tert-butyl 2-methylbutanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-methylbutanoic acid (1.029 Ml, 8.29 mmol) in DCM (10 Ml) was added potassium tert-butoxide (20 wt % in THF) (4.66 Ml, 8.29 mmol) dropwise at 0° C. The resulting suspension was allowed to warm to room temperature, and stirred for 1.5 hr. The reaction mixture was diluted with DCM (10 Ml), MP-®Trisamine Resin (3.86 g, 3.22 mMol/g; Argonaut Technologies, Inc.) was added, and the resulting suspension was stirred at room temperature for 1.5 hours. The resin was removed by vacuum filtration, and the resulting filtrate was washed with 1 N NaOH (1×20 Ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford tert-butyl 2-methylbutanoate. 1H NMR (500 MHz, CDCl3) δ 2.24 (sextet, 1H), 1.61 (m, 1H), 1.44-1.39 (overlapping s, m, 10H), 1.09 (d, 3H), 0.90 (t, 3H). was added the resulting suspension was stirred at room temperature for 1.5 hours The resin was removed by vacuum filtration the resulting filtrate was washed with 1 N NaOH (1×20 Ml) The organic layer was dried over magnesium sulfate filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of t-butyl alcohol (40.7 g, 549 mmol), Et3N (70 mL, 505 mmol), and DMAP (0.366 mL, 3 mmol) in anhydrous CH2Cl2 (100 mL) at 0° C. was added 2-methyl-butyryl chloride (38 g from step 1). The reaction was stirred at 0° C. for 2 h and then room temperature overnight. The cloudy reaction mixture was filtered through celite and concentrated. The residue was diluted with Et2O and washed with 0.1 N HCl. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was distillated at ˜100° C. bath temperature under weak in-house vacuum twice to give the desired 2-methyl-butyric acid tert-butyl ester 2-2 as a clear oil (42 g, ˜85% purity by 1HNMR analysis). 1HNMR (CDCl3, 500 Hz): 2.28-2.20 (m 1H), 1.68-1.56 (m, 1H), 1.44 (s, 9H), 1.46-1.37 (m, 1H), 1.44 (s, 9H), 1.09 (d, J=7.0 hz, 3H), 0.9 (t, J=7.3 Hz, 3H). room temperature overnight The cloudy reaction mixture was filtered through celite concentrated The residue was diluted with Et2O washed with 0.1 N HCl The organic layer was dried (MgSO4) filtered concentrated was distillated at ˜100° C.

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 5.8 ml (41.6 mmol) of diisopropylamine were dissolved in 50 ml of dry THF, and the mixture was cooled to −30° C. 16.6 ml (41.6 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 5.06 g (32.0 mmol) of tert-butyl 2-methylbutanoate in 20 ml of THF was added, the reaction temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 10.0 g (35.2 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 30 ml of THF was added, and the temperature was once more kept below −60° C. The reaction mixture was then slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution and ethyl acetate were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 7.62 g (65.9% of theory) of the title compound. the resulting mixture was warmed to 0° C. cooled to −70° C being kept below −60° C was once more kept below −60° C The reaction mixture was then slowly warmed to RT overnight After phase separation the aqueous phase was extracted twice with ethyl acetate The combined organic phases were dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15.0 g (124.4 mmol) of 2-methylbutyryl chloride were dissolved in 150 ml of abs. THF and cooled to 0° C., and 114 ml (114 mmol) of a 1 M solution of potassium tert-butylate in THF were added dropwise. After the addition had ended, the mixture was stirred at 0° C. for 1 h and then at RT for h, and about half of the solvent was then removed under reduced pressure. After addition of diethyl ether, sat. sodium bicarbonate solution was added dropwise with vigorous stirring. After phase separation, the aqueous phase was extracted with diethyl ether, and the combined organic phases were washed with sat. sodium carbonate solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by vacuum distillation (19 mm Hg, 40-45° C.). This gave a total of 6.35 g of the target product (32.3% of theory). After the addition at RT for h, and about half of the solvent was then removed under reduced pressure After addition of diethyl ether, sat. sodium bicarbonate solution was added dropwise with vigorous stirring After phase separation the aqueous phase was extracted with diethyl ether the combined organic phases were washed with sat. sodium carbonate solution dried over sodium sulphate concentrated under reduced pressure The crude product was purified by vacuum distillation (19 mm Hg, 40-45° C.)