), whereas using more than 5 mol % did not lead to an increase in yield either. With these conditions in hand, we were able to obtain several pyridyl-and pyrimidyl-substituted [2.2]paracyclophanes in good to very good yields. Our method is also suitable for large-scale reactions, as compound 3d was obtained in a very good yield on a gram scale.

Table 1. Optimization of the Suzuki Cross-Coupling Reaction of 2 with Different Substrates.

^aNMR yields.

^bIsolated yields.

^c4-Bromopyridine hydrochloride as the starting material.

Conclusions

In summary, we have developed a Suzuki cross-coupling protocol that enables the convenient synthesis of pyridyl- and pyrimidyl-substituted [2.2]paracyclophanes. To that end, [2.2]paracyclophane is converted to the respective trifluoroborate salt, which is a convenient and bench-stable solid. The coupling substrates can be used in their commercially available bromide form to achieve good to very good yields. We believe that this cross-coupling procedure will find wide applications for the derivatization of [2.2]paracyclophane. Investigations toward further coupling substrates and bistrifluoroborate[2.2]paracyclophanes are currently underway.

Experimental Section

General Information and Methods

¹H NMR spectra were recorded on a Bruker AM 400 (400 MHz), a Bruker DRX 500 (500 MHz), or on a Bruker AVANCE 600 (600 MHz) spectrometer. Chemical shifts are expressed in parts per million (ppm, δ) downfield from tetramethylsilane (TMS) and are referenced to CHCl₃ (7.26 ppm) as the internal standard. All coupling constants are absolute values, and J values are expressed in hertz (Hz). The description of signals includes the following: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, ddd = doublet of dd, dt = doublet of triplet, td = triplet of doublet, bs = broad singlet, and m = multiplet. The spectra were analyzed according to the first order. ¹³C NMR spectra were recorded on a Bruker AM 400 (100 MHz), a Bruker DRX 500 (125 MHz), or on a Bruker AVANCE 600 (150 MHz) spectrometer. Chemical shifts are expressed in parts per million (ppm, δ) downfield from TMS and are referenced to CDCl₃ (77.0 ppm) as the internal standard. The signals for ¹H were assigned by the multiplets and those for ¹³C by distortionless enhancement by polarization transfer (DEPT)-90 and DEPT-135 spectra and by obvious chemical shifts. The multiplicity of ¹³C NMR signals is given as follows: DEPT: + = primary or tertiary (positive DEPT signal), – = secondary (negative DEPT signal), C_q = quaternary C atoms (no DEPT signal). The spectra were analyzed according to the first order. Mass spectrometry (MS) (electron impact, EI) and MS (fast atom bombardment, FAB): Finnigan MAT 90 (70 eV). The peaks are given as the mass-to-charge-ratio (m/z). The molecule peak is given as [M]⁺. For the high-resolution mass, the following abbreviations were used: calcd = theoretical calculated mass; found = mass found in analysis. Infrared spectroscopy (IR): FT-IR Bruker IFS 88 and Bruker Alpha. IR spectra of solids were recorded in KBr or by the attenuated total reflection (ATR) technique and as thin films on KBr for oils and liquids. The deposit of the absorption band was given in wavenumbers ν̃ in cm^–1 between 3600 and 500 cm^–1. Band intensities were characterized as follows: versus = very strong [0–10% transmission (T)], s = strong (11–30% T), m = medium (31–70% T), w = weak (71–90% T), and vw = very weak (91–100% T). Routine monitoring of reactions was performed using silica gel-coated aluminum plates (Merck, silica gel 60, F254), which were analyzed under UV light at 254 nm. Solvent mixtures are understood as volume/volume. Solid materials were powdered. Solvents, reagents, and chemicals were purchased from Aldrich, Fluka, Carbolution, ChemPur, ABCR, TCI, and Fisher Scientific. Tetrahydrofuran was distilled from sodium/benzophenone under argon prior to use. All reactions involving moisture-sensitive reactants were executed under an argon atmosphere using oven-dried and/or flame-dried glassware. All other solvents, reagents, and chemicals were used as purchased unless stated otherwise. Air- or moisture-sensitive reactions were carried out under an argon atmosphere in previously evacuated and heated glassware. Liquids were transferred with plastic syringes and steel cannulas. Solids were used as powders. The reaction control was performed by thin-layer chromatography. Solvents were removed at 40 °C at the rotavapor. If not stated otherwise, crude products were purified by flash chromatography with silica gel 60 (0.040 × 0.063 mm, Geduran) (Merck), which was used as the stationary phase, and solvents of p.a. quality were used as the mobile phase.

Potassium 4-Trifluoroborate[2.2]paracyclophane (2)

In a round-bottom flask under argon, 4-bromo[2.2]paracyclophane (5.02 g, 17.5 mmol, and 1.00 equiv) was dissolved in 250 mL of anhydrous tetrahydrofurane. The solution was cooled to −78 °C, and nBuLi (7.70 mL, 2.5 M, 19.3 mmol, and 1.10 equiv) was added dropwise by a syringe. After 1 h, the yellow solution was quenched with triisopropylborate (6.1 mL, 26.2 mmol, and 1.50 equiv). The now colorless solution was allowed to slowly warm to room temperature. The next day, aqueous potassium hydrogen difluoride (23.3 mL, 4.5 M, 105 mmol, and 6.00 equiv) was added by the syringe, and the mixture was stirred vigorously for 3 h. After removal of the solvents under reduced pressure, the white residue was triturated with acetone (2× room temperature, 2× boiling, and 50 mL each), and the acetone was removed under reduced pressure subsequently. The white residue was washed with dichloromethane and diethylether (100 mL each) and dried in high vaccum to yield a powdery white crystalline solid (4.79 g, 87%).

¹H NMR

¹H NMR (400 MHz, acetone-d₆): δ [ppm] 6.76 (dd, J = 7.8, 1.5 Hz, 1H), 6.69 (s, 1H), 6.43 (d, J = 1.7 Hz, 2H), 6.30 (dd, J = 7.8, 1.5 Hz, 1H), 6.17 (d, J = 1.7 Hz, 2H), 3.67 (ddd, J = 12.5, 10.5, 2.5 Hz, 1H), 3.15–3.00 (m , 3H), 2.93–2.70 (m, 4H). ¹³C NMR (101 MHz , acetone-d₆): δ [ppm] 144.1 (C_quat.), 141.1 (C_quat.), 139.6 (C_quat.), 137.4 (C_quat.), 137.1 (C_quat.), 134.7 (+ , C_ArH), 134.7 (+, C_ArH), 133.7 (+, C_ArH), 133.6 (+, C_ArH), 132.8 (+ , C_ArH), 132.6 (+ , C_ArH), 131.2 (+, C_ArH), 36.51 (−, CH₂), 36.41 (−, CH₂), 36.33 (−, CH₂), 36.16 (−, CH₂). ¹¹B NMR (128 MHz, acetone-d₆): δ [ppm] −15.2 (d, J = 59.2 Hz). ¹⁹F NMR (376 MHz, acetone-d₆): δ [ppm] −143.23 (m). IR (ATR) ν̃: 3569 (w), 3378 (w), 2925 (w), 2851 (w), 1894 (vw), 1589 (w), 1552 (vw), 1500 (vw), 1478 (vw), 1436 (vw), 1410 (w), 1330 (w), 1231 (w), 1186 (vw), 1149 (w), 1107 (w), 938 (w), 901 (w), 834 (w), 793 (w), 736 (w), 719 (w), 643 (w), 615 (vw), 590 (vw), 511 (w), 482 (vw). HRMS (FAB) (C₁₆H₁₅¹¹B₁F₃K₁) calcd, 314.0856; found, 314.0854.

General Cross-Coupling Procedure (3a–d)

In a vial fitted with a magnetic stirring bar, potassium 4-trifluoroborate[2.2]paracyclophane (1.25 equiv), cesium carbonate (4.00 equiv), palladium acetate (0.05 equiv), and the respective bromide (1.00 equiv, if solid) were placed. The vial was evacuated and backfilled with argon three times. After addition of the solvent (toluene/water 3:1 and 6.00 mL/mmol), the respective bromide (1.00 equiv, if liquid) was added via a syringe. The mixture was put into a vial heating block and heated to 80 °C for 24 h. The reaction was cooled to ambient temperature and quenched with sat. aq ammonium chloride. After separation of the phases, the aqueous phase was extracted with dichloromethane (3 × 15 mL). The organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (silica and cyclohexane/ethyl acetate).

4-(2′-Pyridyl)[2.2]paracyclophane (3a)

4-(2′-Pyridyl)[2.2]paracyclophane (3a) was obtained by column chromatography (silica, CH/EA 10:1, R_f = 0.30), yield 77 mg, 43%. ¹H NMR (500 MHz chloroform-d): [ppm] 8.71–8.64 (m, 1H), 7.68 (td, J = 7.7, 1.9 Hz, 1H), 7.43 (dd, J = 8.0, 1.1 Hz, 1H), 7.23–7.09 (m, 1H), 6.75 (d, J = 1.9 Hz, 1H), 6.57–6.37 (m, 6H), 3.67–3.52 (m , 1H), 3.19–3.01 (m , 2H), 3.04–2.79 (m, 4H), 2.64–2.51 (m, 1H). ¹³C NMR (101 MHz, CDCl₃): δ [ppm] 159.1 (C_quat.), 149.7 (+ , C_ArH), 140.6 (C_quat.), 139.8 (C_quat.), 139.6 (C_quat.), 139.4 (C_quat.), 138.2 (C_quat.), 136.3 (+, C_ArH), 136.2 (+, C_ArH), 133.2 (+,C_ArH), 132.9 (+, C_ArH), 132.7 (+, C_ArH), 132.6 (+, C_ArH), 132.4 (+, C_ArH), 130.7 (+, C_ArH), 124.2 (+, C_ArH), 121.4 (+, C_ArH), 35.57 (−, CH₂), 35.34 (−, CH₂), 35.21 (−, CH₂), 34.59 (−, CH₂). IR (ATR) ν̃: 2930 (vw), 2850 (vw), 1582 (vw), 1498 (vw), 1465 (vw), 1422 (vw), 1239 (vw), 1145 (vw), 1087 (vw), 1037 (vw), 991 (vw), 943 (vw), 893 (vw), 849 (vw), 784 (vw), 747 (vw), 729 (vw), 717 (vw), 653 (vw), 639 (vw), 618 (vw), 595 (vw), 559 (vw), 515 (vw), 481 (vw), 408 (vw). MS (EI, 70 eV) m/z [%]: 286 (6) [M + H]⁺, 285 (25) [M]⁺, 181 (100) [M – C₈H₈ + H]⁺, 180 (67) [M – C₈H₈]⁺, 131 (19) [C₁₀H₁₂]⁺, 104 (27) [C₈H₈]⁺. HRMS (C₂₁H₁₉N) calcd, 285.1517; found, 285.1519. The analytical and spectroscopical data match those reported in the literature.⁶

4-(3′-Pyridyl)[2.2]paracyclophane (3b)

4-(3′-Pyridyl)[2.2]paracyclophane (3b) was purified by column chromatography (silica, CH/EA 3:1, R_f = 0.27), yield 126 mg, 70%. ¹H NMR (500 MHz chloroform-d): δ [ppm] 8.77 (d, J = 2.2 Hz, 1H), 8.62 (dd, J = 4.9, 1.7 Hz, 1H), 7.79 (dt, J = 7.7, 2.0 Hz, 1H), 7.40 (dd, J = 7.8, 4.8 Hz, 1H), 6.64 (t, J = 8.3 Hz, 2H), 6.57 (dd, J = 11.1, 1.6 Hz, 5H), 3.36 (ddd, J = 13.0, 10.0, 3.1 Hz, 1H), 3.22–3.11 (m , 3H), 3.09–3.02 (m, 1H), 3.01–2.94 (m, 1H), 2.90 (ddd, J = 13.5, 10.3, 3.2 Hz, 1H), 2.64 (ddd, J = 13.1, 10.0, 4.8 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃): δ [ppm] 150.5 (+, C_ArH), 147.9 (C_quat.), 140.2 (C_quat.), 139.6 (C_quat.), 139.5 (C_quat.), 138.2 (C_quat.), 137.2 (C_quat.), 137 (+, C_ArH), 136.6 (+, C_ArH), 136.1 (+, C_ArH), 136.1 (+, C_ArH), 133.3 (+, C_ArH), 133.1 (+, C_ArH), 132.8 (+, C_ArH), 132.1 (+, C_ArH), 132 (+, C_ArH), 129.6 (+, C_ArH), 123.5 (−, CH₂), 35.5 (−, CH₂), 35.2 (−, CH₂), 34.9 (−, CH₂). IR (ATR) ν̃: 3027 (vw), 2924 (w), 2849 (w), 1591 (vw), 1567 (vw), 1498 (vw), 1474 (w), 1433 (vw), 1412 (w), 1339 (vw), 1185 (vw), 1109 (vw), 1053 (vw), 1018 (w), 942 (vw), 900 (w), 848 (w), 807 (m), 732 (w), 715 (m), 654 (m), 639 (w), 620 (vw), 594 (w), 514 (m), 478 (m), 403 (vw). MS (EI, 70 eV) m/z [%]: 286 (13) [M + H]⁺, 285 (56) [M]⁺, 181 (77) [M – C₈H₈ + H]⁺, 180 (100) [M – C₈H₈]⁺, 131 (25) [M – C₈H₈ – CHN]⁺, 105 (31) [C₈H₈ + H]⁺, 104 (42) [C₈H₈]⁺. HRMS (C₂₁H₁₉N) calcd, 285.1517; found, 285.1517.

The analytical and spectroscopical data match those reported in the literature.⁶

4-(4′-Pyridyl)[2.2]paracyclophane (3c)

4-(4′-Pyridyl)[2.2]paracyclophane (3c) was obtained by column chromatography (silica, CH/EA 3:1, R_f = 0.22), yield 122 mg, 68%. ¹H NMR (400 MHz, chloroform-d): δ 8.73–8.69 (m, 2H), 7.44–7.38 (m, 2H), 6.68–6.49 (m, 7H), 3.39 (ddd, J = 12.5, 10.0, 2.9 Hz, 1H), 3.22–2.84 (m, 6H), 2.66 (ddd, J = 13.1, 10.0, 4.5 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃): δ [ppm] 149.7 (+, C_ArH), 148.9 (C_quat.), 140.2 (C_quat.), 139.6 (C_quat.), 139.5 (C_quat.), 139.1 (C_quat.), 137.3 (C_quat.), 136.3 (+, C_ArH), 133.6 (+, C_ArH), 133.3 (+, C_ArH), 132.8 (+, C_ArH), 132.0 (+, C_ArH), 132.0 (+, C_ArH), 129.8 (+, C_ArH), 124.6 (+, C_ArH), 35.55 (+, C_ArH), 35.28 (+, C_ArH), 35 (−, CH₂), 33.98 (−, CH₂), 35.21 (−, CH₂), 34.59 (−, CH₂). IR (ATR) ν̃: 2923 (m), 2849 (w), 1591 (w), 1499 (w), 1474 (w), 1433 (w), 1411 (m), 1339 (w), 1185 (w), 1106 (vw), 1053 (vw), 1018 (m), 942 (w), 900 (m), 848 (m), 808 (m), 732 (m), 715 (m), 653 (m), 639 (m), 593 (m), 514 (m), 479 (m), 404 (w), 1899 (vw). MS (EI, 70 eV) m/z [%]: 286 (15) [M + H]⁺, 285 (62) [M]⁺, 181 (65) [M – C₈H₈ + H]⁺, 180 (100) [M – C₈H₈]⁺, 131 (14) [C₁₀H₁₂]⁺, 104 (37) [C₈H₈]⁺. HRMS (C₂₁H₁₉N) calcd, 285.1517; found, 285.1519. The analytical and spectroscopical data match those reported in the literature.⁶

4-(5′-Pyrimidyl)[2.2]paracyclophane (3d)

4-(5′-Pyrimidyl)[2.2]paracyclophane (3d) was obtained by column chromatography (silica, CH/EA 3:1, R_f = 0.29), yield 1.18 g, 82%. ¹H NMR (300 MHz, chloroform-d): δ 9.23 (d, J = 1.6 Hz, 1H), 8.87 (d, J = 1.5 Hz, 2H), 6.77–6.36 (m, 8H), 3.37–3.24 (m, 1H), 3.20–2.87 (m, 6H), 2.64 (ddd, J = 15.1, 9.9, 4.0 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃): δ [ppm] 157.14 (+, 2 × C_ArH), 156.82 (+, C_ArH), 140.78 (C_quat.), 139.75 (C_quat.), 139.43 (C_quat.), 137.32 (C_quat.), 136.47 (+, C_ArH), 134.53 (C_quat.), 134.46 (C_quat.), 134.08 (+, C_ArH), 133.56 (+, C_ArH), 133.07 (+ , C_ArH), 132.03 (+, 2 × C_ArH), 129.42 (+, C_ArH), 35.57 (−, CH₂), 35.3 (−, CH₂), 35 (− CH₂), 33.82 (−, CH₂). MS (EI, 70 eV) m/z [%]: 287 (11) [M + H]⁺, 286 (49) [M]⁺, 182 (26) [M – C₈H₈ + H]⁺, 181 (28) [M – C₈H₈]⁺, 104 (100) [C₈H₈]⁺. HRMS (C₂₀H₁₈N₂) calcd, 286.1470; found, 286.1471. The analytical and spectroscopical data match those reported in the literature.⁶

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01774.

• General methods and copies of ¹H, ¹³C, ¹¹B, and ¹⁹F NMR spectra for all compounds synthesized (PDF)

The authors declare no competing financial interest.