Trifluoroacetic acid → HCID 10631992, compound

Participants

Reaction Conditions

Reaction Steps

N-(t-Boc)-4-Methoxy-2-methylaniline (1.00 g, 4.2 mmol) was dissolved in anhydrous THF (15 mL) under an atmosphere of Argon (g). The solution was cooled to −40° C. and sec-butyllithium (1.4 M in cyclohexane, 6.61 mL, 0.59 g) was added slowly as to maintain an internal temperature of <−25° C. After reaching 1 equivalent of sec-butyllithium (˜3.3 mL) the reaction mixture turned bright yellow signifying the deprotonation of the amide nitrogen. Upon completion of the addition of sec-butyllithium, the reaction mixture was then cooled to −50° C. over 10 minutes and a solution of N-Methoxy-N-methylisobutanamide (0.67 g, 4.63 mmol) in THF (3 mL) was added. The reaction mixture was allowed to warm to −10° C. over 30 minutes while stirring. Upon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL). The aqueous layer was extracted once more with Et2O (25 mL). The combined ether layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo providing a yellowish-brown oil. The above reaction was performed a second time immediately after the first reaction was complete. Therefore, the total amount of starting material (N-(t-Boc)-4-methoxy-2-methylaniline, 2.0 g, 8.4 mmol) was doubled. The crude reaction mixture (from 2.0 g) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) was added to the solution and stirred at room temperature for 48 hours. When the reaction reached completion, DCM (50 mL) was added and the reaction mixture was transferred to a separatory funnel and washed with saturated NaHCO3 (50 mL) followed by brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo giving a deep yellow oil which was purified by column chromatography (0-20% ethyl acetate/hexanes) to yield an amber oil (1.21 g, 71%): TLC Rf 0.53 in 20% EtOAc/hexanes. 1H NMR (600 MHz, CDCl3) δ 7.73 (s, 1H), 7.18-7.17 (d, 1H, J=8.7 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.78-6.76 (dd, 1H J1=8.7 Hz, J2=2.4 Hz), 6.16 (s, 1H), 3.84 (s, 3H), 2.60-2.58 (d, 2H, J=7.14 Hz), 1.97-1.95 (m, 1H), 0.97-0.96 (d, 6H, J=6.6 Hz). 13C NMR (150 MHz, CDCl3) δ 154.1, 139.8, 130.9, 129.3, 110.88, 110.72, 101.9, 100.4, 55.9, 37.8, 29.0, 22.5. Elemental analysis calculated for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 77.07; H, 8.50; N, 6.81.

Provenance & Evidence