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

Temperature

-40 °C

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.

1. temperatureto maintain an internal temperature of <−25° C
2. temperatureThe reaction mixture was then cooled to −50° C. over 10 minutes
3. temperatureto warm to −10° C. over 30 minutes
4. customUpon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL)
5. extractionThe aqueous layer was extracted once more with Et2O (25 mL)
6. washThe combined ether layers were washed with brine (50 mL)
7. dry with materialdried over anhydrous Na2SO4
8. concentrationconcentrated in vacuo
9. customproviding a yellowish-brown oil
10. customThe crude reaction mixture
11. stirringstirred at room temperature for 48 hours
12. additionwas added
13. customthe reaction mixture was transferred to a separatory funnel
14. washwashed with saturated NaHCO3 (50 mL)
15. dry with materialThe organic layer was dried over Na2SO4
16. concentrationconcentrated in vacuo
17. customgiving a deep yellow oil which
18. customwas purified by column chromatography (0-20% ethyl acetate/hexanes)

ORD record

ord-c34dfe12b5d34c179b80160fb862e6d7

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09023871B2