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Shriver, James A. ; Kaller, Kaylie S. ; Kinsey, Ally L. ; Wang, Katelyn R. ; Sterrenberg, Summer R. ; Van Vors, Madison K. , et al.

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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Product Details of 1H-Indole-6-carboxylic acid

CAS No. :1670-82-2
Formula : C9H7NO2
M.W : 161.16
SMILES Code : O=C(C1=CC2=C(C=C1)C=CN2)O
MDL No. :MFCD00210441
InChI Key :GHTDODSYDCPOCW-UHFFFAOYSA-N
Pubchem ID :595230

Safety of 1H-Indole-6-carboxylic acid

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of 1H-Indole-6-carboxylic acid

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1670-82-2 ]

[ 1670-82-2 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 50820-65-0 ]
  • [ 1670-82-2 ]
YieldReaction ConditionsOperation in experiment
95% With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; (c) A solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60 C. for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253-254: NMR (80 MHz; CDCl3) 6.51(m, 1H, H3 -indole), 8.04(m, 1H, H7 -indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH).
95% With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; (c) A solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60C for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collect by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253-254; NMR (80 MHz; CDCl3): 6.51(m, 1H, H3-indole), 8.04(m, 1H, H7-indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH).
88% Step 1: Lithium hydroxide (0.72 g, 17.2 mmol, 3 equiv.) in water (10 mL) was added to <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (1 g, 5.7 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and the mixture stirred at 80 C. for 16 hours. The solution was concentrated under vacuum then diluted with dichloromethane (10 mL) and the organic layer extracted with water (3×10 mL). The aqueous phase was acidified to pH<1 with concentrated HCl forming a precipitate. The precipitate was filtered and washed with 1 M aqueous HCl (3×10 mL) to afford 1H-indole-6-carboxylic acid as a white solid, 0.807 g (88% yield). LC (at)215 nm; Rt 1.02: 100%, m/z (ES+): 162 (M+H+.); δH (400 MHz; MeOD) 8.15 (1H, d), 7.72 (1H, m), 7.67 (1H, m), 7.45 (1H, m), 6.53 (1H, m).
85% To a solution of <strong>[50820-65-0]methyl indole-6-carboxylate</strong> (3.0 g) in MeOH (34 mL), a 3M aqueous solution of LiOH (17 mL, 3.0 equiv.) was added. The reaction mixture was heated at reflux for 1 Hr, then cooled at 0C, diluted with water (50 mL) and acidified with HCl 12M (5 mL). The mixture was extracted with AcOEt (3*30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and concentrated to give the product as a yellow solid (2.3 g, 85%). M/Z (M+H)+ = 162.
57% Step 4. 1H-Indole-6-carboxylic acid A solution of <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (1.3 g, 7.43 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was placed into a 250-mL round-bottom flask. Then CH3OH (20 mL), H2O (10 mL), LiOH.H2O (1.9 g, 45.24 mmol, 6.09 equiv) were added. The resulting solution was stirred overnight at 60 C. The resulting mixture was concentrated in vacuo, and diluted with water. The resulting solution was extracted with 2*100 mL of ether and the aqueous layers were combined. The pH value of the solution was adjusted to pH 3 with hydrochloric acid, and the solids were collected by filtration. This resulted in 0.68 g (57%) of 1H-indole-6-carboxylic acid as a light yellow solid.

  • 3
  • [ 67-56-1 ]
  • [ 1670-82-2 ]
  • [ 50820-65-0 ]
YieldReaction ConditionsOperation in experiment
91.9% With sulfuric acid; at 70℃; for 15h; To a solution of lT7-indole-6-carboxylic acid (2 g, 12.41 mmol, 1 eq) in MeOH (100 mL) was added H2SO4 (1.84 g, 18.76 mmol, 1 mL, 98%, 1.51 eq). The mixture was stirred at 70 C for 15 h. TLC (PE/EtOAc = 3/1, Rf= 0.47) showed the starting material was consumed completely. The reaction mixture was quenched with sat.aq NaHCCh (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers dried over Na2S04, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 3/1, TLC: PE/EtOAc = 3/1, Rf= 0.43) to yield methyl 1 //-indole-6- carboxylate (2 g, 11.42 mmol, 91.9% yield, 100.0% purity) as a white solid. ^ MR (500 MHz, DMSO-i/e) S ppm 11.50 (s, 1H), 8.08 (s, 1H), 7.64-7.52 (m, 3H), 6.53 (t, J= 1.9 Hz, 1H), 3.87- 3.82 (m, 3H); ES-LCMS m/z 176.3 [M+H]+.
88% sulfuric acid; for 16h;Heating / reflux; Step 1; 1-2 Step 2 1-3 0 Step 3 NaH, Mel 5 t . fnn N CO, Me Stem 4 Step 4 F lla F 1-5 14 F F 0 Step 1 : Indole-6-carboxylic acid 1-1 (5. 0 g, 31.0 mmol) was dissolved in MeOH (100 mL), a catalytic amount of H2SO4 (1.0 mL) was added and the reaction mixture was stirred at reflux for 16 h. A small amount of solid K2CO3 was added, in order to neutralize the excess H2SO4, and stirring was continued at RT for 1 h. The reaction mixture was concentrated under vacuum to remove the MeOH, diluted with saturated aqueous NaHC03 (-50 mL) and extracted with EtOAc (-200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous MgS04 and concentrated to dryness. The resulting residue was purified by flash column chromatography, using 30% EtOAc in hexane as the eluent, to obtain the pure methyl ester 1-2 (4.78 g, 88% yield).
88% To a stirred solution of 1 H-indole-6-carboxylic acid (1.5 g, 9.31 mmol) in MeOH (200 mL) was added cone. H2SO4 (3 mL). The reaction was refluxed for 15 h and cooled to RT. The mixture was neutralized with sat. NaHCO3 and MeOH was removed under reduced pressure. The remaining mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (20% EtOAc/hexanes) provided 2A (1 Ag, 88%) as a white solid. EPO <DP n="39"/>
88% Stepl 1; lndole-6-carboxylic acid 1-1 (5.0 g, 31.0 mmol) was dissolved in MeOH (100 ml), acatalytic amount of H2SO4 (1.0 ml) was added and the reaction mixture was stirred atreflux for 16 h. A small amount of solid K2CO3 was added, in order to neutralize theexcess HfeSO^ and stirring was continued at RT for 1h. The reaction mixture wasconcentrated under vacuum to remove the MeOH, diluted with saturated aqueousNaHCO3 (~50 ml_) and extracted with EtOAc (-200 ml). The organic layer waswashed with brine (100 mL), dried over anhydrous MgSO4 and concentrated to dryness. The resulting residue was purified by flash column chromatography, using30% EtOAc in hexane as the eluent, to obtain the pure methyl ester 1-2 (4.78 g, 88%yield).
85% With sulfuric acid; for 16h;Reflux; 1 H-indole-6-carboxylic acid (500 mg)In methanol (10 mL) was added concentrated sulfuric acid (0.1 mL)The mixture was stirred under heating reflux for 16 hours.After the reaction solution was cooled to room temperature, potassium carbonate was added to neutralize it,And the mixture was stirred at room temperature for 1 hour. After distilling off the solvent of the reaction solution under reduced pressure,Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added,The mixture was extracted with ethyl acetate and washed with saturated brine.The organic layer was dried over sodium sulfate,The solvent was evaporated under reduced pressure to obtain a residue,Purification by silica gel column chromatography (hexane-ethyl acetate), Methyl1 H-indole-6-carboxylate462 mg (yield 85%) was obtained
53% With sulfuric acid;Heating / reflux; To a solution of 1H-Indole-6-carboxylic acid (1.500 g, 9.31 mmol) in methanol (50 mL) was added concentrated H2SO4 (550 KL, 10.24 mmol). The mixture was stirred overnight at reflux temperature. The mixture was then neutralised to pH 7 by addition of saturated aqueous NAHC03 and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow powder. The product was recrystallised from heptane/ethyl acetate to give the title compound as GREEN/YELLOW crystals (688 mg, yield = 53%) IH NMR (CDCl3) : 8 3.94 (s, 3H, CH30CO), 6.60 (m, 1H), 7. 37 (t, 1H, J = 4.7 Hz), 7.66 (d, IH, J = 8.2 Hz), 7.82 (dd, 1H, J1 = 8.2 Hz, J2 = 1.0 Hz), 8.18 (s, 1H), 8.73 (s, 1H, NH)
sulfuric acid; for 10h;Steam bath heating; A solution of 1H-indole-6-carboxylic acid (10 g) in methanol (300 mL) was treated with concentrated sulfuric acid (0.5 mL) then heated on a steam bath for 10 hours. The solvent was removed under reduced pressure and the residue partitioned between saturated sodium bicarbonate solution (150 mL) and dichloromethane (150 mL). The aqueous layer was further extracted twice with dichloromethane (150 mL). The combined organics were dried over sodium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluding with a mixture of ethyl acetate and pentane (7:3, v/v) to give the title compound (7.4 g) as a white solid, m.p. 79-81 C. MS: 176(MH+).
With sulfuric acid;Heating / reflux; Indole 6-carboxylic acid (10.00 g, 62 MMOL) was esterified by refluxing overnight in a mixture of MEOH (200 mL) and conc. H2SO4 (1 mL). After cooling, the reaction mixture was poured into sat. aqueous NAHC03 and extracted with EtOAc. The extract was washed with aqueous NAHC03 twice and water. Drying (MGS04) and removal of volatiles gave the desired methyl ester as a brown oil (10.4 g).
With sulfuric acid; at 80℃; General procedure: H2SO4 (98%) (0.5mL) was added to a stirred solution of raw material1 in CH3OH (10mL) at room temperature and the mixture was then stirred for 2-3 h at 80 C. TLC was used to monitor the reaction progress until it was complete. A large amount of ice water was then added to the mixture. A saturated solution of sodium carbonate was used to neutralise the mixture until white solid appeared. After filtering the mixed solution, compounds 2a-h (yield 91-99) were obtained.

  • 4
  • [ 908094-01-9 ]
  • [ 1670-82-2 ]
  • [ 50820-65-0 ]
YieldReaction ConditionsOperation in experiment
In diethyl ether; at -15℃; for 1h; Methyl 1H-indole-6-carboxylate; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
In diethyl ether; at -15℃; for 1h; Methyl 1H-indole-6-carboxylate.; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant.
In diethyl ether; at -15℃; for 1h; Methyl 1H-indole-6-carboxylate.; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
In diethyl ether; at -15℃; for 1h; Intermediate 19 Methyl 1H-indole-6-carboxylate. An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
In diethyl ether; at -15℃; for 1h; An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (-15 C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at -15 C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using DCM as eluant.

  • 5
  • [ 1670-82-2 ]
  • [ 174579-31-8 ]
  • [ 1034776-13-0 ]
  • 1H-indole-6-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 60℃; for 18h; A solution of indole-6-carboxylic acid (2.00 g, 12.40 mmol) in dimethylformamide (20.00 mL) under argon was treated with N-methyl morpholine (6.82 mL, 62.04 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU) (7.08 g, 18.62 mmol) and <strong>[174579-31-8](4-amino-phenyl)-acetic acid tert-butyl ester</strong> (2.57 g, 12.40 mmol). The mixture was warmed at 60 C. and stirred for 18 hours. After cooling to room temperature, water (15.00 mL) was added. The resulting slurry was extracted with ethyl acetate and the combined organic phases washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), to yield pure {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (0.51 g) and a mixture of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester and 1H-indole-6-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (3.41 g). This was dissolved in tetrahydrofuran (34.00 mL) and treated with 1N NaOH. The mixture was stirred at room temperature for 4 hours, then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated, and the residue triturated in ether to afford {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester (1.36 g), which was combined with the aliquot obtained by flash chromatography. Total yield of {4-[(1H-indole-6-carbonyl)-amino]-phenyl}-acetic acid tert-butyl ester, 1.87 g (43%), MS (mass spectrometry) (ISP): m/e=351.3 (M+H). As used herein (M+H)=the molecular weight of the compound plus a proton.
  • 6
  • [ 1670-82-2 ]
  • [ 74-88-4 ]
  • [ 50820-65-0 ]
YieldReaction ConditionsOperation in experiment
87% Under a nitrogen atmosphere, to a solution of 1H-indole-6-carboxylic acid (121 g, 752 mmol) in N,N-dimethylformamide (360 ml) was added potassium carbonate (124 g, 900 mmol), and the mixture was stirred at room temperature for 1 hr. Then, iodomethane (56 ml, 900 mmol) was added dropwise at room temperature over 15 min, and the mixture was stirred for 2 hr. Then, to the reaction solution were added water (1.2 L) and hexane (100 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed successively with water and hexane, and dried under reduced pressure to give the title compound (115 g, yield 87%).1H-NMR (400 MHz, DMSO-d6) δ: 3.85 (3H, s), 6.53 (1H, d, J=1.61 Hz), 7.60-7.63 (3H, m), 8.07 (1H, s), 11.48 (1H, s).
83% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; A magnetically stirred solution of 1 H-indole-6-carboxylic acid (5.00 g, 31 .02 mmol) in DMF (40 mL) was treated with potassium carbonate (4.29 g, 31 .02 mmol) and dropwise with methyl iodide (1 .93 mL, 31 .02 mmol). After stirring at room temperature for 3 h, the resulting mixture was diluted with diethyl ether (150 mL) then washed with water (2 x 100 mL) before being dried over magnesium sulphate, filtered and concentrated under reduced pressure. The ensuing residue was subjected to flash chromatography [silica, 20:80 v/v diethyl ether/hexane] and concentration of the appropriate fractions (Rf = 0.42) afforded methyl 1 H-indole-6-carboxylate (4.29 g, 83%) as a light yellow crystalline solid. H NMR (400 MHz, chloroform-d) δ 8.71 (brs, 1 H), 8.19 (s, 1 H), 7.84 (dd, J = 8.4 and 1 .3 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.37 (t, J = 2.8 Hz, 1 H), 6.60 (s, 1 H), 3.95 (s, 3H); 13C NMR (100 MHz, chloroform-d) δ 168.5, 135.3, 131 .7, 127.8, 123.6, 120.9, 120.4, 1 13.7, 103.0, 52.1 ; (+)-LRESIMS m/z (rel. int.) 198 (100) [M + Naf; vmax 3337, 1680, 1617, 1569, 1508, 1438, 1335, 1290, 1262, 1220, 1205, 1 128, 1 1 15, 1084, 982, 91 1 , 828, 775, 736, 659 cm"1.
78.3% 2g of indole-6-carboxylic acid was dissolved 20mLN, N- dimethylformamide was added 2.1g of potassium carbonate, N2The reaction atmosphere 1h, then, added to the system 1mL methyl iodide, the reaction was continued 2h, the reaction was completed, aqueous sodium thiosulfate was added was quenched reaction was added 100mL of water, a lot of white solid was precipitated, suction filtered, washed with water and dried to give an off-white The solid was purified by column chromatography to obtain a white solid 1.73g, yield 78.3%.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19h;Inert atmosphere; Step 1. Synthesis of 1H-Indole-6-carboxylic acid methyl ester Iodomethane (0.75 mL, 12.0 mmol) was added to a suspension of indole-6-carboxylic acid (1.68 g, 10.5 mmol) and potassium carbonate (2.16 g, 15.7 mmol) in DMF (30 mL) under argon. The reaction was stirred at room temperature for 19 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2*). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 176 (MH)+.

  • 7
  • [ 93247-78-0 ]
  • [ 1670-82-2 ]
 

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