Pyridine → HCID 69423590, compound

Participants

Reaction Conditions

Reaction Steps

Methyl 2-methoxyacetate (0.450 mL, 4.53 mmol) was added to a solution of NaHDMS (4.74 mmol) in 40 mL of THF cooled to −78° C. The mixture was stirred at −78° C. for 30 min and then a solution of 2-Methyl-4-trisopropylsilanyloxy-benzaldehyde (1.26 g, 4.3 mmol) in 20 mL of THF was added dropwise. The solution was allowed to warm to 0° C. and stirred for 2.5 hours. The mixture was quenched with HCl 1N (50 mL) at 0° C., extracted with dichloromethane (3×40 mL), dried (MgSO4) and concentrated under vacuum. The residue was dissolved in dichloromethane (50 mL) and cooled to 0° C. To the solution was added trifluoroacetic anhidride (0.82 mL, 5.84 mmol), N,N-dimethylaminopyridine (0.025 g, 0.21 mmol), and pyridine (0.379 mL, 4.59 mmol). And stirred at room temperature for 4 hours. The volatiles were eliminated under vacuum and the residue dissolved in 100 mL of ethyl acetate. Palladium 10% on activated carbon (0.9 g) was added and the mixture hydrogenated at room temperature (5 Atm H2) for 14 hours. The solution was filtered through a pad of celite and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hexanes/Ethyl acetate 3:1) the fractions with Rf0.08 were collected and concentrated under vacuum (0.249 g containing 3-(4-Hydroxy-2-methyl-phenyl)-2-methoxy-acrylic acid c.a. 85% pure by NMR). The residue was added to a solution of 4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (0.359 g, 1.23 mmol), sodium iodide (0.05 g) and potassium tert-butoxide (126 mg, 1.12 mmol) in 5 mL of dimethylformamide. The solution was stirred at room temperature 24 hours, diluted with water and extracted with diethylether (3×30 mL). The combined organic layers were washed with water (5×30 ml), dried (MgSO4) and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate 6:1, Rf0.22). (0.18 mg, 10%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.98 (d, 1H, J=8.6), 7.57–7.25 (m, 7H), 7.16 (s, 1H); 6.98 (dd, J=6.7, 2.1), 6.80–6.76 (m, 2H), 4.20 (t, 4H, J=5.9), 3.85 (s, 3H), 3.69 (s, 3H), 2.36 (s, 3H), 2.29 (t, 2H, J=6.2).

Provenance & Evidence