Synthesis of Chroman-4-ones with gem-Difluoroalkyl Side Chains in Position 2

Abstract

New chroman-4-ones with gem-difluoroalkyl side chains in position 2 are easily accessible in five steps from salicylaldehyde-type derivatives. The crucial intermediates are propargylic alcohols bearing a CF₂R substituent on the triple bond and the key step is their based-mediated isomerization into the corresponding enones. After MOM deprotection, an intramolecular oxa-Michael addition affords the target molecules in good overall yields. Such chromanones appear as useful intermediates for the preparation of bioactive oxygen-containing heterocycles with gem-difluoroalkyl side chains.

Key words

chromanones - fluorine - gem-difluoroalkyls - oxa-Michael additions - heterocycles

• References and Notes

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• 19 Representative Example: Synthesis of Chromanone 6a: 2-Methoxymethoxybenzaldehyde (2a): To a solution of 2-hydroxybenzaldehyde (1 g, 8.19 mmol) in THF (20 mL), sodium hydride (0.98 g, 5 equiv, 60% by weight, dispersed in oil) was added at 0 °C under nitrogen atmosphere. After 5 min, chloromethyl methyl ether (MOMCl, 0.93 mL, 12.29 mmol, 1.5 equiv) was added and the reaction mixture was stirred for 4 h at r.t. Then, a 3 M NaOH solution (20 mL) was added to the reaction mixture and the two phases were separated. The aqueous phase was extracted with EtOAc (100 mL), and the organic phase was washed with a NaOH solution (100 mL), dried over Na₂SO₄, and then concentrated in vacuo. After purification by chromatography on silica gel, the aldehyde 2a was obtained as a colorless oil (1.07 g, 79% yield); R_f 0.45 (pentane–EtOAc, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 10.51 (d, J = 0.7 Hz, 1 H), 7.84 (dd, J = 7.7, 1.8 Hz, 1 H), 7.53 (ddd, J = 8.5, 7.3, 1.9 Hz, 1 H), 7.22 (dd, J = 8.4, 0.7 Hz, 1 H), 7.10 (tt, J = 7.4, 0.9 Hz, 1 H), 5.31 (s, 2 H), 3.53 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 189.7, 159.7, 135.8, 128.4, 125.6, 121.9, 115.1, 94.7, 56.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₀ONa: 189.05276; found: 189.0525 (1 ppm). 4,4-Difluoro-1-(2-methoxymethoxyphenyl)tridec-2-yn-1-ol (3a): To a solution of 3,3-difluorododec-1-yne (ref. 12; 0.48 g, 2.37 mmol, 1 equiv) in anhyd THF (4.8 mL) cooled to –78 °C, was added under nitrogen, a solution of n-butyllithium in hexane (2.4 mL, 1.2 equiv). The mixture was stirred for 1 h at a temperature of ≤ –40 °C. Then, aldehyde 2a (0.47 g, 2.85 mmol, 1.2 equiv) in anhyd THF (5.6 mL) was added at –78 °C and allowed to warm to r.t. for 2 h. The mixture was then treated with a sat. ammonium chloride solution, extracted by Et₂O. The combined organic phases were washed with H₂O, dried over MgSO₄ and concentrated in vacuo. After purification by chromatography on silica gel, the propargylic alcohol 3a was obtained as a yellow oil (0.80 g, 92% yield); R_f 0.41 (pentane–Et₂O, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.46 (dd, J = 7.6, 1.7 Hz, 1 H), 7.32 (ddd, J = 8.3, 7.5, 1.8 Hz, 1 H), 7.15 (dd, J = 8.3, 1.0 Hz, 1 H), 7.05 (td, J = 7.5 Hz, 1.1 Hz, 1 H), 5.70 (br s, 1 H), 5.27 (s, 2 H), 3.52 (s, 3 H), 2.05 (brs, 1 H), 1.95–2.10 (m, 2 H), 1.51–1.56 (m, 2 H), 1.26–1.33 (m, 12 H), 0.88 (t, J = 6.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 154.5, 130.2, 128.2, 127.9, 122.2, 114.9 (t, ¹ J _CF = 232.5 Hz), 114.6, 94.6, 86.4 (t, ³ J _CF = 6.8 Hz), 78.5 (t, ² J _CF = 41.0 Hz), 61.0, 56.4, 39.2 (t, ² J _CF = 25.9 Hz), 31.8, 29.4, 29.3, 29.2, 28.9, 22.7 (t, ³ J _CF = 3.6 Hz), 22.6, 14.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –82.89 (td, ² J _FH = 14.9 Hz, ³ J _FH = 4.1 Hz, 2 F). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₃₀O₃F₂Na: 391.20607; found: 391.2056 (1 ppm). 4,4-Difluoro-1-(2-methoxymethoxyphenyl)tridec-2-en-1-one (4a): To the gem-difluoropropargylic alcohol 3a (0.65 mg, 1.77 mmol, 1 equiv) in THF (3.5 mL) was added DBU (0.4 mL, 1.5 equiv), and the reaction mixture was stirred at 35 °C. After 8 h, ¹⁹F NMR showed 100% conversion, and the mixture was neutralized with a saturated solution of NH₄Cl. After extraction with Et₂O, the organic phases were washed with H₂O, dried over MgSO₄ and concentrated in vacuo. After purification by flash chromatography on silica gel, the enone 4a was isolated as a yellow oil (0.42 g, 65% yield); R_f 0.52 (pentane–Et₂O, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.63 (dd, J = 7.8, 1.8 Hz, 1 H), 7.47 (ddd, J = 8.1, 7.2, 1.8 Hz, 1 H), 7.19 (dd, J = 7.8, 0.8 Hz, 1 H), 7.18 (dt, J = 15.7 Hz, ⁴ J _HF = 2.1 Hz, 1 H), 7.08 (dt, J = 7.5, 0.8 Hz, 1 H), 6.67 (dt, J = 15.7 Hz, ³ J _HF = 11.6 Hz, 1 H), 5.25 (s, 2 H), 3.50 (s, 3 H), 1.88–2.04 (m, 2 H), 1.42–1.50 (m, 2 H), 1.26–1.36 (m, 12 H), 0.88 (t, J = 6.7 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 191.5, 156.2, 136.5 (t, ² J _CF = 27.5 Hz), 133.8, 132.1 (t, ³ J _CF = 7.8 Hz), 130.5, 128.7, 122.0, 121.4 (t, ¹ J _CF = 239.4 Hz), 114.9, 94.6, 56.5, 37.3 (t, ² J _CF = 25.8 Hz), 31.8, 29.4, 29.3, 29.26, 28.23, 22.6, 22.2 (t, ³ J _CF = 4.1 Hz), 14.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –98.05 (tdd, ² J _FH = 16.0 Hz, ³ J _FH = 11.6, 2.1 Hz, 2 F). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₃₀O₃F₂Na: 391.20607; found: 391.2063 (1 ppm). 4,4-Difluoro-1-(2-hydroxyphenyl)tridec-2-en-1-one (5a): To the gem-difluoroenone 4a (0.38 g, 1.03 mmol) in THF (8 mL) was added PTSA (0.71 g, 4 equiv). After 16 h, ¹⁹F NMR showed 100% conversion and the two phases were separated. The aqueous phase was extracted with Et₂O, and the combined organic phases were washed with H₂O, dried over Na₂SO₄, and then concentrated in vacuo. After purification by flash chromatography on silica gel, the product 5a was isolated as a yellow oil (0.27 g, 80% yield); R_f 0.59 (pentane–Et₂O, 9:1). ¹H NMR (300 MHz, CDCl₃): δ = 12.34 (s, 1 H), 7.81 (dd, J = 8.0, 1.6 Hz, 1 H), 7.53 (ddd, J = 8.7, 7.4, 1.6 Hz, 1 H), 7.43 (dt, J = 15.4 Hz, ⁴ J _HF = 2.3 Hz, 1 H), 7.03 (dd, J = 8.4, 0.9 Hz, 1 H), 6.88–7.00 (m, 2 H), 1.92–2.08 (m, 2 H), 1.44–1.54 (m, 2 H), 1.26–1.30 (m, 12 H), 0.88 (t, J = 6.7 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 193.1, 163.6, 139.5 (t, ² J _CF = 27.3 Hz), 137.3, 130.1, 126.1 (t, ³ J _CF = 7.8 Hz), 121.2 (t, ¹ J _CF = 240.0 Hz), 119.4, 119.2, 118.7, 37.2 (t, ² J _CF = 25.8 Hz), 31.8, 29.4, 29.3, 29.2 (2 × C), 22.6, 22.1 (t, ³ J _CF = 4.1 Hz), 14.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –98.57 (tdd, ² J _FH = 16.1 Hz, ³ J _FH = 11.6 Hz, ⁴ J _FH = 2.0 Hz, 2 F). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₆O₂F₂Na: 347.17986; found: 347.1798 (0 ppm). 2-(1,1-Difluorodecyl)chroman-4-one (6a): To a solution of enone 5a (0.12 g, 0.37 mmol) in THF (7 mL) was added solid K₂CO₃ (0.20 g, 4 equiv), and the reaction mixture was stirred at 35 °C. After 18 h, ¹⁹F NMR shows 100% conversion, H₂O was added and the two phases were separated. The aqueous phase was extracted with Et₂O, and the combined organic phases were washed with H₂O, dried over Na₂SO₄, concentrated in vacuo. After purification by chromatography on silica gel the product was obtained as white crystals (0.09 g, 76% yield); R_f 0.35 (pentane–Et₂O, 95:5); Mp 62 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (dd, J = 7.8, 1.5 Hz, 1 H), 7.51 (ddd, J = 8.4, 7.2, 1.8 Hz, 1 H), 7.07 (ddd, J = 8.2, 7.2, 1.0 Hz, 1 H), 7.03 (dd, J = 8.4, 1.0 Hz, 1 H), 4.53–4.62 (m, 1 H), 2.99 (dd, J = 16.9, 12.8 Hz, 1 H), 2.85 (ddd, J = 16.9, 3.4 Hz, ⁴ J _HF = 0.7 Hz, 1 H), 2.02–2.16 (m, 2 H), 1.53–1.61 (m, 2 H), 1.26–1.39 (m, 12 H), 0.89 (t, J = 6.8 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 190.5, 160.1, 136.3, 127.0, 122.2, 121.8 (dd, ¹ J _CF = 247.4 Hz, ¹ J _CF = 241.4 Hz), 120.9, 117.8, 77.3 (dd, ² J_CF = 36.5 Hz, ² J_CF  = 29.3 Hz), 36.1 (t, ³ J_CF = 2.5 Hz), 33.0 (t, ² J _CF = 25.6 Hz), 31.8, 29.4, 29.3 (2 × C), 29.2, 22.7, 21.4 (dd, ³ J _CF = 5.4 Hz, ³ J _CF = 3.2 Hz), 14.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –110.88 (AB system, J _FF = 254.8 Hz, 2 F). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₆O₂F₂Na: 347.17986; found: 347.1802 (1 ppm).