Yield:400825-68-5 100%

Reaction Conditions:

with potassium carbonate in N,N-dimethyl-formamide at 40; for 16 h;Inert atmosphere;

Steps:

4-(3-Fluoropropoxy)benzaldehyde (47)

To a suspension of 4-hydroxybenzaldehyde 45 (0.98 g, 8.0 mmol, 1 equiv.) and potassium carbonate (1.66 g, 12.0 mmol, 1.5 equiv.) in N,N-dimethylformamide (6 mL) at RT was added a solution of 3-fluoropropyl 4-methylbenzenesulfonate (3.71 g, 16 mmol, 2 equiv.) in N,N-dimethylformamide (2 mL) followed by stirring at 40 °C for 16 h. Upon cooling to ambient temperature the reaction mixture was partitioned between water (100 mL) and diethyl ether (100 mL), the aqueous layer was isolated and further extracted with diethyl ether (2 × 100 mL). The combined organic fractions were washed sequentially with aqueous sodium hydroxide (1 M, 100 mL) and then brine, dried (Na₂SO₄) and concentrated under reduced pressure to give a crude residue. Purification by gradient column chromatography on silica gel (55:45 50:50 v/v hexanes:Et₂O) to afford the title compound 47 as a yellow oil (1.46 g, quantitative); R_f 0.30 (50:50 v/v hexanes:Et₂O); IR (ZnSe) 2972, 1686 (C=O), 1598, 1508, 1252, 1158, 1047, 830, 729, 617, 480; ¹H NMR (500 MHz, CDCl₃) δ 9.86 (1H, s, CHO), 7.81 (2H, d, J = 8.9 Hz, ArH), 6.97 (2H, d, J = 8.9 Hz, ArH), 4.68-4.59 (2H, dt, ²J_H-F = 47 Hz, J_H-H = 6.0 Hz, CH₂F), 4.16 (2H, t, J = 6.3 Hz, OCH₂), 2.22-2.14 (2H, m, CH₂CH₂CH₂F); ¹³C NMR (125.8 MHz, CDCl₃) δ 190.9 (CHO), 163.9 (C), 132.1 (aryl), 130.1 (C), 115.1 (aryl), 80.6 (d, ¹J_C-F = 164 Hz, CH₂F), 64.0 (d, ³J_C-F = 5.0 Hz, OCH₂), 30.3 (d, ²J_C-F = 20.1 Hz, CH₂CH₂CH₂); m/z (GC-MS) 181.99 ([M]⁺, C₁₀H₁₁FO₂, 60%), 121.06 ([M-(CH₂)₃F]⁺, 100%), 93.01 ([C₇H₈]⁺, 30%), 65.08 ([C₅H₅]⁺, 26%).

References:

Moussa, Iman A.;Banister, Samuel D.;Manoli, Miral;Doddareddy, Munikumar Reddy;Cui, Jinquan;MacH, Robert H.;Kassiou, Michael [Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,# 17,p. 5493 - 5497] Location in patent:supporting information; experimental part