The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives (2023)

General methods

Reactions were performed under an atmosphere of argon in flame-dried flasks. Solvents and liquid reagents were added by syringe. Et₂O, CH₂Cl₂ and THF were transferred from a MB SPS-800-dry solvent system into the reaction vessels. Dry DMF was purchased from Acros Organics and stored in the presence of molecular sieve under an atmosphere of argon. NEt₃ was distilled from CaH₂ and stored over KOH under argon. Methoxyallene was prepared from propargylic alcohol in two steps according to literature procedures [34,75]. All other solvents and reagents were purchased from commercial suppliers and were used without further purification. Thin-layer chromatography (TLC) analyses were performed on TLC plates purchased from Merck (silica gel 60, fluorescence indicator F254, 0.25 mm layer thickness). Products were purified by flash column chromatography on silica gel 60 (230–400 mesh, Macherey-Nagel). NMR spectra were recorded with Bruker (AC 500, AVIII 700) and JEOL (ECX 400, Eclipse 500) instruments. Chemical shifts are reported relative to solvent residual peaks or TMS. Integrals are in accordance with assignments, and coupling constants are given in Hz. All ¹³C NMR spectra are proton-decoupled. ¹³C NMR signals of Nf-groups [CF₃(CF₂)₃] are not given since unambiguous assignment is not possible due to strong splitting by coupling with the ¹⁹F nuclei. IR spectra were measured with a Jasco FT/IR-4100 spectrometer. HRMS analyses were performed with a Varian Ionspec QFT-7 (ESI–FT ICRMS) or an Agilent 6210 (ESI–TOF) instrument. Melting points were measured with a Reichert apparatus (Thermovar) and are uncorrected.

Three-component-reaction of methoxyallene, nitriles and dicarboxylic acids (typical procedure 1)

To a solution of methoxyallene (7, 2.07 g, 29.6 mmol) in dry Et₂O (25 mL) was added n-BuLi (10.8 mL, 27.0 mmol, 2.5 M in hexanes) at −50 °C. After 30 min stirring at −50 °C, the reaction mixture was cooled to −78 °C and pivalonitrile (9, 0.752 g, 9.06 mmol) in dry Et₂O (10 mL) was added to the mixture. After stirring for 4 h a suspension of diphenic acid (12, 6.54 g, 27.0 mmol) in dry Et₂O (50 mL) was added. The temperature was allowed to rise to rt and the mixture was stirred overnight. The reaction was quenched with sat. aq NaHCO₃ solution (25 mL) and the layers were separated. The aqueous layer was extracted with Et₂O (3 × 50 mL) and the combined organic layers were washed with brine (25 mL), dried with Na₂SO₄ and filtered. The solvent was removed under reduced pressure and the obtained crude product was purified by column chromatography (silica gel, hexanes/EtOAc = 1:2) to provide bis(β-ketoenamide) 14 (1.39 g, 28%) as a pale yellow solid.

Cyclization of β-ketoenamides to 4-hydroxypyridines (typical procedure 2)

Bis(β-ketoenamide) 14 (0.310 g, 0.57 mmol) was placed in an ACE-sealed tube and dissolved in DCE (10 mL). NEt₃ (0.40 mL, 2.89 mmol) and TMSOTf (0.50 mL, 2.76 mmol) were added and the resulting mixture was stirred at 90 °C for 3 d. After cooling to rt the reaction was quenched with sat. aq NH₄Cl solution (10 mL) and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 25 mL) and the combined organic layers were dried with Na₂SO₄ and filtered. The solvent was removed under reduced pressure and the obtained crude product was purified by column chromatography (silica gel, EtOAc) to provide bis(4-hydroxypyridine) 18a (0.174 g, 60%) as a brown liquid and 18b (54 mg, 18%) as pale yellow oil. The products were directly converted into the corresponding nonaflates 19 and 20.

Nonaflation of 4-hydroxypyridines (typical procedure 3)

Bis(4-hydroxypyridine) 18a (0.805 g, 1.57 mmol) was dissolved in THF (25 mL) and NaH (0.313 g, 7.86 mmol, 60% in mineral oil) was added under argon atmosphere. Nonafluorobutanesulfonyl fluoride (2.35 g, 7.79 mmol) was added drop-wise and the mixture was stirred at rt for 12 h. After dilution with Et₂O (25 mL), the reaction was slowly quenched with ice and water (25 mL). The layers were separated and the aqueous layer was extracted with Et₂O (3 × 25 mL). The combined organic layers were dried with Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/EtOAc = 9:1 to 4:1) to provide pyridyl nonaflate 19 (1.20 g, 71%) as a pale yellow oil.

6,6'-(Biphenyl-2,2'-diyl)bis(2-tert-butyl-3-methoxypyridine-6,4-diyl) bisnonaflate (19): IR (ATR) ν: 3065–2870 (=C-H, C-H), 1555–1410 (C=C) cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 1.19 (s, 18H, t-Bu), 3.89 (s, 6H, OMe), 6.92 (s, 2H, Py), 7.10 (dd, J = 7.5, 1.2 Hz, 2H, Ar), 7.30 (td, J = 7.5, 1.4 Hz, 2H, Ar), 7.36 (dd, J = 7.5, 1.4 Hz, 2H, Ar), 7.59 (dd, J = 7.5, 1.2 Hz, 2H, Ar) ppm; ¹³C NMR (CDCl₃, 126 MHz) δ 29.1, 38.7 (q, s, t-Bu), 61.7 (q, OMe), 115.2 (d, Py), 127.4, 128.6, 130.1, 131.6 (4 d, Ar), 138.2, 140.6 (2 s, Ar), 145.3, 149.3, 153.2, 163.7 (4 s, Py) ppm; ¹⁹F NMR (CDCl₃, 470 MHz) δ −80.6 (t, J = 9.6 Hz, 6F, CF₃), −109.5 (t, J = 13.7 Hz, 4F, CF₂), −120.7, −125.8 (2 m_c, 4F each, CF₂) ppm; ESI–TOF (m/z): [M + Na]⁺ calcd for C₄₀H₃₄F₁₈N₂NaO₈S₂, 1099.1361; found, 1099.1394.

Cyclization of β-ketoenamides to pyrimidines (typical procedure 4)

Bis(β-ketoenamide) 14 (0.162 g, 0.296 mmol) and NH₄OAc (0.365 g, 4.73 mmol) were placed in an ACE-sealed tube. The mixture was dissolved in MeOH (5 mL) and stirred for 2 d at 90 °C. After addition of H₂O (10 mL) and Et₂O (20 mL) the layers were separated and the aqueous layer was extracted with Et₂O (2 × 25 mL). The combined organic layers were dried with Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/EtOAc = 5:1) to provide pyrimidines 24a (88 mg, 56%) and 24b (35 mg, 23%), both as colorless oils.

2,2'-Bis(4-tert-butyl-5-methoxy-6-methylpyrimidin-2-yl)biphenyl (24a): IR (ATR) ν: 3070–2855 (=C-H, C-H), 1550–1440 (C=C) cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 0.99 (s, 18H, t-Bu), 2.28 (s, 6H, Me), 3.70 (s, 6H, OMe), 7.30 (dt, J = 7.7, 1.9 Hz, 2H, Ar), 7.34–7.39 (m, 4H, Ar), 7.70 (dd, J = 7.7, 1.0 Hz, 2H, Ar) ppm; ¹³C NMR (CDCl₃, 126 MHz) δ 19.7 (q, Me), 28.7, 37.6 (q, s, t-Bu), 60.9 (q, OMe), 126.4, 128.7, 130.2, 131.4 (4 d, Ar), 138.4, 142.6 (2 s, Ar), 149.8, 159.3, 159.4, 166.9 (4 s, Py) ppm; ESI–TOF (m/z): [M + H]⁺ calcd for C₃₂H₃₉N₄O₂, 511.3068; found, 511.3085.

2'-(4-tert-Butyl-5-methoxy-6-methylpyrimidin-2-yl)-N-(4-methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl)biphenyl-2-carboxamide (24b): IR (ATR) ν: 3325 (N-H), 3065–2865 (=C-H, C-H), 1700, 1665 (C=O), 1550–1445 (C=C) cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 0.71 (s, 9H, t-Bu), 1.26 (s, 9H, t-Bu), 2.31, 2.33 (2 s, 3H each, Me), 3.45, 3.70 (2 s, 3H each, OMe), 6.64 (dd, J = 7.5, 1.0 Hz, 1H, Ar), 7.07, 7.25 (2 dt, J = 7.5, 1.2 Hz, 1H each, Ar), 7.32 (dd, J = 7.5, 1.2 Hz, 1H, Ar), 7.39 (dt, J = 7.5, 1.8 Hz, 1H, Ar), 7.43 (dt, J = 7.5, 1.0 Hz, 1H, Ar), 7.50 (dd, J = 7.8, 1.2 Hz, 1H, Ar), 7.91 (dd, J = 7.8, 1.8 Hz, 1H, Ar), 8.40 (br s, 1H, NH) ppm; ¹³C NMR (CDCl₃, 126 MHz) δ 19.2 (q, Me), 27.2 (q, Me), 28.1, 29.2, 35.9, 37.9 (2 q, 2 s, t-Bu), 58.9, 61.0 (2 q, OMe), 126.8, 127.9, 128.0, 128.5, 129.0, 129.4, 130.3, 130.7, 131.0 (8 d, s, Ar, =C), 137.5, 138.4, 138.9, 140.5, 150.1 (5 s, Ar, =C), 150.4, 159.6, 160.0, 168.4 (4 s, Py), 169.3 (s, CONH), 199.8 (s, C=O) ppm; ESI–TOF (m/z): [M + Na]⁺ calcd for C₃₂H₃₄N₃NaO₄, 552.2833; found, 552.2844.