Compound 5

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Compound data: NMR

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

A modification of Bergmann and Berkovic method was used for the preparation of 1-(2,5-difluoro-34-dimethylphenyl)ethan-1-one (Bergmann, E. D & Berkovic, S. 2,3-Difluorostyrene and 2-chloro-5-fluorostyrene. The preparation of aromatic fluorine compounds. J. Org. Chem. 26, 919–923 (1961)). A 50 mL Schlenk flask equipped with a magnetic stirring bar was charged with 1,4-difluoro-2,3-dimethylbenzene (3.98 g, 28 mmol, 1 equiv) and AlCl₃ (8.96 g, 67.2 mmol, 2.4 equiv). The reaction was heated at 60 °C under vigorous stirring and acetyl chloride (3.0 mL, 42 mmol, 1.5 equiv) was slowly added via syringe over 5 min. Then, the mixture was heated at 95 °C and the progression of the reaction was monitored by GC-MS. At complete conversion (about 2 h) the mixture was slowly poured onto a mixture of ice (200 g) and H₂O (200 mL). The aqueous phase was extracted with Et₂O, dried over MgSO₄ and evaporated to dryness. The residue was purified by column chromatography (hexane/Et₂O, 9:1) affording the desired acetophenone derivative as a pale yellow oil (4.13 g, 80%). ¹H-NMR (500 MHz, CDCl₃) δ 2.21-2.26 (m, 6 H), 2.59-2.64 (m, 3 H), 7.35 (dd, J = 9.5, 6.0 Hz, 1 H) ppm; ¹³C-NMR (125 MHz, CDCl₃) δ 11.2 (dd, J = 6.5, 2.0 Hz), 11.7 (dd, J = 4.5, 2.0 Hz), 31.3 (d, J = 8.3 Hz), 112.7 (dd, J = 26.9, 3.6 Hz), 123.6 (dd, J = 17.0, 6.9 Hz), 126.7 (dd, J = 20.3, 4.1 Hz), 131.4 (dd, J = 18.5, 5.3 Hz), 156.4 (dd, J = 246.8, 2.0 Hz), 156.8 (dd, J = 239.6, 2.0 Hz), 195.0 (dd, J = 3.5, 1.1 Hz) ppm; ¹⁹F-NMR (470 MHz, CDCl₃) δ −121.0 (d, J = 18.8 Hz), −117.6 (d, J = 18.8 Hz) ppm; IR ν_max (neat/cm⁻¹): 3006, 2932, 1684, 1625, 1473, 1416, 1361, 1322, 1286, 1237, 1192, 1088; HRMS calcd for C₁₀H₁₁OF₂ [M+H]⁺: 185.0772, found 185.0772.A modification of Sasaki method was used for the preparation of 2-(2,5-difluoro-3,4-dimethylphenyl)-4,5-dimethylpyridine 5 (Sasaki, I., Vendier, L., Sournia-Saquet, A. & Lacroix, P. G. Facile synthesis of cyclometalated ruthenium complexes with substituted phenylpyridines. Eur. J. Inorg. Chem. 2006, 3294–3302 (2006)). A 50 mL round-bottom flask equipped with a magnetic stirring bar was charged with 1-(2,5-difluoro-34-dimethylphenyl)ethan-1-one (2.58 g, 14 mmol, 1 equiv) and dry pyridine (3.5 mL, 4 M). A solution of Iodine (3.64 g, 14.35 mmol, 1.025 equiv) in dry pyridine (5.6 mL, 2.56 M) was added and the mixture was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature. The precipitate was filtered, washed once with pyridine, diethyl ether, dried under vacuum and recrystallized from boiling ethanol. The corresponding pyridinium derivative was obtained as light brown powder, dried under vacuum and directly employed in the next step. A 100 mL round-bottom flask equipped with a magnetic stirring bar was loaded with the pyridinium salt (4.8 g, 12.38 mmol, 1 equiv), ammonium acetate (3.82 g, 49.52 mmol, 4 equiv), tiglic aldehyde (2.48 mL, 24.76 mmol, 2 equiv), formamide (31 mL, 0.4 M) and heated at 80 °C for 16 h. After this time, the mixture was cooled to room temperature and extracted with Et₂O (3×150 mL). The ethereal phases were united, evaporated to dryness, and the residue was purified by column chromatography (hexane/Et₂O, 85:15) affording 5 as a colourless solid (2.01 g, 58% over 2 steps). ¹H-NMR (500 MHz, CDCl₃) δ 2.24 (d, J = 2.0 Hz, 3 H), 2.26 (d, J = 2.5 Hz, 3 H), 2.29 (s, 3 H), 2.33 (s, 3 H), 7.46 (dd, J = 10.5, 6.5 Hz, 1 H), 7.55 (d, J = 2.0 Hz, 1 H), 8.42 (s, 1 H) ppm; ¹³C-NMR (125 MHz, CDCl₃) δ 11.3 (dd, J = 4.6, 2.0 Hz), 11.4 (dd, J = 6.5, 2.3 Hz), 16.2, 19.4, 113.3 (dd, J = 26.9, 4.0 Hz), 125.1 (d, J = 9.3 Hz), 125.3-125.9 (m, 3 C), 131.2, 145.9, 149.9, 150.7, 154.4 (dd, J = 240.9, 2.1 Hz), 157.1 (dd, J = 237.5, 2.1 Hz) ppm; ¹⁹F-NMR (470 MHz, CDCl₃) δ −125.8 (d, J = 18.3 Hz), −122.3 (d, J = 19.3 Hz) ppm; mp 105-109 ºC; IR ν_max (neat/cm⁻¹): 2994, 2921, 2854, 1594, 1557, 1489, 1467, 1442, 1417, 1236, 1193, 1083; HRMS calcd for C₁₅H₁₆NF₂ [M+H]⁺: 248.1245, found 248.1240.