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CAS No. : | 4769-97-5 | MDL No. : | MFCD00010056 |
Formula : | C8H6N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LAVZKLJDKGRZJG-UHFFFAOYSA-N |
M.W : | 162.15 | Pubchem ID : | 145766 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.12 |
TPSA : | 61.61 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.95 cm/s |
Log Po/w (iLOGP) : | 1.14 |
Log Po/w (XLOGP3) : | 1.88 |
Log Po/w (WLOGP) : | 2.08 |
Log Po/w (MLOGP) : | 0.38 |
Log Po/w (SILICOS-IT) : | 0.32 |
Consensus Log Po/w : | 1.16 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.52 |
Solubility : | 0.491 mg/ml ; 0.00303 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.8 |
Solubility : | 0.259 mg/ml ; 0.0016 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.65 |
Solubility : | 0.36 mg/ml ; 0.00222 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.96 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With iron; ammonium chloride In water; isopropyl alcohol for 2 h; Reflux; Inert atmosphere | General procedure: Method A. Nitrocompound (1 mmol) was dissolve in a 0.1 M mixture of IPA: H2O(4:1) and iron powder (Fe, 3 mmol), ammonium chloride (NH4Cl,2 mmol) were added and refluxed for two hours. After cooling down to room temperature reaction mixture was filtered through celite, extracted with EtOAc (25 mL x 3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure and purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With acetic acid In methanol; ethanol | A. 4-Aminoindole. Iron powder (1.20 g, 21.58 mmol) and acetic acid (2.47 mL, 43.19 mmol) are added to a solution of 4-nitroindole (1.0 g, 6.17 mmol) in ethanol (20 mL). The resulting suspension is heated to reflux for 14 hours. The ethanol is removed by rotary evaporation and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered, and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 1percent methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.815 g of 4-aminoindole as an orange solid (82percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 0 - 20℃; | To a stirred solution of 4-nitroindole (4.0 g, 24.6 mmol) in CH2Cl2 (50 mL) were added catalytic amount of DMAP (Catalyst) and Boc2O (5.9 g, 27.1 mmol) at 0° C., and the resulting reaction mixture was stirred at room temperature for additional 3 h. The mixture was diluted with CH2Cl2, and washed with water. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure to give 1-Boc-4-nitroindole as white solid (6.14 g, 95percent yield). MS (ESI) m/z 262.1 |
95.8% | at 20℃; for 1.75 h; | Step 1: Preparation of 4-Nitro-indole-1-carboxylic acid tert-butyl ester (2) To a 5 L four-necked round bottom flask equipped with mechanical stirrer, nitrogen inlet, thermocouple, and condenser was charged 182.3 g (1.124 mol) of 4-nitroindole, 1400 mL toluene, and 2.7 g of DMAP. At room temperature, solid BOC2O (270.0 g 1.237 mol, 1.10 eq) was added in portions over about 45 minutes to the stirring mixture while maintaining moderate gas evolution. After stirring the resulting solution for 1 hour, HPLC analysis showed the reaction to be complete with no starting material. The batch was quenched with 500 mL water, transferred to a separatory funnel and the phases were split. The organic layer was washed with 500 mL brine, concentrated to a slurry, diluted with 1000 ml heptane, filtered, and washed with fresh heptane. The filter cake was dried under vacuum at RT to constant weight to afford 206.0 gram of pale yellow solid. A second crop of 20.0 gram of product was isolated as post-precipitate from the mother liquors. The overall yield was 226.0 gram, 95.8percent yield of pale yellow solid (100 area percent HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | With sodium hydride In N,N-dimethyl-formamide; benzene for 17h; | |
93% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide Cooling with ice; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | General procedure for synthesis of 1-alkyl-4-nitro-1H-indoles 2-6 General procedure: Sodium hydride (1.2 g, 50 mmol) was added portionwise to a solution of 4-nitroindole 1 (8.2 g, 50 mmol) in abs. DMF (50 mL) cooled in an ice bath. Methyl iodide (3.27 mL, 55 mmol) or corresponding alkyl bromide (55 mmol) was added dropwise and the reaction stirred for 4 h at room temperature with TLC analysis monitoring for the completion of the reaction. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent evaporated to give residue. |
62% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-nitro-1H-indoIe; N,N-dimethyl-formamide With trichlorophosphate Stage #2: With sodium hydroxide Further stages.; | |
81% | With trichlorophosphate at 0 - 20℃; for 1h; Inert atmosphere; | Intermediate: 4-Nitro-l//-indole-3-carbaldehyde To a stirred solution of commercially available 4-nitroindole (486 mg, 3 mmol) in anhydrous DMF under nitrogen, phosphorus chloride oxide (0.834 ml, 9 mmol) was added at 0 °C. The reaction mixture stirred at room temperature for lh and then poured into cold saturated aqueous NaHCCb solution and stirred for 0.5 h and extracted by EtOAc (3 X). The organic layer washed with brine, dried over anhydrous Na2SC>4, and the organic layer removed using rotovap. The crude product purified by ISCO to get the desired product, 461 mg, yield 81% 1 H NMR (400 MHz) (DMSO) d) 12.86 (s, 1H) 10.12 (s, 1H) 8.50 (s, 1H), 7.92-7.86 (m, 2 H), 7.42 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz) (DMSO) d 185.02, 142.29, 138.92, 138.11, 122.23, 118.33, 117.90, 116.30, 115.49. |
With sodium hydroxide; trichlorophosphate 1) 100 deg C, 2 h, 2) 15 min; Yield given. Multistep reaction; |
With trichlorophosphate at 0 - 20℃; for 1h; Inert atmosphere; | ||
With trichlorophosphate at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | With sodium hydride In N,N-dimethyl-formamide; benzene for 17h; | |
60% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran; mineral oil at 20℃; for 15h; Inert atmosphere; | |
Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: p-toluenesulfonyl chloride In N,N-dimethyl-formamide at 20℃; for 2h; | 4.2. General procedure for the synthesis of substituted 3-bromoindole derivatives General procedure: Sodium hydride (132 mg, 3.3 mmol) was added to a stirred solution of the indole (3 mmol) in DMF (6.0 mL) at 0 °C, then stirred for 30 min. To the reaction mixture, tosyl chloride (629 mg, 3.3 mmol) was added and stirred at room temperature for 2 h. After pouring into water, the mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was solved in dichloromethane (30 mL) and cooled on iced bath. To the reaction mixture, bromine (170 μL, 3.3 mmol) was added and stirred at 0 °C for 15 min. The reaction mixture was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: Sodium hydride (1.2 g, 50 mmol) was added portionwise to a solution of 4-nitroindole 1 (8.2 g, 50 mmol) in abs. DMF (50 mL) cooled in an ice bath. Methyl iodide (3.27 mL, 55 mmol) or corresponding alkyl bromide (55 mmol) was added dropwise and the reaction stirred for 4 h at room temperature with TLC analysis monitoring for the completion of the reaction. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent evaporated to give residue. 1-Methyl-4-nitro-1H-indole (2). Yellow solid, mp 112-113, yield 95%. 1H NMR (300 MHz, DMSO-d6) delta 8.09 (d, 1H, J = 8.7 Hz, H-5), 7.99 (d, 1H, J = 8.7 Hz, H-7), 7.76 (d, 1H, J = 3.0 Hz, H-2), 7.36 (t, 1H, J = 8.1 Hz, H-6), 7.03 (d, 1H, J = 3.0 Hz, H-3), 3.93 (s, 3H, CH3-1). Calcd. for C9H8N2O2: C, 61.36; H, 4.58; N, 15.90; Found: C, 61.50; H, 4.30; N, 15.70%. | |
66% | With potassium carbonate; In acetone; for 8h;Reflux; | A mixture of 4-nitro-1H-indole (3.06 g, 18.9 mmole), potassium carbonate anhydrous (13.5 g, 97.8 mmole) and methyl iodide (3.2 g, 22.5 mmole) was heated at reflux in acetone for 8 hours. At the end, reaction mixture was filtered and acetone was evaporated. It was extracted with chloroform (300 mL) and washed water (300 mL). The organic layer was separated, dried with MgSO4, filtered and concentrated. The yellow solid, (2.20 g, 66% yield) of 1-methyl-4-nitro-1H-indole was used without further purification. (M+H) 177 |
With NaH; In tetrahydrofuran; water; ethyl acetate; | EXAMPLE 29A 1-methyl-4-nitro-1H-indole A solution of 4-nitroindole (500 mg, 3.1 mmol) in THF (15 mL) at 0 C. was treated portionwise with NaH (290 mg, 9.3 mmol), stirred for 30 minutes, treated dropwise with methyl iodide (0.95 mL, 15.5 mmol), warmed to room temperature for 18 hours, treated sequentially with water and ethyl acetate (200 mL), and washed with brine (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to provide the desired product, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | palladium; In ethanol; | EXAMPLE 1 General Conversion of 4-Nitroindoles to 1-(Indol-4-yl)piperazines A mixture of the 4-nitroindole (10.0 mmol), 10% palladium on carbon (20% by weight), and absolute ethanol (50 mL) was shaken under a hydrogen atmosphere (3 atm) for 2 hours. The resulting reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to afford the corresponding 4-aminoindole, which was used directly (assumed 100% yield) in the next step below. |
89% | With iron; ammonium chloride; In water; isopropyl alcohol; for 2h;Reflux; Inert atmosphere; | General procedure: Method A. Nitrocompound (1 mmol) was dissolve in a 0.1 M mixture of IPA: H2O(4:1) and iron powder (Fe, 3 mmol), ammonium chloride (NH4Cl,2 mmol) were added and refluxed for two hours. After cooling down to room temperature reaction mixture was filtered through celite, extracted with EtOAc (25 mL x 3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure and purified by column chromatography. |
A mixture of 4-nitroindole (15 grams, 92.5 mmol), iron powder (25.92 grams, 462.9 mmol), concentrated hydrochloric acid (5 mL) and water (50 mL) in ethanol (150 mL) was refluxed at 90 0C and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction (2 hours), the reaction mixture was filtered through hy-flow bed and the filtrate was concentrated under reduced pressure. The residual mass was diluted with ice water (500 mL), basified with aqueous sodium hydroxide solution to pH 9 - 10 and extracted with ethyl acetate (2.x 250 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product (13.2 grams), thus obtained, was purified by column chromatography using silica-gel (100 - 200 mesh), the eluent system being ethyl acetate and n-hexane (1:9) to obtain 12.13 grams of title product. Melting Range: 101.7 - 106.8 0C; I.R (cm-'): 1109, 1519, 2931, 3325, 3394, 3440;1H-NMR (ppm): 3.92 (2H, bs), 6.40 - 6.42 (IH, m), 6.46 - 6.47 (IH, m), 6.86 - 6.88 (IH; d, J = 8.14 Hz), 6.99 - 7.03 (IH, t, J = 7.8 Hz), 7.11 - 7.12 (IH, t, 2.8 Hz), 8.11 (IH, bs); Mass (m/z): 133.15 (M+H) + |
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; | A round-bottom flask was charged with 4-nitroindole (4.8 g, 30 mmol), Palladium on carbon (10%, 480 mg), and THF (50 mL), and the mixture was stirred under one hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 4-amino- IH- indole, which was used directly in the next step without purification. | |
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; | A round-bottom flask was charged with 4-nitroindole (4.8 g, 30 mmol), Palladium on carbon (10%>, 480 mg), and THF (50 mL), and the mixture was stirred under one hydrogen atmosphere overnight. TLC showed the reaction was complete. The catalyst was filtered off and the filtrate was concentrated to afford 4-amino-lH-indole (Q-1), which was used directly in the next step without purification. | |
55%Spectr. | With 6Zr(4+)*C20H12O4(2-)*14O(2-)*3Co(2+); hydrogen; sodium triethylborohydride; In toluene; at 115℃; under 30003.0 Torr; for 72h;Glovebox; Inert atmosphere; | General procedure: Scheme 23 shows the hydrogenation of nitroarenes catalyzed by Zr12-TPDC-Co. In a nitrogen-filled glove box, Zr12-TPDC-CoH (0.50 mg) in 1.0 mL THF was charged into a glass vial. NaBEt3H (10 muL, 1.0 M in THF) was then added to the vial and the mixture was stirred for 1 h. The solid was then centrifuged, washed with THF twice, and transferred to a glass vial in 1.0 mL toluene. The nitroarene substrate was added to the vial, which was placed in a Parr reactor, sealed under nitrogen, and charged with hydrogen to 40 bar. After stirring at 115 C. for 1-2 d, the pressure was released and the MOF catalyst was removed from the reaction mixture via centrifugation. Mesitylene (internal standard) was added to the organic extracts and the yield of the product was determined by integrations of the product and mesitylene peaks in the 1H NMR spectra in CDCl3. Table 20, below summarizes the optimization of conditions for the MOF-CoH catalyzed hydrogenation of nitroarenes using nitrobenzene as an exemplary nitroarene. Table 21 summarizes results of the hydrogenation of various nitroarenes using Zr12-TDPC-CoH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.36% | With sodium ethanolate; oxalic acid diethyl ester In N,N-dimethyl-formamide | 1 Synthesis of 4-nitroindole, the main process parameters is: Methyl-3-nitroaniline in triethyl orthoformate under acid catalysis, the reaction of N- (2- methyl-3-nitrophenyl) ethoxy azomethine, benzoic acid the addition amount of 2-10% methyl -3-nitroaniline amount of substance;2- methyl-3-nitroaniline molar mass and triethylorthoformate ratio of 0.9: 1;N- (2- methyl-3-nitrophenyl) ethoxy azomethine with diethyl oxalate and sodium ethoxide reaction crude 4-nitro-indole;The molar ratio of ethanol and sodium diethyl oxalate is n (sodium ethoxide): n (diethyl oxalate) = 1.1: 1;2-methyl-3-nitrophenyl) ethoxy molar ratio of azomethine and potassium ethanol and diethyl oxalate as: n- (2- methyl-3-nitrophenyl) ethoxymethyl imide) :n (potassium ethoxide and diethyl oxalate) = 1.05;4-Nitro-indole acetic acid after the crude product was recrystallized from ethanol, the weight ratio of acetic acid to ethanol is 1: 5, the ethyl alcohol is 95% ethanol. |
90.6% | With sodium ethanolate; oxalic acid diethyl ester In N,N-dimethyl-formamide at 0 - 35℃; for 2.5h; | 1; 2; 1; 2 to the fractionated N-(2-methyl 3-nitrophenyl)ethoxymethylimine, DMF was added, then 8.04 g of diethyl oxalate was added, and 6.24 g of sodium ethoxide was slowly added dropwise at 0 to 5 °C. heated to 35 , 2.5 hours; after completion of the reaction the reaction mixture was poured into ice water, and the resulting brown precipitate was 11.68g 4- nitroindole crude product, relative to the 2-methyl-3-nitroaniline The crude yield was 72.04%.The 4-nitroguanidine crude product was recrystallized with a volume ratio of water, methanol and acetic acid of 1:2:4 to obtain 10.52 g of pure 4-nitroguanidine, and the recrystallization yield was 90.06%. |
77% | With potassium ethoxide; oxalic acid diethyl ester In N,N-dimethyl-formamide at 30 - 40℃; for 2.5h; |
71% | With potassium ethoxide; oxalic acid diethyl ester In dimethyl sulfoxide; N,N-dimethyl-formamide at 40℃; for 1h; | |
64% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide; N,N-dimethyl-formamide at 50℃; | |
With potassium ethoxide; oxalic acid diethyl ester In dimethyl sulfoxide; N,N-dimethyl-formamide at 40℃; for 24h; | ||
With potassium acetate; oxalic acid diethyl ester In N,N-dimethyl-formamide | 1.3-6.3 (3) Dissolving N-(2-methyl-3-nitrophenyl)ethoxymethylimine prepared above in a three-necked flask, dissolving diethyl oxalate and potassium acetate in N, The mixed solution was prepared in N-dimethylformamide, and added to the above three-necked flask. After the completion of the dropwise addition, the reaction was further stirred for 1 hour, and then poured into ice water to precipitate. After the precipitation was completed, the mixture was collected, and the solid was collected and deionized. Water and anhydrous ethanol are sequentially washed and dried to obtain a target product; the mass ratio of the N-(2-methyl-3-nitrophenyl)ethoxymethylimine, diethyl oxalate, and potassium acetate is 10:6:3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With hydrogen In benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyrophosphoryl chloride at 0 - 20℃; | |
63% | With pyrophosphoryl chloride at 20℃; for 3h; | |
15% | Stage #1: 4-nitro-1H-indoIe; methyl 2-oxo-2-(pyrrolidin-1-yl)acetate With pyrophosphoryl chloride at 20℃; Cooling with ice; Stage #2: With methanol; sodium hydrogencarbonate In water at 0℃; | 71.2 Step 2: methyl (4-nitro-1H-indol-3-yl)-oxo-acetate 9.4 mL (68 mmol) diphosphoryl chloride were slowly added dropwise to 10 g (62 mmol) 4-nitroindole and 11 g (68 mmol) methyl oxo-pyrrolidin-1-yl-acetate with stirring and while cooling with ice. The reaction mixture was heated to RT and stirred for 3 h at RT. Then first of all 10 mL MeOH were added dropwise at 0° C. and then saturated sodium hydrogen carbonate solution was added dropwise at 0° C. After repeated extraction with DCM the organic phase was dried and evaporated down to 100 mL. This residue was left to stand at RT and the precipitate formed was suction filtered, washed and dried in the air. Yield: 2.30 g (15% of theory) ESI-MS: m/z=249 (M+H)+ |
With pyrophosphoryl chloride at 0 - 20℃; for 3h; | A Diphosphoryl chloride (0.938 mL, 6.8 mol) was added dropwise to a solution of 4-nitroindole (1 g, 6.2 mol) and methyl pyrrolidinyl glyoxylate (Downie et al, Tetrahedron, 1993, 49, 4015-4034) (1.1 g, 6.8 mmol) at 0 0C and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO3 were added to the reaction at 0 0C and the solution was extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: mlz = 249 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe; methyl 2-oxo-2-(pyrrolidin-1-yl)acetate With pyrophosphoryl chloride at 0 - 20℃; for 3h; Stage #2: With sodium hydrogencarbonate In methanol; water at 0℃; | 20.A; 42.A Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to a solution of 4- nitroindole (1.00 g, 6.17 mmol) and methyl pyrrolidinyl glyoxylate (Downie et al, Tetrahedron, 1993, 49, 4015-4034) (1.10 g, 6.80 mmol) at 0 0C and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO^ were added to the reaction at 0 °C and the solution was extracted with CH2CI2 (3 * 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: mlz - 249 (M + I); Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to a solution of 4- nitroindole (1.00 g, 6.17 mmol) and methyl pyrrolidinyl glyoxylate (Downie et al, Tetrahedron, 1993, 49, 4015-4034) (1.10 g, 6.80 mmol) at 0 0C and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO^ were added to the reaction at 0 °C and the solution was extracted with CH2CI2 (3 * 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: mlz - 249 (M + I). | |
Stage #1: 4-nitro-1H-indoIe; methyl 2-oxo-2-(pyrrolidin-1-yl)acetate With pyrophosphoryl chloride at 0 - 20℃; for 3h; Stage #2: With sodium hydrogencarbonate In methanol; water at 0℃; | 47.A Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to a solution of 4- nitrondole (1.00 g, 6.17 mraol) and methyl pyrrolidinyl glyoxylate (Downie et al., Tetrahedron, 1993, 49, 4015-4034) (1.10 g, 6.80 mmol) at 0 0C and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO3 were added to the reaction at 0 0C and the solution was extracted with CH2CI2 (3 * 50 mL). The combined organic extracts were dried over Na2SO^ filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: mlz = 249 (M + I). | |
With pyrophosphoryl chloride at 0 - 20℃; for 3h; | 12.A Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to a solution of 4- nitroindole (1.00 g, 6.17 mmol) and methyl pyrrolidinyl glyoxylate (Downie et ah, Tetrahedron, 1993, 49, 4015-4034) (1.10 g, 6.80 mmol) at 0 0C and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO3 were added to the reaction at 0 0C and the solution was extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: mlz = 249 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe; methyl 2-oxo-2-(pyrrolidin-1-yl)acetate With pyrophosphoryl chloride at 0 - 20℃; Stage #2: With sodium hydrogencarbonate In methanol; water at 0℃; | 12.A Step A. Methyl (4-nitro-lH-indol-3-yl)(Oxo)acetate Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to a solution of 4-nitroindole (1.00 g, 6.17 mmol) and methyl pyrrolidinyl glyoxylate (Downie et al., Tetrahedron, 1993, 49, 4015-4034) (1.10 g, 6.80 mmol) at 0 °C and the mixture was allowed to warm to ambient temperature over 3 h. MeOH, then saturated aqueous NaHCO3 were added to the reaction at 0 0C and the solution was extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo until crystals formed. The crystals were collected by vacuum filtration and two more crops were isolated from the filtrate to give the title compound. MS: mlz = 249 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triphenylphosphine In acetonitrile for 26h; Heating; | |
89% | With carbon monoxide; palladium diacetate; triphenylphosphine In acetonitrile at 90℃; for 50h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); triethyl borane In tetrahydrofuran; hexane at 50℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | With potassium carbonate In N,N-dimethyl-formamide at 86℃; for 23h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 36h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: KOH / acetone / 0 °C 1.2: 85.14 percent / acetone / 2 h / 20 °C 2.1: 60.6 percent / TiCl3; aq. HCl; AcOH / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 98 percent / NaH / dimethylformamide / 2 h / cooling 2: 99 percent / H2 / Pd/C / ethanol / 20 °C | ||
Multi-step reaction with 2 steps 1: K2CO3 / dimethylformamide / 24 h / 20 °C 2: H2 / 10percent Pd/C / ethanol / 3102.9 Torr |
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / Cooling with ice 1.2: 4 h / 20 °C 2.1: iron; hydrogenchloride / ethanol; water / 1 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 1.2: 14 h / 0 - 20 °C 2.1: iron; hydrogenchloride / water; ethanol / 20 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; | A solution of 4-nitroindole (4.0 g, 24.7 mmol) in DMF (20 mL) was added slowly over 5 min to a suspension of unwashed sodium hydride (1.09 g, 60 wt.% in mineral oil, 27.2 mmol) in DMF (50 mL) at 0C. An immediate color change to deep red occurred with bubbling of escaping gasses. The reaction mixture was stirred at 0C for 5 min and then at RT for 40 min. A solution of Example 273 Part A(2) compound (12.6 g, 29.6 mmol) in DMF (20 mL) was added and the reaction mixture was stirred at RT over a weekend (64 h total). The solvent was removed under high vacuum on a rotary evaporator, and the resulting orange residue was partitioned between EtOAc (200 mL) and H2O (50 mL). The organic layer was washed with H2O (2 x 50 mL) and brine (50 mL), dried over MgSO4, and concentrated to give a yellow foam. The crude product was purified by flash chromatography on silica gel (600 g) eluting with a step gradient of 20% to 25% to 30% EtOAc/hexane to give title compound (10.9 g, 73%) as a yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide at 0 - 20℃; Stage #3: With water; ammonium chloride In N,N-dimethyl-formamide | 1 Step 1: Synthesis of 4-nitro-1-(phenylsulfonyl)-1H-indole (7) To a solution of 4-nitroindole (1, 4.0 g, 24.6 mmol) in DMF (20 mL) was added sodium hydride (60%, 1.48 g, 37 mmol) in portions. After being stirred at room temperature for 15 minutes, benzenesulfonyl chloride was added by drops at 0° C., and the resulting reaction mixture was stirred at room temperature for additional 2 hours. The reaction was quenched by addition of aqueous ammonium chloride solution (5 mL), followed by addition of water. The resulting pale-yellow solid was collected by filtration, washed with water, and dried in vacuum to give the product (7.2 g, 97% yield), MS (ESI) m/z 302.9. |
95% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.333333h; Inert atmosphere; Stage #2: benzenesulfonyl chloride In tetrahydrofuran for 1h; Inert atmosphere; | 1 Introduction of the phenylsulfonyl-protection group - general procedure 1 General procedure: During 20 min, NaH (60 % dispersion in mineral oil, 3.40 g, 90.0 mmol) was added to a stirred solution of the respective indole or pyrrolopyridine (80 mmol) in 60 mL of anhydrous THF at 0 °C. After stirring at rt for 1 h, benzenesulfonyl chloride (10.9 mL, 90 mmol) was added slowly. The reaction mixture was stirred for an additional 1 h and then poured into 150 mL of 5% aq. NaHC03 and extracted with ether (3x 150 mL). The combined organic layers were dried (Na2S04), and the solvent was removed under reduced pressure to give a beige solid. Recrystallization from ethanol afforded the title compound as colorless crystals Lit.: (Johansson, Brandt et at. 2005) Preparation from 13a (Maybride) as described in the general procedure 1. Yield: 7.86 g, 26 mmol (95%). ‘H NMR (DMSO-d6): ö = 8.45 (d, J = 8.3 Hz, 1H), 8.27 - 8.18 (m, 2H), 8.15 - 8.03 (m, 2H), 7.74 (ddd, J = 6.6, 3.8, 1.2 Hz, 1H), 7.62 (dd,J = 15.7, 8.0 Hz, 3H), 7.36 (dd, J = 3.7, 0.6 Hz, 1H). |
95% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: benzenesulfonyl chloride In tetrahydrofuran; mineral oil for 1h; Inert atmosphere; | Introduction of the phenylsulfonyl-protection group - general procedure 1 General procedure: During 20 min, NaH (60 % dispersion in mineral oil, 3.40 g, 90.0 mmol) was added to astirred solution of the respective indole or pyrrolopyridine (80 mmol) in 60 mL of anhydrousTHF at 0 °C. After stirring at rt for 1 h, benzenesulfonyl chloride (10.9 mL, 90 mmol) wasadded slowly. The reaction mixture was stirred for an additional 1 h and then poured into 150mL of 5% aq. NaHCO3 and extracted with ether (3x 150 mL). The combined organic layerswere dried (Na2SO4), and the solvent was removed under reduced pressure to give a beigesolid. Recrystallization from ethanol afforded the title compound as colorless crystals. |
72% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 75 - 81℃; for 1.25h; | INTERMEDIATE 2; 1-Benzenesulfonyl-4-nitro-1H-indole A solution of 4-nitro-lH-indole (9.49 kg) in acetonitrile (69.5 kg) was heated to 81°C.TV,/V-Diisopropylethylamine (Hiinigs base) (8.98 kg) was added followed by a portion wiseaddition of benzenesulfonyl chloride. The exotermic addition of benzenesulfonyl chloridewas done with such speed that the temperature was kept between 75-81 °C. The addition25 time was 45 min. after stirring the reaction mixture for 30 min at 80 °C, analysis showedthe disappearance of the starting material. Water (8.2 L) was added to the reaction mixtureat 80°C. (NOTE. A serious error was made, as the recipe called for the addition of 16 L ofwater). The reaction mixture was kept at 80 °C for 50 min. Upon cooling, the productstarted to crystallize at approximately 74 °C. The resulting slurry was cooled to 10 °C. The30 product was isolated on a nutsche filter and washed with a mixture of acetonitrile (21.9 kg)and water (9.1 L). Drying at 70 °C and full vacuum gave 12.71 kg (72%) of the titlecompound. .H NMR (400 MHz, DMSO-d6) 5 ppm 7.34 (d, J=3.91 Hz, 1 H) 7.55 - 7.65 (m, 3 H) 7.69 - 7.76 (m, 1 H) 8.05 - 8.09 (m, 2 H) 8.18 - 8.23 (m, 2 H) 8.42 (dd, J=8.30, 0.73Hz, 1 H). 13CNMR(101 MHz, DMSO-d6) 6 ppm 107.64 (s, 1 C) 119.75 (s, 1 C) 120.18 (s,1 C) 124.20 (s, 1 C) 124.66 (s, 1 C) 126.78 (s, 2 C) 129.94 (s, 2 C) 131.17 (s, 1 C) 135.07(s, 1 C) 135.36 (s, 1 C) 136.34 (s, 1 C) 139.96 (s, 1 C) |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 1.5h; | 5.1.141.A A. l-Benzenesulfonyl-ltf-indol-4-ylamine.; 4-Nitroindole (1.07 g, 6.6 mmol) was dissolved in acetonitrile (12 mL) and diisopropylethylamine (1.2 mL, 7.92 mmol) was added. The solution was heated to 80 0C and the benzenesulfonyl chloride (0.93 mL, 7.26 mmol) was then added. The mixture was stirred at 80 0C for 1.5 h. The reaction was cooled, diluted with water (20 mL), and filtered. The crude 1 -benzenesulfonyl-4-nitro- 1 //-indole was washed with water (10 mL) and then with methanol (5 mL). Crude 1- benzenesulfonyl-4-nitro-lH-indole was then taken up in methanol (50 mL). To this suspension was added 10% Pd/C (0.5 g) and ammonium formate (1.0 g, 15.6 mmol). The mixture was stirred at reflux for 1.5 h, after which the reaction was complete as indicated by LCMS (MS (ESI) m/z 213 A [M+l]+). The reaction was concentrated and the crude residue was subjected to silica gel chromatography (90% hexanes in EtOAc). Concentration of the desired fractions afforded the title compound (1.42 g, 5.22 mmol, 79%). | |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 80℃; for 3h; | A.13.1 A.13.1. Synthesis of 1-(benzenesulfonyl)-4-nitro-indole a106 A.13.1. Synthesis of 1-(benzenesulfonyl)-4-nitro-indole a106. To a solution of 4-nitro-1 H-indole (25 g, 154.32 mmol) in ACN (250 mL), DIPEA (29.5 mL, 169.75 mmol) was added at rt. The reaction was cooled to 0 °C and benzensulfonyl chloride (23 mL, 185.18 mmol) was added. The reaction was heated at 80 °C for 3 h. After completion, the reaction was quenched with an aqueous saturated solution of sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed with water, dried over Na2S04, filtered and concentrated under vacuum to afford 34.95 g of 1- (benzenesulfonyl)-4-nitro-indole a106. Yield: 97% (crude). 1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.39 (m, 1 H), 8.26 - 8.17 (m, 2H), 8.12 - 8.04 (m, 2H), 7.78 - 7.68 (m, 1 H), 7.67 - 7.54 (m, 3H), 7.38 - 7.26 (m, 1 H). | |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 3h; | A.6.1 A,6. 1. Synthesis of 1 -(benzenesulfonyl)-4-nitro-indole a49. To a solution of 4-nitro-1H-indole (25 g, 154.32 mmol) in ACN (250 mL), DIPEA (29.5 mL, 169.75 mmol) was added at it. The reaction was cooled to 0 00 and benzensulfonylchloride (23 mL, 185.18 mmol) was added. The reaction was heated at 80 °C for 3 h. After completion, the reaction was quenched with an aqueous saturated solution of sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed with water, dried over Na2SO4, filtered and concentrated under vacuum to afford 34.95 g of 1- (benzenesulfonyl)-4-nitro-indole a49.Yield: 97% (crude).1H NMR (400 MHz, DMSO-d6) 68.47-8.39 (m, 1H), 8.26-8.17 (m, 2H), 8.12-8.04 (m,2H), 7.78-7.68 (m, 1H), 7.67-7.54 (m, 3H), 7.38-7.26 (m, 1H). | |
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 2h; | 289 To a solution of 4-nitro-indole (1 equiv.) in dimethylformamide was added sodium hydride (1.50 equiv.) and benzenesulfonyl chloride (1.0 equiv.). The mixture was stirred at 0˜30° C. for 2 h, and quenched with aqueous ammonium chloride at 0° C. The mixture was filtered, the solids were washed with water and petroleum ether, and the resulting solution was concentrated and dried in vacuo to give 4-nitro-1-(phenylsulfonyl)-1H-indole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium <i>tert</i>-butylate; oxalic acid diethyl ester In DMF (N,N-dimethyl-formamide) at 38 - 45℃; for 1.08333h; | INTERMEDIATE 1; 4-Nitro-1H-indoIe p-Toluenesulfonic acid monohydrate (0.10 kg) was added to triethyl ortho formate (8.00kg) at 111 °C. The mixture was stirred for 5 min and then 3-nitro-o-toluidine (4.10 kg) wasadded portion wise. The addition is slightly exothermic and the speed of addition was adjusted to avoid letting the temperature fall below 111°C. The addition time was 65 min.During the addition, formed ethanol starts to distill off. After the addition was completed,the reaction mixture was distilled at atmospheric pressure for 70 min at 125 °C. hi total 4.5L of ethanol was distilled off. When the distillation speed slowed down, vacuum (800 mbar5 - 140 mbar) was applied to finalize the distillation. The distillation was aborted whenapprox. 6L remained in the reactor. The reaction mixture was diluted with N,N-dimethylformamide (DMF) (15 L) and cooled to 43 °C. Diethyl oxalate (4.20 kg) wasadded. To the resulting mixture, potassium tert-butoxide (4.08 kg) was added portionwisewhile keeping the temperature between 38-45 °C. The addition time was 55 min. After10 completed addition, the reaction was stirred at 40-45 °C for 10 min. The reaction mixturewas then added to water (90 L) at 50-60 °C. The product crystallized during the addition.After cooling to 20 °C, the product was isolated on a nutsche filter. The resulting productcake was washed with 25 L of water and dried at 80 °C while applying full vacuum. Theproduct weighed 2.90 kg (66%) after drying. lH NMR (400 MHz, DMSO-d6) 5 ppm 7.0515 (d, J=2.93 Hz, 1 H) 7.28 (t, J=7.93 Hz, 1 H) 7.75 (d, J=2.93 Hz, 1 H) 7.89 (d, J=7.32 Hz, 1H) 8.04 (d, J=8.06 Hz, 1 H) 11.96 (s, 1 H). 13C NMR (101 MHz, DMSO-d6) 5 ppm 101.11(s, 1 C) 116.79 (s, 1 C) 119.13 (s, 1 C) 120.06 (s, 1 C) 121.26 (s, 1 C) 130.65 (s, 1 C)138.13 (s, 1 C) 139.09 (s, 1 C) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1-fluoro-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one In 1,4-dioxane; water at 140℃; for 5h; | |
Stage #1: 4-nitro-1H-indoIe With N-chloro-succinimide In chloroform for 30h; Heating / reflux; Stage #2: With phosphoric acid; water; acetic acid at 70℃; for 1.53333h; Stage #3: With sodium hydroxide; sodium hydrogencarbonate more than 3 stages; | 17.A A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated under reduced pressure to give an orange solid. The solid was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70 0C, then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 ν NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30 °C. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z = 179 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe With N-chloro-succinimide In chloroform for 30h; Heating / reflux; Stage #2: With phosphoric acid; water In acetic acid at 70℃; for 1.53333h; Heating / reflux; Stage #3: With sodium hydroxide; sodium hydrogencarbonate more than 3 stages; | 16.A A mixture of 4-nitroindoIe (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CηCb (500 mL) was heated at reflux for 30 h, then concentrated under reduced pressure to give an orange solid. The solid was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70 0C, then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30 0C. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: mlz - 179 (M + 1). |
Stage #1: 4-nitro-1H-indoIe With N-chloro-succinimide In chloroform for 30h; Heating / reflux; Stage #2: With phosphoric acid In acetic acid at 70℃; for 1.53333h; Heating / reflux; Stage #3: With sodium hydroxide; water; sodium hydrogencarbonate In acetic acid at 0 - 30℃; | 8.A A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and iV-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70 °C, then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30 °C. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane: EtOAc - 100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: mlz = 179 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe With N-chloro-succinimide In chloroform for 30h; Heating / reflux; Stage #2: With phosphoric acid; acetic acid In water at 70℃; for 1.53333h; | 44.A A mixture of 4-nitro indole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated under reduced pressure to give an orange solid. The solid was dissolved in AcOH (200 mL) and the resulting solution was wanned to 70 0C, then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 Ν NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30 0C. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z = 179 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe With N-chloro-succinimide In chloroform for 30h; Heating / reflux; Stage #2: With phosphoric acid; acetic acid In water for 1.53333h; Heating / reflux; | A A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated to dryness under reduced pressure. The residue was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70 0C, then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 Ν NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30 0C. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 0: 100, and then triturated with MeOH to give the title compound. MS: mlz = 179 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe With N-chloro-succinimide In chloroform for 30h; Reflux; Stage #2: With phosphoric acid; acetic acid at 70℃; for 1.53333h; Reflux; Stage #3: With sodium hydrogencarbonate; sodium hydroxide In water at 30℃; | 44.A Step A. 4-Nitro-1.3-dihvdro-2H-indol-2-oneA mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide (6.07 g, 30.1 mmol) in CHCl3 (500 mL) was heated at reflux for 30 h, then concentrated under reduced pressure to give an orange solid. The solid was dissolved in AcOH (200 mL) and the resulting solution was warmed to 70 °C, then 85% H3PO4 (80 mL) was added over 2 min. The mixture was heated to reflux for 90 min then cooled on ice. The cooled mixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followed by aqueous NaHCO3, keeping the temperature below 30 °C. The mixture was extracted with EtOAc (3 x 1 L) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane: EtOAc - 100:0 to 0:100, and then triturated with MeOH to give the title compound. MS: m/z = 179 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid for 4.5h; | A N, N,Λ^,Λ^-Tetramethyldiaminomethane (2.2 mL, 15.6 mol) in acetic acid (30 mL) was added dropwise over 60 min to a solution of 4-nitroindole (2.30 g, 14.2 mol) in acetic acid (30 mL). After 3.5 h, the reaction was cooled to 0 °C, and 20 % aqueous sodium hydroxide was added to adjust the pΗ to 11. The mixture was extracted with CHCl3 (3 x 300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: mlz = 220 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe; bis-(dimethylamino)methane In acetic acid for 4.5h; Stage #2: With sodium hydroxide In water | 41.A N^NNyV'-Tetramethyldiaminomethane (2.2 mL, 15.6 mol) in acetic acid (30 mL) was added dropwise over 60 min to a solution of 4-nitroindoIe (2.30 g, 14.2 mol) in acetic acid (30 mL).After 3.5 h, the reaction was cooled to 0 0C3 and 20 % aqueous sodium hydroxide was added to adjust the pη to 11. The mixture was extracted with CηCI3 (3 * 300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: mlz = 220 (M +I)- | |
Stage #1: 4-nitro-1H-indoIe; bis-(dimethylamino)methane In acetic acid for 3.5h; Stage #2: With sodium hydroxide In water at 0℃; | 46.A NjNjNjN'-Tetramethyldiaminomethane (2.2 mL, 15.6 mol) in acetic acid (30 mL) was added dropwise over 60 min to a solution of 4-nitroindole (2.30 g, 14.2 mol) in acetic acid (30 mL). After 3.5 h, the reaction was cooled to 0 0C, and 20 % aqueous sodium hydroxide was added to adjust the pH to 11. The mixture was extracted with CHCI3 (3 x 300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: mlz - 220 (M + 1). |
With acetic acid for 4.5h; | 11.A N,N,N,N-Tetramethyldiaminomethane (2.2 ϖiL, 15.6 mol) in acetic acid (30 mL) was added dropwise over 60 rain to a solution of 4-nitroindole (2.30 g, 14.2 mol) in acetic acid (30 mL). After 3.5 h, the reaction was cooled to 0 0C, and 20 % aqueous sodium hydroxide was added to adjust the pΗ to 11. The mixture was extracted with CHCl3 (3 x 300 mL) and the combined organic extracts were dried over Νa2Sθ4, filtered, and concentrated in vacuo to give the title compound. MS: mlz = 220 (M + I)- | |
Stage #1: 4-nitro-1H-indoIe; bis-(dimethylamino)methane With acetic acid for 4.5h; Stage #2: With sodium hydroxide In water at 0℃; | 11.A Step A. N.N-Dimethyl-l-(4-nitro-lH-indol-3-yl)methanamineN,N,λ^λ''-Tetramethyldiaminomethane (2.2 mL, 15.6 mol) in acetic acid (30 mL) was added dropwise over 60 min to a solution of 4-nitroindole (2.30 g, 14.2 mol) in acetic acid (30 mL). After 3.5 h, the reaction was cooled to 0 °C, and 20 % aqueous sodium hydroxide was added to adjust the pH to 11. The mixture was extracted with CHCl3 (3 x 300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: mlz = 220 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Example 15 Synthesis of 1-methyl-4-nitroindole. 1-methyl-4-nitroindole was prepared from 4-nitroindole in 96% yield using the same experimental conditions and isolation procedure described in Example 11 for the preparation of the isomeric 1-methyl-4-nitroindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With acetic acid; In methanol; ethanol; | A. 4-Aminoindole. Iron powder (1.20 g, 21.58 mmol) and acetic acid (2.47 mL, 43.19 mmol) are added to a solution of 4-nitroindole (1.0 g, 6.17 mmol) in ethanol (20 mL). The resulting suspension is heated to reflux for 14 hours. The ethanol is removed by rotary evaporation and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered, and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 1% methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.815 g of 4-aminoindole as an orange solid (82% yield). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide In dichloromethane; water; dimethyl sulfoxide | 2 (Compound 14 in Table 1) STR4 EXAMPLE 2 1-[2',6'-dichloro-4'-trifluoromethylphenyl]-4-nitroindole (Compound 14 in Table 1) STR4 A mixture of 4-nitroindole (0.5 g, 3.0 mmol), potassium hydroxide pellets (0.7 g, 12.0 mmol) in 40.0 ml dimethylsulfoxide were stirred for 30 minutes at room temperature. Then 3,5-dichloro-4-fluorobenzotrifluoride was added and stirred at room temperature for 3 hours. Water and methylene chloride were added and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water, dried and stripped under vacuum to yield 1.0 g of yellow solid of the desired product. The structure was confirmed by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. | |
With potassium hydroxide In dichloromethane; water; dimethyl sulfoxide | 2 1-[2',6'-dichloro-4'-trifluoromethylphenyl]-4-nitroindole (Compound 14 in Table 1) STR4 EXAMPLE 2 1-[2',6'-dichloro-4'-trifluoromethylphenyl]-4-nitroindole (Compound 14 in Table 1) STR4 A mixture of 4-nitroindole (0.5 g, 3.0 mmol), potassium hydroxide pellets (0.7 g, 12.0 mmol) in 40.0 ml dimethylsulfoxide were stirred for 30 minutes at room temperature. Then 3,5-dichloro-4-fluorobenzotrifluoride was added and stirred at room temperature for 3 hours. Water and methylene chloride were added and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water, dried and stripped under vacuum to yield 1.0 g of yellow solid of the desired product. The structure was confirmed by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | EXAMPLE 10 General Synthesis of 4-Nitroindole via Fischer Indolization of 3-nitrophenylhydrazine Derivatives A mixture of <strong>[51516-96-2]3-nitrophenylhydrazine hydrochloride</strong> (1.90 g, 10.0 mmol) and the appropriate ketone (12.5 mmol, 1.25 equivalents) in absolute ethanol (20 mL) was heated at reflux under nitrogen overnight. The resulting reaction solution was evaoprated under reduced pressure, and the residue (assumed hydrazone) was used directly. To this residue was added polyphosporic acid (PPA, 15 g), and the resulting viscous mixture was heated at 100 C. for 1 hour. The resulting black reaction solution was cooled, and ice (50 g) was added carefully with stirring. The resulting aqueous mixture was extracted with methylene chloride (3*50 mL), and these extracts were dried (magnesium sulfate) and evaporated under reduced pressure. If necessary, chromatography of the residue using silica gel (approximately 100 g) and elution with an appropraie solvent system afforded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: cycl-isopropylidene malonate; 4-nitro-1H-indoIe With formaldehyd; rac-Pro-OH In water; acetonitrile at 20℃; for 18h; Stage #2: With copper In pyridine; ethanol for 2h; Heating / reflux; | 39.A A mixture of 4-nitroindole (1.00 g, 6.17 mmol), Meldrum's acid (889 mg, 6.17 mmol), proline (36 mg, 0.31 mmol), and formaldehyde (37% in η2O, 0.50 mL, 6.17 mmol) was stirred in CH3CN (4 mL) at ambient temperature for 18 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (2 * 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. After drying under high vacuum, the solid residue was dissolved in pyridine (16 mL) and EtOH (4 mL). To the resulting solution was added copper powder (50 mg, 0.79 mmol) and the mixture was heated at reflux for 2 h then allowed to cool. The solvent was removed in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (50 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanerCHzCh - 20:80 to 0:100, to give the title compound. MS: mlz = 263 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
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With pyrophosphoryl chloride at 0 - 20℃; for 18h; | 19.A Diphosphoryl chloride (23.5 mL, 170 mmol) was added dropwise to a stirred mixture of4-nitroindole (25.0 g, 154 mmol mmol) and ethyl 1-piperidineglyoxylate (29.0 g, 170 mmol) at 0 0C.The mixture was allowed to warm slowly to ambient temperature and stirring was continued for 18 h.The reaction mixture was cooled to 0 0C and quenched carefully by addition of EtOH (50 mL), followed by saturated aqueous NaηCθ3 until no further effervescence was observed. The precipitated yellow solid was isolated by filtration, washed with H2O3 and dried in vacuo to give the title compound. MS: mlz = 263 (M + 1). | |
Stage #1: 4-nitro-1H-indoIe; ethyl 2-oxo-2-(piperidine-1-yl)acetate With pyrophosphoryl chloride at 0 - 20℃; for 18h; Stage #2: With sodium hydrogencarbonate In ethanol; water at 0℃; | 18.A Diphosphoryl chloride (23.5 mL, 170 mmol) was added dropwise to a stirred mixture of 4-nitroindole (25.0 g, 154 mmol mmol) and ethyl 1-piperidineglyoxylate (29.0 g, 170 mmol) at 0 0C. The mixture was allowed to warm slowly to ambient temperature and stirring was continued for 18 h. The reaction mixture was cooled to 0 0C and quenched carefully by addition of EtOH (50 mL), followed by saturated aqueous NaηCθ3 until no further effervescence was observed. The precipitated yellow solid was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: mlz = 263 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With sodium hexamethyldisilazane In tetrahydrofuran; acetonitrile for 1h; Cooling with acetone-dry ice; Stage #2: 4-Chloro-2-methylthiopyrimidine In tetrahydrofuran; acetonitrile at 20℃; for 21h; | 6 A solution of sodium(bistrimethylsilyl)amide (1 M in THF, 26.42 mL) was slowly added to a cooled (acetone/dry-ice bath) solution of 4-nitroindole (4.2 g, 25.9 mmol) in a mixture of acetonitrile/THF (2/1, 75 mL) and the resulting mixture was stirred for 1 hour. 4-Chloro-4-methylthiopyrimidine (4.202 g, 26.2 mmol) was then added and the reaction mixture was warmed to RT and stirred for 21 h. The resulting mixture was evaporated under reduced pressure and the solid residue was triturated with a mixture of hexane/EtOAc/Et2O (5/1/1). The solid was collected by filtration, washed and dried under reduced pressure to give 2.56 g of 1-(2-methylsulfanyl-pyrimidin-4-yl)-4-nitro-1H-indole which was used without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide at 5℃; for 1h; Stage #2: (4-chloromethyl-2-isopropylphenoxy)triisopropylsilane In N,N-dimethyl-formamide at 5℃; for 3h; | 60 Reference Example 60 1-(3-isopropyl-4-triisopropylsilanyloxybenzyl)-4-nitro-1H-i ndole (3-isopropyl-4-triisopropylsilanyloxyphenyl)methanol (478 mg) was dissolved in dichloromethane (5.0 mL), thionyl chloride (162 µL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. A reaction mixture was concentrated under reduced pressure to obtain (4-chloromethyl-2-isopropylphenoxy)triisopropylsilane. 60% sodium hydride (59.2 mg) was suspended in N,N-dimethylformamide (1.0 mL), and a solution of 4-nitro-1H-indole (200 mg) in N,N-dimethylformamide (1.0 mL) was added dropwise at 5°C. After stirred at 5°C for 1 hour, a solution of the previously obtained (4-chloromethyl-2-isopropylphenoxy)triisopropylsilane in N,N-dimethylformamide (2.0 mL) was added dropwise at 5°C, and the mixture was stirred for 3 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, developing solvent: n-hexane/ethyl acetate = 9/1) to obtain the title compound (481 mg). 1H NMR (CDCl3) δ (ppm): 1.08(18H,d), 1.09(6H,d), 1.21-1.34(3H,m), 3.36(1H,m), 5.33(2H,s), 6.70(1H,s), 7.06(1H,d), 7.26(3H,m), 7.38(1H,d), 7.66(1H,d), 8.15(1H,d). | |
481 mg | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5℃; for 1h; Stage #2: (4-chloromethyl-2-isopropylphenoxy)triisopropylsilane In N,N-dimethyl-formamide; mineral oil at 5℃; for 3h; | 3.1.20 1-(3-Isopropyl-4-triisopropylsilanyloxybenzyl)-4-nitro-1H-indole (7a) To a suspension of NaH (60% in oil, 59.2mg, 1.5mmol) in DMF (1.0mL) was added dropwise a solution of 4-nitro-1H-indole (200mg, 1.2mmol) in DMF (1.0mL) at 5°C. After stirring at the same temperature for 1h, a DMF solution (2.0mL) of 1b (ca. 1.5mmol) was added. The resulting mixture was stirred for an additional 3h, and the reaction was quenched with ice water, and then extracted with EtOAc. The organic layers were successively washed with water and brine, and dried over Na2SO4. After evaporation of the solvent, the resulting residue was purified by flash chromatography on silica gel (hexane/EtOAc=9/1) to give the title compound (481mg, 84%) as a yellow solid: mp 98-100°C; 1H NMR (CDCl3) δ 1.08 (18H, d, J=7.4Hz), 1.09 (6H, d, J=6.6Hz), 1.27 (3H, m), 3.34 (1H, m), 5.29 (2H, s), 6.67 (1H, s), 7.05 (1H, s), 7.26 (3H, m), 7.38 (1H, d, J=6.2Hz), 7.66 (1H, d, J=8.4Hz), 8.13 (1H, d, J=8.1Hz); MS (ESI) m/z 467 (M+H)+; HRMS (ESI) m/z calcd for C27H39N2O3Si (M+H)+ 467.2724, found 467.2720. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.44% | With potassium hydroxide In tetrahydrofuran at 25 - 30℃; | 8 4-Nitro indole (1 grams, 6.1 mmol) was dissolved in tetrahydrofuran (5 mL) in two necked round bottom flask (50 mL), equipped with guard tube and thermometer socket. Potassium hydroxide powder (1.22 grams, 85 %, 18.5 mmol) was added to the above reaction mass, followed by the addition of 4-fluorobenzene sulfonyl chloride (1.84 grams, 9.2 mmol) dissolved in tetrahydrofuran (5 mL) at room temperature and the progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mass was poured onto ice-cold water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated the mass under reduced pressure to get 1.9 grams (96.44 %) of the title product, which can be used for the next step without further purification. Melting Range: 140.5 - 145.1 0C; LR (Cm"1): 1159, 1347, 1506;1H-NMR (ppm): 7.14 - 7.18 (2H, t), 7.44 - 7.48 (2H, m), 7.80 - 7.81 (IH, d, J = 3.67 Hz), 7.91 -7.94 (2H, m), 8.21 - 8.23 (IH, m), 8.32 - 8.34 (IH, m);Mass (m/z): 321.1 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With potassium hydroxide In acetone at 0℃; for 0.0833333h; Stage #2: ethyl iodide In acetone at 20℃; for 0.25h; | 11.A To a stirred solution of 4-nitroindole (2.5 g, 15.4 mmol) in 50 ml acetone at 0° C was added 4.32 g (76.9 mmol) powdered potassium hydroxide and the solution stirred for 5 min. Ethyl iodide (4.8 g, 30.8 mmol) was added and the solution stirred vigorously for 15 min at ambient temperature. Toluene (300 ml) was added and the insoluble material was removed by filtration. The solution was washed with 5 % aqueous citric acid followed by water, dried (anhydrous sodium sulfate) and solvent removed in vacuo. Residue was triturated with hexane-ethyl acetate (7:3) to afford l-ethyl-4-nitro-lH-indole (2.6 g, 13.6 mmol); LC/MS, API-ES, Pos, (M+H)+, 191.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | dmap; In dichloromethane; at 0 - 20℃; | To a stirred solution of 4-nitroindole (4.0 g, 24.6 mmol) in CH2Cl2 (50 mL) were added catalytic amount of DMAP (Catalyst) and Boc2O (5.9 g, 27.1 mmol) at 0 C., and the resulting reaction mixture was stirred at room temperature for additional 3 h. The mixture was diluted with CH2Cl2, and washed with water. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure to give 1-Boc-4-nitroindole as white solid (6.14 g, 95% yield). MS (ESI) m/z 262.1 |
95.8% | dmap; In toluene; at 20℃; for 1.75h;Product distribution / selectivity; | Step 1: Preparation of 4-Nitro-indole-1-carboxylic acid tert-butyl ester (2) To a 5 L four-necked round bottom flask equipped with mechanical stirrer, nitrogen inlet, thermocouple, and condenser was charged 182.3 g (1.124 mol) of 4-nitroindole, 1400 mL toluene, and 2.7 g of DMAP. At room temperature, solid BOC2O (270.0 g 1.237 mol, 1.10 eq) was added in portions over about 45 minutes to the stirring mixture while maintaining moderate gas evolution. After stirring the resulting solution for 1 hour, HPLC analysis showed the reaction to be complete with no starting material. The batch was quenched with 500 mL water, transferred to a separatory funnel and the phases were split. The organic layer was washed with 500 mL brine, concentrated to a slurry, diluted with 1000 ml heptane, filtered, and washed with fresh heptane. The filter cake was dried under vacuum at RT to constant weight to afford 206.0 gram of pale yellow solid. A second crop of 20.0 gram of product was isolated as post-precipitate from the mother liquors. The overall yield was 226.0 gram, 95.8% yield of pale yellow solid (100 area % HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With dimethylaluminum chloride In dichloromethane at 0℃; for 0.5h; Stage #2: ethyl 3-(chloroformyl)propionate In dichloromethane at 20℃; for 18h; | 20.A To a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH2Cl2 (60 mL) at 0 0C was added dimethylaluminum chloride (1 M in hexanes, 14.8 mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl 4~chloro~4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and the resulting mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) and extracted with CH2Cl2 (3 x 150 mL). The combined organic extracts were dried over Na2SC^, filtered, and concentrated in vacuo. The residue was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:Et0Ac - 100:0 to 65:35, and the resulting crude product was recrystallized from CH2Cl2:Me0H to give the title compound. MS: rø/z = 291 (M + l). | |
Stage #1: 4-nitro-1H-indoIe With dimethylaluminum chloride In dichloromethane at 0℃; for 0.5h; Stage #2: ethyl 3-(chloroformyl)propionate In dichloromethane at 0 - 20℃; | 20.A Step A. Ethyl 4-(4-nitro-l//-indol-3-yl)-4-oxobutanoateTo a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH2Cl2 (60 mL) at 0 0C was added dimethylaluminum chloride (1 M in hexanes, 14.8 mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl 4-chloro-4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and the resulting mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) and extracted with CH2Cl2 (3 x 150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:Et0Ac - 100:0 to 65:35, and the resulting crude product was recrystallized from CH2Cl^MeOH to give the title compound. MS: mlz = 291 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: ethyl bromide In N,N-dimethyl-formamide; mineral oil | 2.3. General procedures for the synthesis of 1-substituted 4-nitroindole derivatives 5, 9, and 13 General procedure: In a round-bottomed flask, to 55.5 mmol of NaH (60% dispersion in mineral oil) a solution of 4-nitro-indole derivative, 26 (18.5 mmol) in 20-30 mL dry DMF was dropped and after 30 min at room temperature, a solution of halo-derivative in dry DMF was added and the reaction mixture was left stirred until the end (TLC). Then, the reaction mixture was workup in a standard way. The raw products were purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: cyclopropylcarbinyl bromide In N,N-dimethyl-formamide; mineral oil | 2.3. General procedures for the synthesis of 1-substituted 4-nitroindole derivatives 5, 9, and 13 General procedure: In a round-bottomed flask, to 55.5 mmol of NaH (60% dispersion in mineral oil) a solution of 4-nitro-indole derivative, 26 (18.5 mmol) in 20-30 mL dry DMF was dropped and after 30 min at room temperature, a solution of halo-derivative in dry DMF was added and the reaction mixture was left stirred until the end (TLC). Then, the reaction mixture was workup in a standard way. The raw products were purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: ethyl acrylate In N,N-dimethyl-formamide; mineral oil | 2.3. General procedures for the synthesis of 1-substituted 4-nitroindole derivatives 5, 9, and 13 General procedure: In a round-bottomed flask, to 55.5 mmol of NaH (60% dispersion in mineral oil) a solution of 4-nitro-indole derivative, 26 (18.5 mmol) in 20-30 mL dry DMF was dropped and after 30 min at room temperature, a solution of halo-derivative in dry DMF was added and the reaction mixture was left stirred until the end (TLC). Then, the reaction mixture was workup in a standard way. The raw products were purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.6% | Stage #1: 4-nitro-1H-indoIe; 2-bromoethanol With potassium hydroxide In acetone for 6h; Reflux; Stage #2: With hydrogenchloride In water | 1 Step 1 : Synthesis o f 2-(4-nitro- l H-indo l- l -yl)ethanol450 ml o f acetone and 26 g (464 mmo l) of potassium hydroxide are successively placed in a 1 litre three-necked flask equipped with a thermometer, a condenser, a bubbler, a magnetic stirrer and a dropping funnel. Once the so lution has been obtained, 15 g (92.5 mmo l) o f 4-nitroindole are added, followed by dropwise addition o f 15 ml (203.5 mmo l) o f 2-bromoethanol, and the mixture is refluxed for 6 hours.The medium is cooled and the inso luble matter formed is filtered off and washed thoroughly with acetone.The mother liquors are evaporated to dryness, the residue is then taken up in demineralized water and the pH is adjusted to neutral pH with IN hydrochloric acid so lution.The mixture is then transferred into a separating funnel and extraction is performed using dichloromethane. The organic phase is washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate and evaporated to dryness, then purified on a column of silica using twice 15 g of crude product, to give 7.9 g of the expected compound, i.e. a synthesis yield of 41.6%.Analysis by mass spectrometry confirms the expectedcompound: the quasi-molecular ions [M+H] + , [M+Na] + ,[M+Na+CH30H] + , [Μ]~ of the expected molecule are mainlydetected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 12h; | B10.A Intermediate Β1Θ -(3-rnorphojsnopropyj)-1 W-sndoj-4-amsneSte A: 1-(3-bromopropy.)-4-nitro-1 H-indo.e To a solution of 4-riitroindoie (5 g, 31 mrnol) in anhydrous A ,A/-dimethylformamide (200 mL) was added grounded potassium hydroxide (1 .74 g, 31 mrnol} in portions. Then a solution of 1 ,3-dibromopropane (18 g, 89 mrnol) in Λ/,Λ/'-dimethylformamide was added dropwise. The mixture was stirred at room temperature for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The residue was purified by silica gel chromatography to afford the product 1 -(3-bromopropyi)-4-nitro-1 H-indole as brown-red oil (8.18 g, yield 94 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A: Preparation of methyl (4-chlorophenyl)(4-nitro-lH-indol-l-yl)acetate (1)A solution of 4-nitroindole (6.89 g, 42.5 mmol) in DMF (20 mL) was added dropwise to a stirred suspension of sodium hydride (1.70 g of a 60% wt/wt dispersion in mineral oil, 42.5 mmol) in DMF (100 mL) at 0 0C. After 10 min, a solution of He (11.2 g, 42.5 mmol) in DMF (20 mL) was added slowly dropwise, and the resulting mixture was stirred at 0 0C for 3 h. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with ether. The combined organics were washed with water and brine, dried (MgS04), filtered and concentrated in vacuo. The resulting crude oil was purified by by flashchromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford the title compound 1. mlz (ES) 345 (MH)+; IP = C rating. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5h; Microwave irradiation; | 15.1 Step 1: Preparation of methyl 2-(4-nitro-1H-indol-1-yl)acetate (78) To a solution of 4-nitro-1H-indole (500 mg, 3.08 mmol) in DMF (10 ml), K2CO3 (511 mg, 3.70 mmol) and methyl 2-bromoacetate (343 μl, 3.70 mmol) were added, and the mixture was stirred at 100° C. under MW irradiation for 30 minutes. The insoluble inorganic salts was filtered off, and the solvent was evaporated, recovering crude desired methyl 2-(4-nitro-1H-indol-1-yl)acetate which was used in the next step without further purification (810 mg). MS/ESI+ 235.1 [MH]+. | |
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5h; Microwave irradiation; | 15.1 Step 1 : Preparation of methyl 2-(4-nitro-1 H-indol-1 -yl)acetate (78) Example 15 (S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)- phenyl)-2-(2-(4-(methylsulfonamido)-1 H-indol-1 -yl)acetoxy)ethyl)pyridine 1 -oxide (Compound 84) Scheme 15 Step 1 : Preparation of methyl 2-(4-nitro-1 H-indol-1 -yl)acetate (78) To a solution of 4-nitro-1 H-indole (500 mg, 3.08 mmol) in DMF (10 ml), K2C03 (51 1 mg, 3.70 mmol) and methyl 2-bromoacetate (343 μΙ, 3.70 mmol) were added and the mixture was stirred at 100°C under MW irradiation for 30 min. The insoluble inorganic salts was filtered off, and the solvent was evaporated, recovering crude desired methyl 2-(4-nitro-1 H-indol-1 -yl)acetate which was used in the next step without further purification (810 mg). MS/ESI+ 235.1 [MH] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With sodium hydride In hexane; N,N-dimethyl-formamide at 0 - 20℃; for 0.333333h; Stage #2: 2,2,2-trifluoroethyl trifluoromethanesulphonate In hexane; N,N-dimethyl-formamide at 0 - 20℃; | 84 To 720 mg (4.44 mniol) 4-nitroindole (B8.1 , commercially available) in -25 mL DMF at 0°C was added 213 mg NaH (60% dispersion in hexanes). The reaction was stirred at 0°C for 5 minutes and then for 15 minutes at room temperature. The reaction was chilled back down to 0°C and then 1.24 g (5.33 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched with 5 mL saturated NaHC03 (aq) and then 25 mL water was added. Solid precipitated and was filtered. The filtered solid which still contained some staring material was carried forward. To this crude material (B8.2) dissolved in MeOH was added Pd/C and a balloon filled with H2. The reaction was stirred overnight before being filtered through celite and concentrated. This yielded crude l-(2,2,2-trifluoroethyl)-lH-indol-4-amine (B8.3) which was utilized instead of 5-aminoindazole (Scheme 1). Additionally a Cbz- deprotection utilizing BBr3 in DCM (Scheme 7, example 82) was undertaken to give the title compound. MS found for C]6H20F2N6O as (M+H)+458.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine; pyridinium hydrobromide perbromide; at 0℃; for 0.5h; | 0050] To a solution of TA-109 (11.0 g, 0.06 mol) in pyridine (60 mL) was added dropwise pyridinium hydrobromide perbromide (20.0 g, 0.06 mol) in pyridine (20 mL) at 0 C. After being stirred for 0.5 h at 0 C., the reaction mixture was poured into Et2O and the precipitate was removed by filtration. The filtrate was washed successively with 1N aqueous sodium hydroxide (50 mL), water (50 mL), and brine (20 mL) and concentrated. The residue was purified by column chromatography using hexane and increasing amounts of EtOAc to give TA-110 (16.3 g, 87% yield). 1H NMR (400 MHz, CDCl3) delta 12.35 (s, 1H) 7.90 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H); |
2.5 g | With bromine; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.16h; | 4-Nitro-lH-indole (2.0 g) was added to N,N-dimethylformamide (30 mL) in a reaction vessel. While the reaction temperature was maintained at lower than 0C, a dilution of bromine (318 mu) in N,N-dimethylformamide (10 mL) was added to the reaction vessel over 10 min, and then stirred at room temperature for 18 hrs. The reaction mixture was extracted three times with water (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and subjected to vacuum distillation, and dried to obtain the desired compound (2.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: p-Tolylisocyanate In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; | ||
Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: p-Tolylisocyanate In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; | General procedure for the synthesis of N-p-tolyl-1H-indole-1-carboxamide General procedure: Toa stirred suspension of indole (100 mol %) in anhydrous DMF (30 mL) was added NaH (200 mol %, 60% dispersion in mineral oil) at 0 oCunder N2 atmosphere. The reaction mixture was then stirred at room temperature for 3 h,and p-tolyl isocyanate (150 mol %) was added dropwise. The reaction mixture was then stirred at room temperature for overnight. The reaction mixture was washed with H2O and extracted with EtOAc (50 mL). The organic layer was then washed with an aqueous solution of 1 nHCl (50 mL). The organic layer was dried over Mg2SO4 and concentrated in vacuo. The by residue was purified flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe; 3-(p-methoxyphenyl)-1-propanol With cyanomethylene triphenylphosphorane In toluene at 80℃; Stage #2: With palladium 10% on activated carbon; ammonium acetate In toluene at 60℃; for 2h; | 2.1 1-[3-(4-Methoxyphenyl)propyl1-1H, 4-aminoindole Nitro-indole (100 mg, 0.617 mmol), phosphine (279 mg, 0.925 mmol) and alcohol (0.617 mmol) were heated at 80°C in toluene (2 mL) overnight. The mixture was cooled down to room temperature. To the mixture was added 10% Pd/C (10 mg) and ammonium acetate (389 mg, 6.17 mmol). The mixture was stirred at 60°C for 2 hours then filtered on arbocel under nitrogen. The arbocel pad was washed with EtOH. The mixture was evaporated in vacuo. The residue was dissolved in MeOH and passed through an SCX-2 cartridge. The cartridge was washed with MeOH (25 mL). The cartridge was then flushed with a 2M methanolic ammonia solution (25 mL). The ammonia solution was evaporated to afford the product as a red oil LCMS m/z 281 MH+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; trans-1,2-cyclohexanediamine In toluene at 110℃; for 24h; Microwave irradiation; Inert atmosphere; Sealed tube; | General procedure: To a microwave vial was added 18(100mg,0.194mmol),CuI(2mg,0.01mmol), the melatonin(54mg,0.23 mmol), andK3PO4(83mg,0.39 mmol), and the reaction vessel was fitted with arubber septum. The vessel was evacuated and back-filledwith argon and thisevacuation/back-fill procedure was repeated one additional time. Toluene (3 mL) and trans-1,2-Cyclohexaneiamine(5μL,0.043mmol) were then successivelyadded under a stream of argon. Thereaction tube was quickly sealed and the contents were stirred while heating in anoil bath at110°Cfor 24h. The reaction mixture was cooled to ambient temperature,diluted with ethyl acetate, and filtered through a plug of silica gel, eluting with additionalethyl acetate. The filtrate was concentrated and the resulting residue was purified bycolumn chromatography(3:1 petrolum/EtOAc) to provide the product N-(2-(1-(2,4-bis(benzyloxy)-5-(isoindoline-2-carbonyl)phenyl)-5-methoxy-1H-indol-3-yl)ethyl)acetamide19 as a white solid(97mg,75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.77% | With [2,2]bipyridinyl; oxygen; copper diacetate; sodium hydrogencarbonate In 1,2-dichloro-ethane at 25 - 60℃; for 120h; | |
With [2,2]bipyridinyl; copper diacetate; sodium hydrogencarbonate In 1,2-dichloro-ethane at 20 - 60℃; for 170h; | 10.1 (Step 1) (Step 1) Cyclopropyl boronic acid (1.0 g), sodium bicarbonate (0.99 g), copper acetate (II) (1.1 g), and 2,2'-bipyridine (0.92 g) were added to a solution of 4-nitro-1H-indole (0.96 g) in 1,2-dichloroethane (60 ml). The reaction solution was stirred at room temperature for 7 days, and then further stirred at 60°C for 2 hours. The insolubles were filtrated through celite, and then the resultant was washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent: hexane/ethyl acetate) to obtain 1-cyclopropyl-4-nitro-1H-indole as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In toluene; at 100℃; for 8h; | (Step 1) Trans-N,N'-dimethylcyclohexane-1,2-diamine (a racemate) (0.643 ml) and toluene (10 ml) were added to a mixture of 4-nitro-1H-indole (660 mg), <strong>[92525-10-5]3-iodine-1-methyl-1H-pyrazole</strong> (853 mg), tripotassium phosphate (864 mg), and copper iodide (I) (775 mg), and the reaction solution was stirred at 100C for 8 hours. The reaction solution was returned to room temperature, then diluted with ethyl acetate, and washed successively with 28% aqueous ammonia and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (developing solvent: hexane-ethyl acetate) to obtain 1-(1-methyl-1H-pyrazol-3-yl)-4-nitro-1H-indole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 60℃; for 3h; | 27 Synthesis of 1-(2-methoxyethyl)-4-nitro-1H-indole (1) To a solution of 4-nitro-1H-indole (5.1 g, 30.77 mmol), 1-bromo-2-methoxy ethane (5.134 g, 37 mmol) in DMF (30 mL), NaH (1.610 g, 80% dispersion in mineral oil, 40 mmol) was added potion- wise at room temperature. The mixture was stirred at 60 °C for 3 h until TLC (petroleum ether: ethyl acetate = 6: 1 as mobile phase) indicated the completion of the reaction. The mixture was allowed to cool down to room temperature, and then poured onto water (60 mL) and extracted with ethyl acetate (50 mL x4). The combined organic layers was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (ethyl acetate/ petroleum ether from 1/10 to 1/3 as mobile phase) to give compound 1 (4.778 g, 21.5 mmol, 69%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With toluene-4-sulfonic acid In acetonitrile at 60℃; for 1h; regioselective reaction; | 10 General procedure for the reaction between DACS and indoles General procedure: In a typical reaction, DAC (0.20 mmol) was mixed with indole (0.20 mmol) and PTSA (10 mol%) in ethanol (1.0 mL). The mixture was then stirred at 60°C for 20 min. After reaction, the mixture was cooled to room temperature, and the product was obtained by isolation with preparative TLC (eluting solution: petroleum ether/ethyl acetate=5/1 (v/v)). Tests for substrate scope were all performed with an analogous procedure. Large scale synthesis was also performed in a similar procedure. The product was isolated by silica column chromatography (eluting solution: petroleum ether/ethyl acetate=8/1 (v/v)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere; Cooling with ice; | 1.2 General procedure: NaH of 60% dispersion in mineral oil (228 mg, 5.7 mmol) was added in 30 mL of anhydrous THF solvent into a 100 mL dried two necked round bottom flask equipped with a dropping funnel and substituted indole/pyrrolo-pyridine (2.84 mmol) was added to the solution under argon atmosphere in ice-water bath, and the resulting solution was stirred for 30 min in an ice-water bath. Into the flask, the prepared solution of epoxide 10 (2.84 mmol in THF) was added through dropping funnel under argon atmosphere at the ice-water bath and stirred overnight at RT. After adding 1 mL of H2O (1N HCl in case for compound 15), the reaction mixture was condensed under reduced pressure, and then dispersed into 50 mL of EtOAc, washed with 50 mL (× 2) water, brine, dried over anhydrous MgSO4, and evaporated to dryness. The mixture was purified with flash column chromatography as an eluent EtOAc/hexane, and then the condensed compounds were then recrystallized in EtOAc/hexane to give any one of the target products 11-27, 11R, 30-32, and 80. |
Stage #1: 4-nitro-1H-indoIe With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide Cooling with ice; Stage #2: isopropyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | General procedure for synthesis of 1-alkyl-4-nitro-1H-indoles 2-6 General procedure: Sodium hydride (1.2 g, 50 mmol) was added portionwise to a solution of 4-nitroindole 1 (8.2 g, 50 mmol) in abs. DMF (50 mL) cooled in an ice bath. Methyl iodide (3.27 mL, 55 mmol) or corresponding alkyl bromide (55 mmol) was added dropwise and the reaction stirred for 4 h at room temperature with TLC analysis monitoring for the completion of the reaction. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent evaporated to give residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide Cooling with ice; Stage #2: Isobutyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | General procedure for synthesis of 1-alkyl-4-nitro-1H-indoles 2-6 General procedure: Sodium hydride (1.2 g, 50 mmol) was added portionwise to a solution of 4-nitroindole 1 (8.2 g, 50 mmol) in abs. DMF (50 mL) cooled in an ice bath. Methyl iodide (3.27 mL, 55 mmol) or corresponding alkyl bromide (55 mmol) was added dropwise and the reaction stirred for 4 h at room temperature with TLC analysis monitoring for the completion of the reaction. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent evaporated to give residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 4-nitro-1H-indoIe With sodium hydride In N,N-dimethyl-formamide Cooling with ice; Stage #2: i-pentyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | General procedure for synthesis of 1-alkyl-4-nitro-1H-indoles 2-6 General procedure: Sodium hydride (1.2 g, 50 mmol) was added portionwise to a solution of 4-nitroindole 1 (8.2 g, 50 mmol) in abs. DMF (50 mL) cooled in an ice bath. Methyl iodide (3.27 mL, 55 mmol) or corresponding alkyl bromide (55 mmol) was added dropwise and the reaction stirred for 4 h at room temperature with TLC analysis monitoring for the completion of the reaction. The solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent evaporated to give residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; boron tribromide; acetic acid; In toluene; at 0 - 4℃; for 0.5h; | (3) The obtained 10 mmol of <strong>[135531-92-9]5-methoxy-4-nitroindole</strong> was dissolved in a solution of acetic acid / toluene,Control the temperature at 0-4 ,After adding 30 mmol of BBr3 for 30 min,Add 7 mmol of methanol, stop the reaction,After removing the solvent under reduced pressure,Recrystallization required 4-nitroindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium(II) trifluoroacetate; triphenylphosphine In water at 80℃; for 1h; Sealed tube; Green chemistry; | General procedure for the synthesis of compounds 2a-2m General procedure: A mixture of nitroarene 1 (2.0 mmol), 1.0 cm3 HCOOH,33 mg Pd(TFA)2 (0.1 mmol,5 mol%), and 52 mg PPh3(0.2 mmol, 10 mol%) in 1.0 cm3 water was sealed and heated to 80 C for an appropriate time (Table 2). After completion of the reaction, the mixture was cooled to room temperature and diluted with 20 cm3 DCM. The solid was removed by filter, and the filtrate was washed with 20 cm3water and 20 cm3 brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel to afford product 2a-2m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | 4-nitroguanidine (100 mg, 0.62 mmol),DMF (4 mL),NaH (60% dispersion in mineral oil, 74 mg, 1.85 mmol, 3 eq.) was added to the reaction flask in turn.After stirring at room temperature for 5 minutes, after NaH is uniformly dispersed,Slowly inject methyl trifluoroacetate (0.25 mL, 2.48 mmol, 4 eq.) into the reaction flask.After 4 hours of reaction, the TLC plate, the material points disappeared,That is, the reaction is complete and stirring is stopped.Extract twice with ethyl acetate and distilled water, then wash with saturated NaCl solution.The organic phase was combined, and the organic phase was dried over anhydrous magnesium sulfate.Rotate the solvent,Purification by column chromatography gave yellow solid 1-methyl-4-nitroindole (106 mg, yield 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-nitro-1H-indoIe With potassium hexamethylsilazane In tetrahydrofuran at -20℃; for 0.333333h; Stage #2: sophocarpine In tetrahydrofuran at 20℃; Overall yield = 68.3 %; | 3.2.2. General Procedure for the Synthesis of Compounds 3a-n General procedure: To a solution of the corresponding substituted indole (0.36 mmol) in THF (2 mL) was added 2mol/L KHDMS (0.36 mmol) at -20 °C; the resulting solution was stirred at the same temperature for for 20 min, and then sophocarpine (0.3 mmol) was added. The reaction temperature was allowed to raise to r.t. and stirred overnight. After the completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with dichloromethane/methanol as the eluent. Compounds 3a-n were mostly presented in pairs of 13S/13R stereoisomers, of which 13S-isomers were the major stereoisomers. The NMR peaks recorded below were signals of the major stereoisomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | Stage #1: 4-nitro-1H-indoIe With lithium hexamethyldisilazane In tetrahydrofuran at -20℃; for 0.333333h; Stage #2: sophocarpine In tetrahydrofuran at -20 - 20℃; for 16h; | 3 Example 3: 13-(4-Nitro-1H-indenyl)matrine (MG-3) and preparation thereof _:13-(4-nitro-1H-indenyl)matrine (MG-3), the structural formula is as follows: Add 2 mL of anhydrous tetrahydrofuran to a dry 25 mL round bottom flask at -20 °CAnd 4-nitro indole (0.36mmol, 68.3mg),2mol/L of LiHMDS in tetrahydrofuran (0.36 mmol, 180 μL) was slowly added.After the addition, the reaction was carried out at -20 ° C for 20 min.Sophocarpine added (0.3mmol, 73.6 mg), was slowly warmed to room temperature,Continue to react for 16 h.After completion of the reaction, the reaction was quenched by the addition of 20 mL of a saturated aqueous solution of ammonium chloride, and extracted three times with 20 mL of dichloromethane.The organic phase was combined and washed with aq.Separation by silica gel column chromatography, eluent: dichloromethane: methanol 10:1,A yellow solid was obtained in 83.8 mg, yield 68.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3h; | 166.1 Step 1-Benzyl N-[2-[2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate To a mixture of 2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (100 mg, 246 umol, Intermediate EY) in DMF (2 mL) was added K2CO3 (68.1 mg, 493 umol) and 4-nitro-1H-indole (39.9 mg, 246 umol). The reaction mixture was stirred at 100° C. for 3 hours. On completion, the reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with water (4 mL) and extracted with dichloromethane (2*6 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EA=1:1) to give the title compound (67.0 mg, 57% yield) as a light yellow oil. LC-MS (ESI+) m/z 494.1 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With ammonium iodide; 1,10-Phenanthroline; acetic acid In 1,4-dioxane at 100℃; for 6h; Sealed tube; | 4.2. General procedure for the NH4I/1,10-phenanthroline catalyzed direct sulfenylation of N-heteroarenes with ethyl arylsulfinates General procedure: A Schlenk tube (25 mL) was charged with indole (0.3 mmol), ethyl arylsulfinate (0.4 mmol), NH4I (20 mol%), and 1,10-phenanthroline (10 mol%). 1,4-Dioxane (2 mL) and HOAc (0.5 mL) were added under air atmosphere, the tube was sealed and heated in an oil bath at 100 °C for 6 h. The crude mixture was allowed to cool to room temperature. Then, ethyl acetate and saturated aq. solution of NaCl (5 mL) were added and the layers separated. The aqueous phase was washed three times with ethyl acetate (5 mL x 3). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude was purified by flash column chromatography with Al2O3 (petroleum ether/EtOAc) giving desired products 3a-z and 4a-t. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.116667h; Microwave irradiation; | 1 Example 1N-ethyl-4-nitroguanidinePreparation 4-nitroguanidine (100 mg, 0.62 mmol),DMF (4 mL),Potassium tert-butoxide (108 mg, 1.86 mmol, 3 eq.) was added to the reaction flask in turn.After stirring at room temperature for 5 minutes,After the potassium tert-butoxide is uniformly dispersed,Slowly inject ethyl trifluoroacetate (0.29 mL, 2.48 mmol, 4 eq.) into the reaction flask.400 W microwave irradiation for 2 minutes.After cooling to room temperature, extract twice with ethyl acetate and distilled water.Wash with saturated NaCl solution,Combine the organic phase,Drying the organic phase with anhydrous magnesium sulfate,Remove magnesium sulfate by filtration,Rotate the solvent,Purification by column chromatography to obtain a yellow-brown liquidN-ethyl-4-nitroguanidine(84 mg, yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 5h; Inert atmosphere; Overall yield = 96 percent; Overall yield = 34.2 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 5h; Inert atmosphere; Overall yield = 67 percent; Overall yield = 25.9 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 5h; Inert atmosphere; Overall yield = 83 percent; Overall yield = 28 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 24h; Inert atmosphere; Overall yield = 80 percent; Overall yield = 26.9 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 24h; Inert atmosphere; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 48h; Inert atmosphere; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 24h; Inert atmosphere; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 24h; Inert atmosphere; Overall yield = 82 percent; Overall yield = 31.0 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 5h; Inert atmosphere; Overall yield = 74 percent; Overall yield = 26.1 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63 % ee | With rubidium carbonate; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide In water; toluene at 20℃; for 5h; Inert atmosphere; Overall yield = 90 percent; Overall yield = 26.8 mg; enantioselective reaction; | N-Alkylation of Nitroindoles General procedure: Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of compounds was held for 1 h under vacuum. The vial was filled with an argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O(0.14 mmol) were added and the reaction mixture was stirred at r.t. for 5 h under argon unless stated otherwise. The progress of the reaction was monitored by TLC and NMR spectroscopy. After completionof the reaction, the reaction mixture was directly purified by column chromatography to afford pure products 3, 5, or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With norborn-2-ene; dichloro bis(acetonitrile) palladium(II); dipotassium hydrogenphosphate In N,N-dimethyl acetamide; water at 80℃; for 5h; Inert atmosphere; | General Alkylation Procedure (GP) General procedure: A round-bottom flask was charged with the corresponding indole (1.0 eq.), norbornene (2.0 eq.), base [K2CO3 (2.0 eq.) or K2HPO4 (3.0 eq.); as indicated], PdCl2(MeCN)2 (10 mol%), and the corresponding bromide (2.0 eq.). A 0.5 M solution of water in DMA (ca. 5 mL per mmol indole) was added. The mixture was then placed in a preheated oil bath at 80 °C. Vigorous stirring was applied and the mixture was kept under a balloon pressure of argon for 24 h. After cooling to r.t., the mixture was diluted with Et2O (80 mL) and washed with water (80 mL). The aqueous layer was extracted with Et2O (2 80 mL). The combined organic layers were washed with brine (80 mL) and dried (Na2SO4). All volatiles were removed in vacuo and the crude material was subjected to FCC (silica gel, pentane/Et2O) to yield the respective product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.15h; | 1.2.6. Synthesis of intermediates 14a-f NaH (60%, 300mg, 7.5mmol) was added to a stirred solution of 4-nitro-1H-indole (810mg, 5mmol) in anhydrous DMF (20 mL) at 0 oC. Then substituted benzyl bromide (5.5 mmol) was added after 15 min. The mixture was stirred for 3 h and quenched with H2O (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the product. The obtained product was used directly in the following steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.15h; | 1.2.6. Synthesis of intermediates 14a-f NaH (60%, 300mg, 7.5mmol) was added to a stirred solution of 4-nitro-1H-indole (810mg, 5mmol) in anhydrous DMF (20 mL) at 0 oC. Then substituted benzyl bromide (5.5 mmol) was added after 15 min. The mixture was stirred for 3 h and quenched with H2O (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the product. The obtained product was used directly in the following steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.15h; | 1.2.6. Synthesis of intermediates 14a-f NaH (60%, 300mg, 7.5mmol) was added to a stirred solution of 4-nitro-1H-indole (810mg, 5mmol) in anhydrous DMF (20 mL) at 0 oC. Then substituted benzyl bromide (5.5 mmol) was added after 15 min. The mixture was stirred for 3 h and quenched with H2O (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the product. The obtained product was used directly in the following steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.15h; | 1.2.6. Synthesis of intermediates 14a-f NaH (60%, 300mg, 7.5mmol) was added to a stirred solution of 4-nitro-1H-indole (810mg, 5mmol) in anhydrous DMF (20 mL) at 0 oC. Then substituted benzyl bromide (5.5 mmol) was added after 15 min. The mixture was stirred for 3 h and quenched with H2O (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the product. The obtained product was used directly in the following steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.15h; | 1.2.6. Synthesis of intermediates 14a-f NaH (60%, 300mg, 7.5mmol) was added to a stirred solution of 4-nitro-1H-indole (810mg, 5mmol) in anhydrous DMF (20 mL) at 0 oC. Then substituted benzyl bromide (5.5 mmol) was added after 15 min. The mixture was stirred for 3 h and quenched with H2O (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the product. The obtained product was used directly in the following steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.15h; | 1.2.6. Synthesis of intermediates 14a-f NaH (60%, 300mg, 7.5mmol) was added to a stirred solution of 4-nitro-1H-indole (810mg, 5mmol) in anhydrous DMF (20 mL) at 0 oC. Then substituted benzyl bromide (5.5 mmol) was added after 15 min. The mixture was stirred for 3 h and quenched with H2O (20 mL), extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the product. The obtained product was used directly in the following steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.4% | Stage #1: 4-isopropylthiazole-2-carbonyl chloride With aluminum (III) chloride In dichloromethane at 25℃; for 0.25h; Inert atmosphere; Stage #2: 4-nitro-1H-indoIe In dichloromethane at 60℃; for 12h; Inert atmosphere; | 1.4 Step 4: (4-Isopropylthiazol-2-yl)-(4-nitro-1H-indol-3-yl)methanone To a solution of 4-isopropylthiazole-2-carbonyl chloride (220 mg, 1.16 mmol, N/A purity, 1 eq) in DCM (4 mL) was added AlCb (850 mg, 6.37 mmol, 5.50 eq). The mixture was stirred under N2 atmosphere at 25 °C for 0.25 h. 4-Nitro-lT/-indole (200 mg, 1.23 mmol, 1.06 eq) was added. The mixture was stirred under N2 atmosphere at 60 °C for 12 h. The reaction mixture was quenched with MeOH (20 mL) and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 100/1 to 1/4, TLC: PE/EtOAc = 0/1, Rf= 0.10) to yield (4-i sopropylthiazol-2-yl )-('4-nitro- 1 //-indol-3- yl)methanone (100 mg, 306.65 pmol, 26.4% yield, 96.7% purity) as a yellow solid. ^ NMR (400 MHz, CDCh) d ppm 9.10 (br s, 1H), 8.83 (d, J= 2.7 Hz, 1H), 7.78 (d, J= 7.8 Hz, 1H), 7.72 (d, J= 8.1 Hz, 1H), 7.44-7.37 (m, 1H), 7.26 (s, 1H), 3.16 (td, J= 7.0, 13.6 Hz, 1H), 1.35 (d, 6.8 Hz, 6H); ES-LCMS m/z 316.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,6-Dichloropyrimidine With Aluminum Chloride In 1,2-dichloro-ethane for 0.0833333h; Inert atmosphere; Stage #2: 4-nitro-1H-indole In 1,2-dichloro-ethane at 85℃; for 3h; Inert atmosphere; | 4.2 General procedure for the preparation of the final compounds 5a-y General procedure: To the solution of 2,4-dichloropyrimidine 2 (159mg, 1.07mmol, 1.00eq) in dichloroethane (10mL) was added aluminum chloride (AlCl3, 170mg, 1.27mmol, 1.20eq) under a N2 atmosphere. After stirring for 5min, different substituents indole (1a-y, 1.07mmol, 1.00eq) was added, and the mixture was heated at 85°C for 3h. Upon completion of the reaction, the reaction mixture was cooled at room temperature and poured into ice-cold water (30mL) with continuous stirring for 20min. The crude products were isolated by extracting with ethyl acetate. The organic phase was separated and washed with brine, dried over sodium sulphate, and evaporated under vacuum to obtain a yellow solid (3a-y). The obtained solid was used without further purification for the next step. It was dissolved in 2-pentanol (10mL), and p-Toluene sulfonic acid hydrate (203mg, 1.17mmol, 1.10eq) was added in one portion to a mixture solution of 2,6-dimethylaniline (129mg, 1.07mmol, 1.00eq). The resulting mixture was then stirred at 125°C for 18h. Once completion of the reaction, the solution was poured into ice-cold water and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to afford the target compounds 5a-y. | |
Stage #1: 2,6-Dichloropyrimidine With Aluminum Chloride In 1,2-dichloro-ethane for 0.0833333h; Inert atmosphere; Stage #2: 4-nitro-1H-indole In 1,2-dichloro-ethane at 85℃; for 3h; Inert atmosphere; | 4.2 General procedure for the preparation of the final compounds 5a-y General procedure: To the solution of 2,4-dichloropyrimidine 2 (159mg, 1.07mmol, 1.00eq) in dichloroethane (10mL) was added aluminum chloride (AlCl3, 170mg, 1.27mmol, 1.20eq) under a N2 atmosphere. After stirring for 5min, different substituents indole (1a-y, 1.07mmol, 1.00eq) was added, and the mixture was heated at 85°C for 3h. Upon completion of the reaction, the reaction mixture was cooled at room temperature and poured into ice-cold water (30mL) with continuous stirring for 20min. The crude products were isolated by extracting with ethyl acetate. The organic phase was separated and washed with brine, dried over sodium sulphate, and evaporated under vacuum to obtain a yellow solid (3a-y). The obtained solid was used without further purification for the next step. It was dissolved in 2-pentanol (10mL), and p-Toluene sulfonic acid hydrate (203mg, 1.17mmol, 1.10eq) was added in one portion to a mixture solution of 2,6-dimethylaniline (129mg, 1.07mmol, 1.00eq). The resulting mixture was then stirred at 125°C for 18h. Once completion of the reaction, the solution was poured into ice-cold water and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to afford the target compounds 5a-y. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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