Abstract: The spontaneous conversion of 3-indoxyl to indigo was a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids.
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With copper(l) iodide; potassium carbonate; lithium chloride; In N,N-dimethyl-formamide; at 120℃; for 64h;Inert atmosphere;
Description 205-bromo-1-(3-fluoro-pyridin-4-yl)-1H-indole (D20)5-bromo-1H-indole [CA.S. 10075-50-0] (2 g, 10.202 mmol) was dissolved in DMF (16 ml). A nitrogen stream was bubbled through the mixture and then were added 3-Fluoro- 4-iodopyridine [CA.S. 22282-75-3] (2.502 g, 11.222 mmol), lithium chloride (0.432 g, 10.202 mmol), copper(I) iodide (0.0195 g, 0.102 mmol) and K2CO3 (4.23 g, 30.605 mmol). The reaction mixture was heated at 120 0C for 2 days. After cooling to room temperature, the reaction mixture was refilled with lithium chloride (0.100 g) and (copper(I) iodide (0.010) stirred at 1200C for 16 h. After cooling to room temperature, the reaction mixture was washed with NH3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent: Heptane/EtOAc up to 15percent as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D20 (1.37 g, 46 percent).
With tetra-(n-butyl)ammonium iodide; zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine; In toluene; at 20℃;Inert atmosphere;
General procedure: Procedure A: To a solution of 1H-indole-5-sulfonamide/5-(methylsulfonyl)-1H-indole (2 equiv.), zinc triflate (1.2 equiv.) and tetrabutylammonium iodide (1 equiv.) in dry toluene (ca. 3 mL per mmol of indole) was added N,N-diisopropylethylamine (2.2 equiv.) under argon. The reaction mixture was heated at 50 °C for 30 min, followed by addition of the p-halo-benzyl bromide (1 equiv.). The mixture was stirred overnight at 50 °C under argon. The reaction was quenched with saturated aqueous NH4Cl, diluted with distilled water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate anhydrous, filtered and concentrated. The samples were further purified with silica flash chromatography then PTLC.
With lithium tert-butoxide; In N,N-dimethyl-formamide; at 100℃; under 760.051 Torr; for 24h;
General procedure: In a dried two-necked test tube was charged with LiOtBu (160 mg, 2.00 mmol) and indole 1a (23.4 mg, 0.4 mmol). The reaction vessel was evacuated under high vacuum and the atmosphere was replace with a balloon of CO2. Then DMF (2 mL) was added and the mixture was stirred for 24 h at 100C. Then the result mixture was cooled and carefully quenched with a solution of HCl (2 N) and extracted with EtOAc (5x). The combined organic layers were washed with water (2x), brine (1x) and dry over MgSO4. The dried organics were concentrated under reduce pressure and the residue was purified by preparative TLC (hexane:acetone = 1:1) to afford the desired product 2a (153.0 mg, 95%) as a white solid.
2-(5-bromo-1H-indol-3-ylthio)-6-(difluoromethoxy)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With manganese(III) triacetate dihydrate; acetic acid; at 80℃; for 2h;Inert atmosphere;
General procedure: Manganese triacetate (2 mmol) is added portion wise to a pre dissolved solution of Indole (1mmol) and benzimidazolethiol (1mmol) in acetic acid (10mL) at room temperature under Nitrogen atmosphere. The reaction mixture is stirred at 80 C for 2 hours. After completion of reaction, as monitored by T.L.C analysis, the reaction mixture was quenched by the addition of water 20 ml. The organic compounds are extracted with ethyl acetate (3x20ml). The combined layers are dried over anh.Na2SO4. The required product is purified by column chromatography, eluted with 8% methanol in DCM to get the product. The product is confirmed by 1H, 13C, NMR, IR and mass
With potassium carbonate; In ethanol; at 140℃;Schlenk technique;
General procedure: A mixture of indole-3-carboxylic acid 1 (0.50 mmol) and K2CO3 (13.8 mg, 0.10 mmol, 20 mol%) in EtOH (3 mL) was added into a Schlenk flask (25 mL) and stirred at 140 C. The reaction was monitored by thin layer chromatography until the disappearance of starting material 1. Then the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate 20:1 to 10:1).
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