6-Methoxy-1H-indole-3-carbaldehyde

A solution of 6-methoxyindole (33) in DMF (0.04 mL) was added to an ice-cold mixture of DMF (0.07 mL) and POClGeneral procedure: To a dried two-neck round-bottom flask containing DMF (0.7mL for 1.10mmol of starting material) chilled in an ice bath, POClGeneral procedure: A method for synthesizing compound III-1 wherein R1, R2 and R3 are simultaneously hydrogen in the formula III, the method comprising the steps of:(1) Add to a 50 mL round bottom flask1.0mmol indole(In the formula I, R1, R2, and R3 are both hydrogen) and1.0 mmol (0.140 g) of hexamethylenetetramine, then 2 mL of N, N-dimethylformamide (DMF), stirred in a magnetic stirrer to dissolve the solid, followed by the addition of 0.05 mmol (0.012 g) of crystalline trichloride Aluminum, connected to a reflux condenser, heated at 120 ° C, the reaction progress was monitored by TLC, and the reaction was cooled to room temperature after 1 h to prepare a suspension;(2) The suspension prepared in the step (1) is suction filtered with a funnel padded with diatomaceous earth.The filter cake was washed well with ethyl acetate, suction filtered, and the above operation was repeated until the filtrate had no product, and all the filtrates were combined.Dilute with 15 mL of saturated saline solution, disperse and separate the layers, and the aqueous layer was further extracted with ethyl acetate three times.Each time 10 mL, the ethyl acetate layer was combined and washed with 10 mL of 2 mol/L diluted hydrochloric acid.Wash with 10 mL of saturated sodium bicarbonate solution, and finally wash with 10 mL of saturated brine.The washed ethyl acetate layer was dried over anhydrous sodium sulfate, and after drying, the desiccant was filtered off.Then use a rotary evaporator to recover the solvent to concentrate the product, and finally, The residue is subjected to silica gel column chromatography using a mixture of n-hexane-ethyl acetate (V/V = 2:1) as an eluent to obtain a purified product.The mass of the compound III-indole-3-carbaldehyde is 0.137g, The product yield was 94percent.General procedure: a mixture of indole (1 mmol), HMTA (2.5 mmol), and 10percent CAN–SiO2 was refluxed in CH3CN (5.0 mL). After the reaction was complete, the mixture was evaporated to give a crude residue of CAN–SiO2 and product. The crude residue was washed with EtOAc (10 mL 5) and dried to leave a crude product that was purified by short flash column chromatography (EtOAc/hexane = 1:3).General procedure: A 50 mL round-bottomed flask equipped with a magnetic stirringbar was charged with the appropriate indole 1 (0.5 mmol, 1.0 equiv), 37percent aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25percent aqNH3 (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl3 (0.01 mmol, 0.0016 g, 2 molpercent), and DMF (2 mL). The flask was fitted with a reflux condenser, and the mixture was stirred at 130 °C under open air.When the reaction was complete (TLC), the mixture was cooledto r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL), and extracted with EtOAc (3 x 7 mL). The organic layers werecombined, washed with sat. aq NaHCO3 (10 mL) and sat. aq NaCl(10 mL), dried (Na2SO4), and concentrated under reduced pressure.The residue was purified by flash column chromatography(silica gel, hexane–EtOAc).General procedure: To a solution of an appropriate indole, azaindole or alternative heterocycles (1.0 eq) and di-ferf-butyl dicarbonate (1eq. to 2 eq., more in particular 1.2 eq) in acetonitrile was added DMAP (0.1 to 0.5 eq. more in particular 0.1 eq). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with a saturated ammonium chloride solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The BOC-protected compound was used in the next step without further purification.A solution of 6-methoxyindole (33) in DMF (0.04 mL) was added to an ice-cold mixture of DMF (0.07 mL) and POCl3 (0.07 mL) and the reaction mixture was stirred at room temperature for 2.5h to yield General procedure: To a dried two-neck round-bottom flask containing DMF (0.7mL for 1.10mmol of starting material) chilled in an ice bath, POCl3 (1.95 equiv) was added slowly. After stirring for 20min, a solution of an indole derivative (1.0 equiv) in DMF (3mL for 1.10mmol of starting material) was added dropwise. The reaction was allowed to warm to room temperature and allowed to stir for 1.5h. The reaction was quenched by adding ice followed by 1N NaOH (40mL) dropwise in an ice bath. The crude mixture was allowed to stand at room temperature and the precipitate formed was filtered to afford the 3-formyl-indole derivative product.General procedure: The intermediatesindole-2(3)-carbohydrazide (2) and indole-3-carboxaldehyde(4) were prepared starting from commercially available indole, as described previously. Indole-3-carboxylic acids 1were prepared from the reaction of indole with trifluoroaceticanhydride followed by hydrolysis with sodium hydroxide. Toobtain the corresponding ester, a solution of indole-3-carboxylicacid 1 (1 mmol) in absolute ethanol (20 mL) was refluxed witha catalytic amount of concentrated sulfuric acid for 20 h and theresidue was extracted with ethyl acetate (30 mL), washed with asaturated sodium bicarbonate solution (20 mL), dried, andevaporated. As shown in Scheme 1, a solution of theappropriate ester (1 mmol) and hydrazine hydrate (2 mmol)in ethanol (15 mL) was refluxed for 24 h and cooled, and thesolid that was obtained was filtered and recrystallized fromethanol to give pure indole-2(3)-carbohydrazide (2) in 85-90% yield.For preparation of indole-3-carboxaldehydes 4, withcontinuous stirring, phosphorous oxychloride (8.41 mL, 90mmol) was added to 0 C dimethylformamide (28 mL, 370mmol) for 30 min followed by addition of a solution of indole 3(85.47 mmol) in DMF (10 mL, 130 mmol) at roomtemperature until it became a yellow paste. At the end of thereaction, 30 g of crushed ice was added to the paste followed bydropwise addition of a sodium hydroxide solution (1 N solution, 100 mL) while the mixture was being stirred. Theresulting suspension was heated rapidly to 90 C, cooled atroom temperature, and refrigerated overnight. The product wasfiltered, washed with water (2 × 100 mL), and air-dried toafford the pure indole-3-carboxaldehydes 4 in 80-90% yields(Scheme 1).Finally, to the mixture of indole-2(3)-carboxylic acidhydrazide 2 (1 mmol) and indole-3-carboxaldehyde 4 (1mmol) in absolute ethanol (20 mL) was added a catalyticamount of glacial acetic acid, and the mixture was refluxed at 80C for 5 h and cooled and the solid that separated out wasfiltered and recrystallized from ethanol to afford bis(indolyl)-hydrazide-hydrazones in 75-90% yields (Scheme 1).General procedure: General procedure (4): To a dried two-neck round-bottom flask containing DMF (0.7 mL for 1.10 mmol of starting material) chilled in an ice bath, POCI3 (1.95 equiv) was added slowly. After stirring for 20 min, a solution of the indole derivative (1.0 equiv) in DMF (3 mL for 1.10 mmol of starting material) was added drop-wise. The reaction was allowed to warm to room temperature and allowed to stir for 1.5 h. The reaction was quenched by adding ice followed by 1 N NaOH (40 mL) drop-wise in an ice bath. The crude mixture was allowed to stand at room temperature and the precipitate formed was filtered to afford the 3-formyl-indole derivative product. Intermediate 7 6-methoxy-1/-/-indole-3-carbaldehyde Intermediate 7 (1.579 g, 9.011 mmol) was prepared as a black solid from 6-methoxyindole (2.244 g, 15.25 mmol) according to general procedure (4). Yield: 59%. 1H NMR (400 MHz, Acetone) delta: 10.95 (bs, 1 H), 9.97 (s, 1 H), 8.08 - 8.05 (m, 2H), 7.06 (d, J = 2.2, Hz, 1 H), 6.90 (dd, J = 8.7, 2.3 Hz, 1 H), 3.82 (s, 3H).General procedure: A round-bottomed flask containing (28mL, 370mmol) freshly distilled dimethylformamide (DMF) was cooled to 0C for about 30min and freshly distilled phosphorus oxychloride (8.41mL, 90mmol) was subsequently added with stirring to the DMF over a period of 30min. A solution of indole 19 (85.47mmol) in DMF (10mL, 130mmol) was added to the yellow solution over a period of 1h. The solution was stirred at room temperature till it become a yellow paste. At the end of the reaction, 30g of crushed ice was added to the paste with stirring to make a clear cherry-red aqueous solution. Sodium hydroxide solution (1N, 100mL) was added dropwise with stirring to this cherry-red solution. The resulting suspension was heated rapidly to 90C and allowed to cool at room temperature, after which it was refrigerated for overnight. The product was filtered, washed with water (2×100mL) and air-dried to afford pure indole-3-carboxaldehydes 20 in 80-90% yields. Indole-3-carboxaldehyde, pale yellow solid; mp 194-196C (Lit. [37]196-197C).General procedure: POCl3 (13.09 g, 85.36 mmol) was slowly added dropwise to DMF(10 mL) under ice bath. The mixture was stirred at ice bath for30 min. Then, DMF (6.24 g, 85.36 mmol) solution of indole (5 g, 42.68 mmol) was added dropwise to the reaction system. Keepingthe reaction at room temperature for 3 h, ice water and 10% NaOHaq. were added into the reaction system to pH of 7-8 and continue to stir to a lot of white solid precipitation. The solid was recrystallizedfrom ethyl acetate and petroleum ether to obtain compound3 in yields of 97.6%.General procedure: Under ice-cooling, anhydrous N, N-dimethylformamide (15 mL) was added to a 100 mL one-necked flask, and phosphorus oxychloride (5.6 mL, 60.10 mmol) was added slowly. After stirring for 20 minutes, 1H-indole (3.52 g, 30.05 mmol) was dissolved in N-N-dimethylformamide (10 mL). After 10 minutes, the reaction was carried out at room temperature for 1.5 hours. After the reaction, ice-water bath undera saturated aqueous solution of sodium added slowly to the reaction mixture until the reaction mixture pH = 8 ~ 9, a red solid precipitated after 15 minutes, after filtration, the resulting solid was washed with water (200mL × 3and solid dried to give the title compound (pink solid, 4.02 g, 92.05%).(5-3) Production of General procedure: (5.0 ml, 33.00 mmol) of anhydrous N, N-dimethylformamide was added to a round bottom flask under nitrogen.After cooling to 0 C, phosphorus oxychloride (6.0 ml, 33.00 mmol) was slowly added dropwise, and after returning to room temperature, Slowly add (1.00 g, 6.6 mmol) of a mixture of 5-chloroindole N, N-dimethylformamide, and react at room temperature for 3 h.Until the raw material disappears completely, pour the reaction solution into water, and adjust the pH with a saturated sodium carbonate solution (pH=8).Then, it was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate and evaporated.Obtained crude product, purified by column chromatography ( petroleum ether: ethyl acetate = 2:1).A yellow solid 5-chloroindole-3-carbaldehyde (0.95 g, 80.2%) was obtained.c) A mixture of DMF (7 mL, 90 mm) and POCl3 (2.25 mL, 24.5 mmol) which had been cooled to 5 C., was treated with known 6-methoxy-1H-indole. After stirring at room temperature for 1 hour, the mixture was heated at 45 C. for 1 hour, then allowed to cool to room temperature overnight. The reaction mixture was poured into ice (100 mL), and stirred for 30 minutes at which time a solution of KOH (9.6 g, 171 mm) in H2O (20 mL) was added dropwise. After stirring for 30 minutes, then heating for 1 hour at 60 C., the reaction was cooled to 30 C., and the pH adjusted to 7 with 1N HCl. The mixture was extracted with EtOAc(50 mL*3), the organic fractions were combined, dried over MgSO4, filtered and evaporated. The residue was purified by crystallization from methanol to afford

Molecular Weight:175.18
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:175.063328530
Monoisotopic Mass:175.063328530
Topological Polar Surface Area:42.1
Heavy Atom Count:13
Complexity:195
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes