Toluene → 3-Tert-butoxycarbonylamino-2-p-tolyl-propionic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 2-p-tolyl-succinic acid 4-tert-butyl ester 1-methyl ester (15.3 g, 54.8 mmol) in 110 ml, of DCM was treated with neat TFA (63 mL) at room temperature. The mixture was stirred for five hours to completion, after which the reaction mixture was concentrated and dried in vacuo overnight to afford a white solid. The solid was suspended in 190 mL of toluene, cooled to 0° C., and treated successively with diphenylphosphoryl azide (13.4 mL, 62.1 mmol) and triethyl amine (19.7 mL, 141 mmol). The reaction mixture (homogeneous) was allowed to warm to room temperature and stirred for four hours to completion. The solution was quenched with 1% citric acid solution and extracted with EtOAc. The combined organic was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a light brown oil. The crude azide was dissolved in 190 mL of tert-butanol, treated with neat SnCl4 (0.25 mL, 2.82 mmol), and carefully heated to 90° C. with evolution of nitrogen. The mixture was stirred at 90° C. for 2.5 hours and cooled to room temperature. The solution was quenched with saturated NaHCO3 solution and then concentrated. The oily mixture was extracted with EtOAc, and the combined organic was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by on silica gel (9:1 hexanes:EtOAc) to afford the 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid methyl ester as a pale yellow oil (12.3 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 7.14 (s, 4H), 4.86 (br s, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.58 (m, 1H), 3.49 (m, 1H), 2.33 (s, 3H), 1.42 (s, 9H). HPLC Rt=3.31 min.

Provenance & Evidence