Trifluoroacetic acid → 2-ethyl-5-methoxy-1H-indole

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 Ar (g). The solution was cooled to −40° C. and sec-butyllithium (1.4 M in cyclohexane, 6.65 mL, 0.60 g) was added slowly 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. The reaction mixture was then cooled to −50° C. over 10 minutes and a solution of N-methoxy-N-methylpropanamide (520 mg, 4.4 mmol) in THF (3 mL) was added in a dropwise fashion. 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 crude reaction mixture was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) was added to the reaction mixture 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 a yellow/brown oil (0.261 g, 35%): TLC Rf 0.43 in 20% EtOAc/hexanes. 1H NMR (600 MHz, CDCl3) δ 7.78 (s, 1H), 7.20-7.18 (d, 1H, J=8.64 Hz), 7.04 (d, 1H, J=2.4 Hz), 6.80-6.78 (dd, 1H J1=8.64 Hz, J2=2.4 Hz), 6.20 (s, 1H), 3.86 (s, 3H), 2.82-2.76 (q, 2H, J=7.62 Hz), 1.36-1.34 (t, 3H, J=7.62 Hz); 13C NMR (150 MHz, CDCl3) δ 154.3, 142.4, 131.2, 129.5, 111.09, 110.96, 102.3, 98.8, 56.1, 21.7, 13.5. Elemental analysis calculated for C11H13NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.28; H, 7.97; N, 7.39.

Provenance & Evidence