2-Methyl-1-pentanol → (2R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)acetate

Participants

Reaction Steps

(R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (23.00 g, 82 mmol), 2-methylpentan-1-ol (16.70 g, 163 mmol), and triphenylphosphine (36.46 g, 139 mmol) were combined in tetrahydrofuran (600 mL). After stirring 10 min, diethylazodicarboxylate (21.9 mL, 138 mmol) was added via syringe at room temperature. The reaction was mildly exothermic resulting in the temperature rising to the mid thirties ° C. during the addition. Intermittent cooling with a tap water bath was used to prevent the reaction mixture temperature from rising higher than this, but it was not cooled down to room temperature during the addition. After the addition was complete, the mixture was stirred at room temperature for 18 h. The reaction mixture was transferred to a separatory funnel containing water (400 mL). The aqueous layer was extracted with ether (3×400 mL). The combined organic layers were washed with brine (250 mL), dried over MgSO4, filtered and concentrated. The crude product was taken up in ether (ca. 800 mL) and was stirred for 30 min. The mixture was filtered through a pad of diatomaceous earth (Celite®) to remove most of the triphenylphosphine oxide and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to afford (2R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)acetate (29.43 g, 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.20-7.29 (m, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.45 (d, J=6.5 Hz, 1H), 5.22 (d, J=7.3 Hz, 1H), 3.77 (dd, J=9.1, 5.8 Hz, 1H), 3.69 (s, 3H), 3.65-3.70 (m, 1H), 1.85-1.96 (m, 1H), 1.41 (s, 9H), 1.14-1.50 (m, 4H), 0.98 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 366.4 [(M+H)+, calcd for C20H32NO5 366.2].

Provenance & Evidence