4-Fluorobenzaldehyde → Methyl 3-cyclobutyl-3-{[(4-fluorophenyl)methyl]amino}propanoate

Participants

Reaction Conditions

Reaction Steps

(Trimethylsilyl)diazomethane (3.65 mL of a 1.0 M solution in diethyl ether, 7.3 mmol) was added over 2 min to a solution of racemic 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.89 g, 3.66 mmol) in a 1:1 mixture of methanol/benzene (50 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 40 min, then was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (10 mL) at 25° C. and a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL) was subsequently added. After stirring at 25° C. for 3.5 h, the reaction mixture was concentrated in vacuo to afford a sticky oil. This material was dissolved in toluene (80 mL) and the solution was concentrated in vacuo (the process was then repeated). The resulting residue was dissolved in methanol (25 mL) at 25° C. and 4-fluorobenzaldehyde (0.393 mL, 3.66 mmol), sodium acetate (0.600 g, 7.31 mmol), powdered/activated 4 Å molecular sieves (0.85 g) and sodium cyanoborohydride (0.46 g, 7.32 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.424 g, 1.60 mmol, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.68-1.80 (2H, m), 1.82-1.89 (1H, m), 1.92-1.99 (1H, m), 2.04-2.11 (1H, m), 2.32-2.45 (2H, m), 2.94-2.99 (1H, m), 3.67 (3H, s), 3.76 (2H, d, J=6.8 Hz), 6.96-7.01 (2H, m), 7.25-7.30 (2H, m).

Provenance & Evidence