Indole → HCID 11196672, compound

Temperature

80 °C

General synthetic procedures. Compounds were purified by flash chromatography using SiO2 (EM Science) as the stationary phase. 1H and 13C NMR spectra were taken on Varian Inova 400 and 500 MHz spectrometers in CDCl3, and chemical shifts are reported as parts per million (ppm) downfield of the internal control trimethylsilane (TMS). High-resolution mass spectrometry (HRMS) data were obtained on a Micromass Q-TOF hybrid quadrupole liquid chromatography-mass spectrometer at the Stanford University Mass Spectrometry Facility. Purity of final compounds was assessed using a Waters 2795 HPLC system equipped with a dual wavelength UV detector, a reverse-phase (C18) 2.1×30 mm Agilent Zorbax HPLC column containing a 3.5-μm Stablebond stationary phase, and a mobile phase of water and acetonitrile, each containing 0.1% formic acid. E)-4-(2-methoxyphenyl)but-3-en-2-one. To a solution of o-anisaldehyde (3.00 g, 22.0 mmol) in acetone and water was added 2.0 mL of 50% NaOH, and the resulting mixture was allowed to stir for 3 days at room temperature. The reaction mixture was then extracted twice with dichloromethane, and the organic layers were pooled, dried with MgSO4, and concentrated in vacuo to yield 1 as a white solid (4.12 g, 100%). Compound 1 was carried on to the next reaction without further purification. 5-(2-methoxyphenyl)cyclohexane-1,3-dione. To a solution of sodium ethoxide (0.53 g Na dissolved in 1.37 mL of ethanol, 23.4 mmol) in 15 mL of anhydrous ethanol was added diethyl malonate (3.60 mL, 23.4 mmol) followed by 1 (4.12 g, 23.4 mmol). The reaction mixture was refluxed for 16 h, after which it was cooled and extracted with chloroform/water. The aqueous layer was collected and distilled, leaving a residue, which was re-dissolved in 15 mL of 2N NaOH and refluxed for 4 h. After the solution was cooled to room temperature, 15 mL of 5N H2SO4 was added and the mixture was refluxed for an additional 2 h. Cooling of the reaction mixture then yielded 2 as a pale yellow precipitate, which was isolated by filtration and washed with water (5.00 g, 100%) HPI-1. To a dry round-bottom flask was added 3-hydroxybenzaldehyde (1.12 g, 9.16 mmol), dione 2 (2.00 g, 9.16 mmol), methoxyethyl acetoacetate (1.47 g, 9.16 mmol), ammonium acetate (1.10 g, 9.16 mmol), and the ionic liquid N,N-methylbutylimidazolium tetrafluoroborate (0.21 mL). The solution was stirred for 10 min at 90° C. The reaction mixture was applied directly to SiO2 column, and HPI-1 was purified by flash chromatography (ethyl acetate/hexanes, 6:4) to yield HPI-1 as pale yellow crystalline solid (2.69 g, 64%). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.18-6.61 (m, 8H), 5.06 (s, 1H), 5.01 (s, 1H), 4.12 (m, 2H), 3.81 (s, 3H), 3.55 (m, 2H), 3.33 (s, 2H), 3.32 (s, 3H), 2.64-2.49 (m, 4H), 2.36 (s, 3H). 13C (500 MHz, CDCl3): δ 196.6, 167.7, 157.1, 156.1, 151.0, 148.4, 144.6, 130.3, 129.1, 127.9, 127.1, 120.6, 119.8, 115.0, 113.3, 112.3, 110.6, 105.3, 70.4, 62.8, 58.7, 55.1, 42.3, 36.2, 33.1, 32.5, 19.2. HRMS (m/z): [M]+ calc. for C27H29NO6Na, 486.1893; found, 486.1891. HPLC (water/acetonitrile, 0.1% formic acid, 0-95%, 25 min): retention time, 10.3 min; 96% pure. Methyl-4,7-dimethoxy-1H-indole-2-carboxylate. A dry round-bottom flask was charged with NaN3 (0.900 g, 13.7 mmol) and 5 mL DMF. Methyl bromoacetate (1.20 mL, 13.1 mmol) was added dropwise to this solution, and the mixture was stirred for 2.5 h at room temperature. A white precipitate formed, and an equivalent volume of H2O was added. The resulting slurry was extracted three times with diethyl ether, and the pooled organic layer was washed six times with water, dried over MgSO4, and concentrated in vacuo to give methyl azidoacetate (1.5 g, 50%). This crude material was combined with 2,5-dimethoxybenzaldehyde (0.640 g, 3.83 mmol) in 15 mL of methanol (pre-chilled in an acetone/water dry ice bath), and the mixture was added at −10° C. to a solution of NaOMe (0.650 g, 11.5 mmol) in methanol 6 (6 mL). The yellow slurry was then stirred for 45 min at −10° C. and then overnight at 4° C. Ice water was added to the reaction, and the resulting precipitate was collected, dissolved in dichloromethane, dried over MgSO4, and concentrated in vacuo to give the azidocinnamate intermediate (0.65 g, 66%). The yellow solid was refluxed in 12 mL of xylenes for 30 min, after which N2 evolution ceased, and then refluxed for an additional 15 min. A yellow precipitate formed upon cooling of the reaction mixture, which was collected by filtration and washed with petroleum ether to give indole 3 as a yellow solid (0.46 g, 79%). 4,7-Dimethoxy-1-(2-oxopropyl)-1H-indole-2-carboxylic acid (4). α-Bromoacetone was prepared by combining 225 mL dichloromethane/methanol (7:3) and acetone (1.00 mL, 13.6 mmol) with tetrabutylammonium tribromide (6.20 g, 12.9 mmol). After 1 h, the red solution became colorless, and the dichloromethane/methanol was removed by distillation. The remaining solution was diluted with 25 mL of diethyl ether and washed three times with water to remove tetrabutylammonium bromide. The solution was than dried over MgSO4 and concentrated to give a 50%<-bromoacetone solution in diethyl ether. The N-alkyl indole was then prepared under anhydrous conditions by combining 3 (0.100 g, 0.425 mmol), α-bromoacetone (0.180 g, 1.28 mmol), anhydrous K2CO3 (0.170 g, 1.28 mmol), 18-crown-6 (16 mg, 0.064 mmol), and 0.5 mL DMF in a round-bottom flask fitted with a reflux condenser. This solution was allowed to stir at 80° C. for 3 h. The indole was then purified by SiO2 flash chromatography (ethyl acetate/hexanes, 7:3) and saponified with 2 N NaOH (aq) in methanol at 40° C. to obtain the carboxylic acid 4 (0.10 g, 83%). HPI-2. Cyclooctylamine (3.80 mL, 26.8 mmol) and ethyl formate (2.10 mL, 25.5 mmol) were stirred together for 3 h. Water (50 mL) was added to the reaction, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, and 7 concentrated in vacuo to yield crude N-cyclooctylformamide (3.21 g, 80%). The formylated product was then dehydrated by phosphorus oxychloride (1.20 mL, 12.4 mmol) in 10 mL of petroleum ether/pyridine (3:5). Purification by SiO2 flash chromatography using hexanes afforded the isocyanide product (2.1 g, 75%). An oven-dried and N2-purged sealed vial was charged with carboxylic acid 4 (122 mg, 0.44 mmol), N,N-dimethylethane-1,2-diamine (48.2 μL, 0.44 mmol), cyclooctyl isocyanide (60.6 mg, 0.440 mmol) and 300 μL of MeOH. After 16 h, the reaction mixture was purified directly by SiO2 flash chromatography (ethyl acetate/hexanes, 1:9) to yield HPI-2 as a tan crystalline solid (90 mg, 42%). 1H NMR (400 MHz, CDCl3): δ 7.62 (s broad, 1H), 7.31 (d, J=4.0 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.35 (d, J=8 Hz, 1H), 5.59 (d, J=12 Hz, 1H), 4.21 (m, 1H), 4.08 (d, J=12 Hz, 1H), 3.92 (s, 6H), 3.72 (m, 2H), 3.57 (m, 2H), 2.76 (m, 2H), 2.48 (s, 6H), 1.75 (s, 3H), 1.64-1.24 (m, 14H). 13C (500 MHz, CDCl3): δ 178.46, 161.04, 148.50, 142.24, 127.59, 127.21, 120.35, 104.99, 104.96, 98.97, 65.19, 57.65, 55.89, 55.58, 52.82, 50.28, 44.86, 39.37, 32.13, 31.87, 26.88, 26.77, 25.26, 23.97, 23.20, 21.04. HRMS (m/z): [M]+ calc. for C27H40N4O4Na, 507.2947; found, 507.2948. HPLC (water/acetonitrile, 0.1% formic acid, 0-95%, 25 min): retention time, 9.35 min; 99% pure.

1. customfitted with a reflux condenser
2. customThe indole was then purified by SiO2 flash chromatography (ethyl acetate/hexanes, 7:3) and saponified with 2 N NaOH (aq) in methanol at 40° C.

ORD record

ord-edf36c59c2704eb690a04919e3d40172

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08119640B2