Epichlorohydrin → 4-(oxiran-2-ylmethoxy)-1H-indole

Participants

Reaction Conditions

Reaction Steps

The solvents used in reactions were dried prior to use. All other reagents were used as received without purification. All moisture-sensitive reactions were performed in flame-dried and/or oven-dried glassware under a positive pressure of nitrogen unless otherwise noted. Thin-layer chromatography was carried out with glass TLC plates precoated with silica gel 60 F254. Flash column chromatography was accomplished with silica gel BW820MH. Proton nuclear magnetic resonance spectra were recorded in deuterated solvents at 270 or 600 MHz. To a solution of 4-hydroxy indole (1) (0.50 g, 3.8 mmol) in dimethylsulfoxide (10 mL) at 45° C. was added potassium hydroxide (0.4 g, 7.6 mmol) followed by epichlorohydrin (1.4 g, 15.2 mmol). The reaction mixture was stirred at 45° C. for 4 h. The reaction was quenched with a saturated solution of NH4Cl, extracted with diethyl ether (3×50 mL). The combined organics were dried with MgSO4, and concentrated. The product was purified by elution from silica gel column with benzene/acetone mixtures to give the glycidyl 4-indolyl ether (2) (0.75 g, 3.8 mmol, 99%) as a clear oil. To a solution of glycidyl 4-indolyl ether (2) (215 mg, 1.14 mmol) in methanol (2 mL) was added isobutyl amine (160 mg, 2.28 mmol). The solution was heated to 100° C. and stirred for 32 h. The product was purified by elution from silica gel column with benzene/acetone mixtures to give the corresponding amine (3) (120 mg, 0.46 mmol, 40%) as a clear oil. To a solution of 4,4′-bipiperidine (420 mg, 5.0 mmol) and triethylamine (2 mL) in 150 mL of CHCl3 was added a solution of 1-adamantanecarbonyl chloride (4) (500 mg, 2.5 mmol) in 50 mL of CHCl3. The resulting mixture was refluxed for 0.5 h, diluted with brine, and dried over MgSO4. The solution was then concentrated in vacuum and purified by elution from silica gel column with CHCl3/methanol mixtures to give the corresponding amide (5) (750 mg, 2.3 mmol, 90%) as a clear oil. See FIG. 11 and FIG. 13.

Provenance & Evidence