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CAS No. : | 614-96-0 | MDL No. : | MFCD00005680 |
Formula : | C9H9N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YPKBCLZFIYBSHK-UHFFFAOYSA-N |
M.W : | 131.17 | Pubchem ID : | 11978 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 43.26 |
TPSA : | 15.79 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) : | -5.39 cm/s |
Log Po/w (iLOGP) : | 1.7 |
Log Po/w (XLOGP3) : | 2.41 |
Log Po/w (WLOGP) : | 2.48 |
Log Po/w (MLOGP) : | 1.89 |
Log Po/w (SILICOS-IT) : | 3.06 |
Consensus Log Po/w : | 2.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.84 |
Solubility : | 0.191 mg/ml ; 0.00145 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.38 |
Solubility : | 0.542 mg/ml ; 0.00413 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.63 |
Solubility : | 0.0305 mg/ml ; 0.000232 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
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 |
---|---|---|
92% | Stage #1: at 0℃; for 1 h; Stage #2: at 20℃; for 5 h; Stage #3: With sodium hydroxide In N,N-dimethyl-formamide at 100℃; for 0.166667 h; |
General procedure: Oxalyl chloride (0.3 mL) was added in a drop-wise manner to cooled (ice-bath) DMF (3 mL) under stirring. The mixture was then stirred at 0 °C for 1 h. A solution of the substituted indole (4 mmol) in DMF (1.5 mL) was then added to the reaction mixture in a dropwise manner. The resulting mixture was stirred at room temperature for 5 h. A 2 N solution of sodium hydroxide (2 mL) was then added, and the mixture was heated at 100 °C for 10 min. The mixture was then cooled and extracted with ethyl acetate (3 X 50 mL). The organic layers were combined and washed with sequentially water and brine. The organics were dried (Na2SO4) and distilled to dryness to give the crude residue, which was purified by flash column chromatography using ethyl acetate/petroleum ether (3:1, v/v) as the eluent to give pure indole-3-carbaldehyde (4a-k). |
90% | Stage #1: at 0 - 20℃; for 1.5 h; Stage #2: at 0℃; for 1 h; Heating / reflux |
Example 3; 1. Synthesis of 3-cyanoindole derivatives with a terminal carboxylic acid; A basic synthetic method of a derivative with a terminal carboxylic acid is shown in the following scheme. [Show Image] An objective compound was prepared by (1) formylation of 3-position of the corresponding indole using phosphorus oxychloride in the presence of dimethylformamide (Vilsmeier method), (2) cyanation by dehydrating reaction with hydroxylamine in sodium formate and formic acid, (3) coupling with ethyl 4-fluorobenzoate in the presence of potassium fluoride on almina and 18-crown-5-ether in dimethylsulfoxide and then, (4) hydrolysis with lithium hydroxide in total 4 steps in that order. The results are shown in the following Table 1. In addition, XO-CH146 (R=H) was prepared from the third step using 3-cyanoindole purchased.; 1. Synthesis of XO-CH164 XO-CH155; Under an argon atmosphere, 5-methyl indole (1.04 g, 7.93 mmol) was dissolved in dimethylformamide (10 mL), and to the solution was added dropwise phosphorus oxychloride (2mL) under ice-cooling, and the resulting mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added dropwise an aqueous sodium hydroxide solution (5 g/15 mL) under ice-cooling, and the mixture was heated for reflux for an hour. The reaction mixture was adjusted to pH2 to 3 with concentrated hydrochloric acid under ice-cooling, and then, the solid was collected by filtration and dried at 60°C under reduced pressure to give XO-CH155 as a pale pink solid (1.13 g, 90percent yield). |
74% | at 0 - 40℃; for 1.5 h; | General procedure: Phosphorus oxychloride (0.42 g, 2.74 mmol) was added dropwise to a solution of the indole 5b, 5e–5g (0.30 g, 2.29 mmol) in DMF (0.84 g, 11.4 mmol) at 0 °C for 30 min. The solution was then heated at 40 °C for 1 h. Ice was added to the reaction vessel, followed by a solution of sodium hydroxide (2 M). The solution was refluxed for 40 min. The mixture was cooled and extracted using ethyl acetate, and the organic phase was washed with brine. The organic extracts were combined, dried over Na2SO4, and concentrated. The crude residue was purified by chromatography on a silica gel column using hexane-ethyl acetate as an eluent to obtain the desired product [19]. |
71.5% | Stage #1: at 0℃; for 0.666667 h; Inert atmosphere Stage #2: at 0 - 35℃; for 1.33333 h; Stage #3: With sodium hydroxide In water; N,N-dimethyl-formamide at 100℃; for 0.5 h; Cooling with ice |
General procedure: To a 100 mL three-necked round flask was introduced anhydrous N,N-dimethylformamide (4.2 mL, 34.35 mmol) at 0 °C under argon followed by slow addition of phosphorus oxychloride (1.3 mL, 13.62 mmol). Solution was mixed at 0 °C for 40 min. A solution of 5-methyl-1H-indole (1.627 g, 12.41 mmol) in 2.5 mL of DMF was slowly added maintaining the temperature below 10 °C. The solution was stirred for 40 min at 0 °C and then 35 °C for additional 40 min. Then ice was added to the flask and a solution of sodium hydroxide (5.5 g, 137.25 mmol dissolved in 14.6 mL of water) was introduced using a dropping funnel. Solution was vigorously stirred during the addition, then heated to 100 °C for 30 min and left to reach room temperature. The brown precipitate was filtered off and washed with large volumes of water. The powder was dried in vacuum. Yield 71.5percent. 1H NMR (DMSO-d6, 400 MHz): δ 2.41 (s, 3H), 7.07 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.90 (s, 1H), 8.32 (s, 1H), 9.89 (s, 1H), 12.01 (s, 1H); MS (ESI), m/z: 158.10 [M - H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With water; iodine; oxygen; sodium carbonate In 1,4-dioxane at 100℃; for 36 h; Schlenk technique; Sealed tube | General procedure: Under air, a 20 mL of Schlenk tube equipped with a stir bar was charged with indole 1 (0.2 mmol, 1 equiv),TMEDA (75 µL, 0.5 mmol, 2.5 equiv), Na2CO3 (42.4 mg, 0.4mmol, 2.0 equiv), 1,4-dioxane (0.5 mL) and H2O (100 µL). Then I2 (101.5 mg, 0.4 mmol, 2.0 equiv) was added and the tube was sealed with a rubber plug and charged with O2. The reaction mixture was stirred at 100 °C for 36 h in oil bath. After cooling to room temperature, the resultant mixture was evaporated with EtOAc (20 mL) under reduced pressure and the residue was purified by flash column chromatography on a silica gel to give the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iodine; oxygen; pyrographite In N,N-dimethyl-formamide at 120℃; for 0.8 h; | General procedure: A 50 mL round bottom flask equipped with a magnetic stirring bar was charged with substituted indole 1 (1.0 mmol, 1.0 equiv), HMTA (2.0 mmol, 0.2803 g, 2.0 equiv), activated carbon (0.1 g) and DMF (2 mL). Then I2 (0.2 mmol, 0.0507g, 20 molpercent) was added and the flask was equipped with a reflux condenser. The reaction mixture was stirred at 120 oC under open air and monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The resultant mixture was filtered through a pad of celite and the filter cake was washed thoroughly with EtOAc (4 × 6 mL). The filtrate was washed with 0.5 M aqueous HCl (10 mL), saturated NaHCO3 solution (10 mL) and saturated NaCl solution ( 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with hexane and ethyl acetate to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iron(III) chloride; ammonia In water; N,N-dimethyl-formamide at 130℃; for 1 h; | General procedure: A 50 mL round-bottomed flask equipped with a magnetic stirringbar was charged with the appropriate indole 1 (0.5 mmol,1.0 equiv), 37percent aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25percent aqNH3 (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl3 (0.01 mmol, 0.0016 g,2 molpercent), and DMF (2 mL). The flask was fitted with a reflux condenser,and the mixture was stirred at 130 °C under open air.When the reaction was complete (TLC), the mixture was cooledto r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL),and extracted with EtOAc (3 x 7 mL). The organic layers werecombined, washed with sat. aq NaHCO3 (10 mL) and sat. aq NaCl(10 mL), dried (Na2SO4), and concentrated under reduced pressure.The residue was purified by flash column chromatography(silica gel, hexane–EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97 %Spectr. | With lithium tert-butoxide In N,N-dimethyl-formamide at 100℃; for 24 h; | General procedure: In a dried two-necked test tube was charged with LiOtBu (160 mg, 2.00 mmol) and indole 1a (23.4 mg, 0.4 mmol). The reaction vessel was evacuated under high vacuum and the atmosphere was replace with a balloon of CO2. Then DMF (2 mL) was added and the mixture was stirred for 24 h at 100°C. Then the result mixture was cooled and carefully quenched with a solution of HCl (2 N) and extracted with EtOAc (5x). The combined organic layers were washed with water (2x), brine (1x) and dry over MgSO4. The dried organics were concentrated under reduce pressure and the residue was purified by preparative TLC (hexane:acetone = 1:1) to afford the desired product 2a (153.0 mg, 95percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: Oxalyl chloride (0.3 mL) was added in a drop-wise manner to cooled (ice-bath) DMF (3 mL) under stirring. The mixture was then stirred at 0 C for 1 h. A solution of the substituted indole (4 mmol) in DMF (1.5 mL) was then added to the reaction mixture in a dropwise manner. The resulting mixture was stirred at room temperature for 5 h. A 2 N solution of sodium hydroxide (2 mL) was then added, and the mixture was heated at 100 C for 10 min. The mixture was then cooled and extracted with ethyl acetate (3 X 50 mL). The organic layers were combined and washed with sequentially water and brine. The organics were dried (Na2SO4) and distilled to dryness to give the crude residue, which was purified by flash column chromatography using ethyl acetate/petroleum ether (3:1, v/v) as the eluent to give pure indole-3-carbaldehyde (4a-k). | |
92.07% | Add 30 mL of N,N-dimethylformamide (DMF) to a 250 mL three-necked flask, cool to below 0 C, and slowly add phosphorus oxychloride (6.30 mL, 67 mmol). After the addition is complete, let stand at room temperature and continue to stir. After 30 min, 25 mL of 5-methyl-1H-indole (II-4, 8.00 g, 61 mmol) in DMF was added dropwise in an ice bath. The temperature was controlled below 10 C. After the addition was completed, the temperature was raised to 35 C and stirred for 1 h.The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched by adding 60 g of crushed ice under ice cooling, and then slowly added dropwise.1mol/L NaOH solution, adjust pH=89, and control the temperature in the dropping process to not exceed 40C. After the addition is completed, the mixture is heated to reflux for 1 hour.Stirring was carried out, cooled to room temperature, 55 mL of water was added dropwise, filtered, and the filter cake was washed with water until neutral. After drying, 8.94 g of a pale yellow solid was obtained.III-4, yield 92.07%. | |
90% | Example 3; 1. Synthesis of 3-cyanoindole derivatives with a terminal carboxylic acid; A basic synthetic method of a derivative with a terminal carboxylic acid is shown in the following scheme. [Show Image] An objective compound was prepared by (1) formylation of 3-position of the corresponding indole using phosphorus oxychloride in the presence of dimethylformamide (Vilsmeier method), (2) cyanation by dehydrating reaction with hydroxylamine in sodium formate and formic acid, (3) coupling with ethyl 4-fluorobenzoate in the presence of potassium fluoride on almina and 18-crown-5-ether in dimethylsulfoxide and then, (4) hydrolysis with lithium hydroxide in total 4 steps in that order. The results are shown in the following Table 1. In addition, XO-CH146 (R=H) was prepared from the third step using 3-cyanoindole purchased.; 1. Synthesis of XO-CH164 XO-CH155; Under an argon atmosphere, 5-methyl indole (1.04 g, 7.93 mmol) was dissolved in dimethylformamide (10 mL), and to the solution was added dropwise phosphorus oxychloride (2mL) under ice-cooling, and the resulting mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added dropwise an aqueous sodium hydroxide solution (5 g/15 mL) under ice-cooling, and the mixture was heated for reflux for an hour. The reaction mixture was adjusted to pH2 to 3 with concentrated hydrochloric acid under ice-cooling, and then, the solid was collected by filtration and dried at 60C under reduced pressure to give XO-CH155 as a pale pink solid (1.13 g, 90% yield). |
74% | With trichlorophosphate; at 0 - 40℃; for 1.5h; | General procedure: Phosphorus oxychloride (0.42 g, 2.74 mmol) was added dropwise to a solution of the indole 5b, 5e-5g (0.30 g, 2.29 mmol) in DMF (0.84 g, 11.4 mmol) at 0 C for 30 min. The solution was then heated at 40 C for 1 h. Ice was added to the reaction vessel, followed by a solution of sodium hydroxide (2 M). The solution was refluxed for 40 min. The mixture was cooled and extracted using ethyl acetate, and the organic phase was washed with brine. The organic extracts were combined, dried over Na2SO4, and concentrated. The crude residue was purified by chromatography on a silica gel column using hexane-ethyl acetate as an eluent to obtain the desired product [19]. |
71.5% | General procedure: To a 100 mL three-necked round flask was introduced anhydrous N,N-dimethylformamide (4.2 mL, 34.35 mmol) at 0 C under argon followed by slow addition of phosphorus oxychloride (1.3 mL, 13.62 mmol). Solution was mixed at 0 C for 40 min. A solution of 5-methyl-1H-indole (1.627 g, 12.41 mmol) in 2.5 mL of DMF was slowly added maintaining the temperature below 10 C. The solution was stirred for 40 min at 0 C and then 35 C for additional 40 min. Then ice was added to the flask and a solution of sodium hydroxide (5.5 g, 137.25 mmol dissolved in 14.6 mL of water) was introduced using a dropping funnel. Solution was vigorously stirred during the addition, then heated to 100 C for 30 min and left to reach room temperature. The brown precipitate was filtered off and washed with large volumes of water. The powder was dried in vacuum. Yield 71.5%. 1H NMR (DMSO-d6, 400 MHz): delta 2.41 (s, 3H), 7.07 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.90 (s, 1H), 8.32 (s, 1H), 9.89 (s, 1H), 12.01 (s, 1H); MS (ESI), m/z: 158.10 [M - H]-. | |
General procedure: Phosphorous oxychloride (2 mmol) was added dropwise to dimethylformamide (3 mL) cooled under ice-bath and allowed to stir for 30 min. A solution of indoles 4a-4h or azaindole 5 (1 mmol) in DMF (5 mL) was added dropwise for 5 min at 0 oC. The mixture was further allowed to stir for 3 h at 90-100 oC. Reaction mixture was cooled to room temperature and poured into crushed ice. Excess POCl3 was quenched with 1 N NaOH and left overnight at room temperature. Ice-cold reaction mixture was then extracted (50 mL × 3) with EtOAc. Combined organic layer was concentrated on rotary evaporator and crude products were purified by silica gel (No.100-200) column chromatography to get indole-3-carboxaldehydes 1a-1h or 6 in 60-80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; triethylamine In dichloromethane for 16h; Ambient temperature; | |
96% | Stage #1: 5-methyl-1H-indole; benzoyl chloride With dmap; triethylamine In dichloromethane at 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | 11 To a solution of the 5-methyl-lH-indole (2.6 g, 20 mmol) in anhydrous CH2Cl2 (100 mL) was added benzoyl chloride (2.5 mL, 22 mmol), DMAP (0.25 g, 2 mmol) and Et3N (11.1 mL, 80 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCO3 (100 mL) was added and the organic layer separated. The aqueous was extracted with CH2Cl2 (2 x 30 mL). The combined organic layer was dried (Na2SO4) and concentrated in vacuo to afford the title intermediate (4.5 g, 96%) as a white solid. |
91% | With dmap; triethylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 0 - 20℃; |
81% | With dmap; triethylamine In dichloromethane at 20℃; | |
With aluminum oxide In neat (no solvent) at 100℃; Microwave irradiation; Green chemistry; | ||
With dmap; triethylamine In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | |
98% | Stage #1: 5-methyl-1H-indole With Tris(3,6-dioxaheptyl)amine; potassium <i>tert</i>-butylate In benzene at 20℃; for 2h; Stage #2: methyl iodide In benzene at 20℃; for 1h; | |
98% | Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; | General Procedure 2 General procedure: The indole derivative (1.0 eq.) was dissolved in dry THF (or DMF) and at 0 °C NaH (1.5 eq., 60% dispersion in mineral oil) was added portion wise. After stirring for 30 min at 0°C, the reaction mixture was stirred at ambient temperature for further 30 min. Then methyl iodide / other alkyl halides (1.5 eq.) was added at 0 °C, afterwards the reaction mixture was allowed to warm to room temperature and stirred overnight. After cooling back to 0 °C, it was quenched with water, extracted with EA, the organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified via flash column chromatography (petroleum ether/ethyl acetate, 100:1-50:1) to give the N-alkylated indoles. |
91% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 3.3. General procedure for the preparation of 1-methylindoles General procedure: Indoles were methylated by a similar procedure to that reported in the literature.26 To a stirred suspension of NaH (60% dispersion inmineral oil; 480 mg, 12.0 mmol) in DMF (10 mL) was added dropwise a solution of an indole (10.0 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at room temperature for 30 min. To the mixture was added dropwise iodomethane (d 2.28; 934 mL, 15.0 mmol) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and evaporated to leave a residue, which was purified by column chromatography using the indicated eluent. |
90% | With sodium hydride In tetrahydrofuran for 4h; | |
83% | Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 20℃; Inert atmosphere; | |
75% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; | |
33% | Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Schlenk technique; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Schlenk technique; | |
With sodium hydride 1.) DMF, 0 deg C, 30 min, 2.) DMF, RT, 16 h; Multistep reaction; | ||
With potassium <i>tert</i>-butylate In benzene | ||
With Tris(3,6-dioxaheptyl)amine; potassium <i>tert</i>-butylate In benzene at 20℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With potassium hydroxide In N,N-dimethyl-formamide Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; | ||
With potassium <i>tert</i>-butylate In diethyl ether at 0℃; for 24h; | ||
With potassium <i>tert</i>-butylate In diethyl ether at 0℃; for 24h; | ||
With potassium <i>tert</i>-butylate In diethyl ether at 0℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; | ||
Stage #1: 5-methyl-1H-indole With Tris(3,6-dioxaheptyl)amine; potassium <i>tert</i>-butylate In toluene at 20℃; Stage #2: methyl iodide In toluene at 20℃; | ||
Stage #1: 5-methyl-1H-indole With Tris(3,6-dioxaheptyl)amine; potassium <i>tert</i>-butylate In toluene at 20℃; Stage #2: methyl iodide In toluene at 20℃; | General procedure for the synthesis of 5-substituted-1-methyl-1H-indoles (5b-f). General procedure: To a cold solution of indoles 4b-f (5 mmol) in anhydrous toluene (50 mL), potassium t-butoxide (0.76 g, 6.8 mmol) and tris[2-(2-methoxyethoxy)ethyl] amine (TDA-1) (1 or 2 drops) were added. The reaction mixture was stirred at room temperature for 1-24 h and then methyl iodide (0.31 mL, 5 mmol) was added. TLC analysis (dichloromethane/petroleum ether 9/1) revealed that methylation was complete after 0.5-1 h. The solvent was evaporated under reduced pressure. The residue, treated with water, was filtered off and air dried or extracted with dichloromethane (3 x 15 mL), dried (Na2SO4) and evaporated to afford the pure methyl derivatives 5b-e [28] and 5f (see supplementary material). | |
With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; | ||
With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.333333h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 2h; Inert atmosphere; Stage #2: methyl iodide In dimethyl sulfoxide; mineral oil for 2h; Inert atmosphere; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil Inert atmosphere; | ||
With sodium hydride In N,N-dimethyl-formamide | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; | ||
With potassium hydroxide In dimethyl sulfoxide at 20℃; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; Cooling; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 12h; Cooling; Inert atmosphere; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.25h; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(l) iodide; copper; potassium carbonate at 190 - 210℃; | |
77% | With copper(l) iodide; metformin hydrochloride; caesium carbonate In N,N-dimethyl-formamide at 130℃; for 24h; Inert atmosphere; | 4.2.25. 5-Methyl-1-phenyl-1H-indole (3y). General procedure: 4.2. Experimental procedure for the synthesis of 3: A solution of the indole 1 (1 mmol), aryl halide 2 (1.5 mmol), CuI (0.1 mmol, 10 mol %), metformin hydrochloride (0.2 mmol, 20 mol %), Cs2CO3 (2 mmol, 2 equiv), and DMF (2 mL) was heated to 130 C under N2. The reaction mixture was stirred for the appropriate time (Table 4), and the progress of the reaction was followed by TLC. After completion of the reaction, the mixture was cooled to room temperature, and diluted with EtOAc (10 mL). The solid was removed by filter, and the filtrate was washed with water and brine.The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the product 3. |
73% | With cetyltrimethylammonim bromide; potassium carbonate In water at 110℃; for 10h; | 1 2.3 General experimental procedure for N-arylation reaction General procedure: The catalyst 3 (30 mg, 0.03 mmol of Cu), indole (1.0 mmol), aryl halides (1.2 mmol), K2CO3 (276 mg, 2 mmol), cetyltrimethylammonium bromide (36 mg, 0.1 mmol), and water (3 mL) were added to a reaction vessel. The mixture was stirred at 110 °C for 10 h, then cooled to room temperature and catalyst was filtered, the filtrate was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were extracted with water, saturated brine solution, and dried over anhydrous Na2SO4. The organic layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography by using ethyl acetate/hexane (1:4) as eluent to give the corresponding N-substituted indoles. |
With potassium phosphate; copper(l) iodide In N,N-dimethyl-formamide at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With acetic anhydride; acetic acid; at 20.0℃; for 168.0h; | Acrylic acid (16.5 mL, 240.6 mmol) was added to a solution of 5-methyl-1H-indole (10.5 g, 80.2 mmol) in acetic acid (20 mL) and acetic anhydride (20 mL) and the mixture was stirred at room temperature for 1 week. Aqueous sodium hydroxide (4N, 100 mL) was added and the mixture was washed with ethyl acetate. The aqueous fraction was acidified to pH 1 with hydrochloric acid (5M) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a brown solid (7 g, 43%). H NMR (360MHz, CDCl3) [delta]7.85 (1H, br s), 7.38 (1H, s), 7.24 (1H, d, J 8.3 Hz), 7.02 (1H, dd, J 8.3, 2.3 Hz), 6.97 (1H, d, J 2.3 Hz), 3.09 (2H, t, J 7.6 Hz), 2.76 (2H, t, J 7.6 Hz), and 2.46 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With trimethylamine-N-oxide; In toluene; at 100℃; for 20h;Inert atmosphere; Schlenk technique; | General procedure: In a 2-neck RBF, 1 (20 mg, 0.0005 mmol) and TMNO (45 mg, 0.6 mmol) were suspended in toluene (4 mL) and to this solution indoline (60 mg, 0.5 mmol) was added. The reaction mixture was then heated to 100 oC for 20 h and it was filtered and solvent evaporated. The crude product obtained was purified by column chromatography using hexane/ethylacetate (7:1) as eluent to give pure indole (47 mg, 79%). A similar procedure was used for the other indolines and N-heterocycles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap In acetonitrile at 20℃; | |
100% | With triethylamine In tetrahydrofuran for 48h; Reflux; | |
100% | With dmap In dichloromethane at 20℃; for 6h; | 17.1 t-Butyl 5-methyl-1H-indole-1-carboxylate 5-Methyl-1H-indole (2.0 g, 15.25 mmol), 125 di-t-butyl dicarbonate (4.99 g, 22.88 mmol) and 126 DMAP (93 mg, 0.76 mmol) were dissolved in 29 dichloromethane (100 mL). The reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was diluted with dichloromethane, and it was washed with sat. 127 ammonium chloride followed by brine. The organic layer was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified on an ISCO chromatography (0-30% ethyl acetate/hexane) to give the 128 product as colorless oil (3.53 g, 100%); 1H NMR (300 MHz) (CDCl3) δ 8.02 (d, J=8 Hz, 1H), 7.56 (d, J=3 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J=8 Hz, 1H), 6.50 (d, J=4 Hz, 1H), 2.45 (s, 3H), 1.68 (s, 9H). |
99% | With dmap; triethylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 20℃; for 19h; | |
98% | With triethylamine In tetrahydrofuran for 48h; Reflux; | General procedure for the synthesis of 5-substituted-tert-butyl 1H-indole-1-carboxylates (6a-e). General procedure: Di-tert-butyl dicarbonate (8.73 g, 40 mmol) and triethylamine (3.3 mL, 23.7 mmol) were added to a solution of appropriate indoles 4a-e (20 mmol) in tetrahydrofuran (10 mL). The reaction mixture was heated under reflux for 24-48 h. After cooling the solvent was evaporated under reduced pressure and the residue (derivatives 6a and 6c) was purified by column chromatography using dichloromethane or dichloromethane/petroleum ether (9/1) as eluent or recrystallized with ethanol (derivatives 6b, 6d, 6e). For compounds 6a,c-e see supporting information. Derivatives 6b, 6c and 6e were also reported with a different method [33]. |
97% | With dmap In tetrahydrofuran at 20℃; | |
79% | With dmap In dichloromethane at 20℃; for 14h; Schlenk technique; Inert atmosphere; | |
With dmap In dichloromethane at 20℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With prolinium trifluoromethanesulfonate In lithium hydroxide monohydrate; acetonitrile at 20℃; for 5h; | |
93% | With C40H32N4O7Ti2(2+)*2C8F17O3S(1-) In tetrahydrofuran at 20℃; for 0.416667h; | 1.2 General Procedure for Synthesis of bis(indolyl) methanes: General procedure: A mixture of carbonyl compound (1 mmol), indole (0.234 g, 2 mmol) and 1 (17.7 mg, 1 mmol%) in THF (0.5 mL) was stirred at room temperature for the appropriate reaction time under the TLC analysis until indole was consumed completely. Then the solvents of the resulted mixture were removed by evaporation in vacuum, and the residue was dissolved in diethyl ether (30 mL) followed by filtration. After the catalyst was washed three times with diethyl ether (10 × 3 mL), and the catalyst was used for catalyzing the next cycle of reaction. To the filtrate, after evaporation of the solvent a dark grayish solid mixture was obtained. Purification of the product was performed by a short column chromatography eluted with ethyl acetate/petroleum ether (1:3) to give the desired product. |
91% | With 1-benzyl-[(4S,5S)-4,5-dihydro-4,5-diphenyl]-2-iodo-3-methyl-1H-imidazolium trifluoromethanesulfonate In chloroform at 20℃; for 42h; |
90% | With aluminium potassium sulfate dodecahydrate In lithium hydroxide monohydrate at 80℃; for 0.833333h; | |
88% | With sodium lauryl sulfate In lithium hydroxide monohydrate at 20℃; for 1h; | |
87% | With sulfuric acid In lithium hydroxide monohydrate at 20℃; for 0.0833333h; Green chemistry; | General procedure for the synthesis of 3,3’-diindolylmethanes 8a-8x General procedure: To the stirred mixture of the appropriate indole (3.1-6.7 mmol) and the appropriate aldehyde (1.5-3.3 mmol, 0.5 equiv.) dissolved in water (5 mL) concentrated sulfuric acid (1 equiv.) was added. The progress of the reaction was monitored immediately after the addition of H2SO4 by TLC using ethyl acetate: petroleum ether (20:80). After completion of the reaction as indicated by TLC, the aqueous mixture was dissolved in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting crude product was purified by recrystallization with an appropriate solvent system or by washing it with nonpolar solvents. Few compounds were purified by silica gel column chromatography using non-chlorinated solvent systems such as ethyl acetate: petroleum ether (b.p.42-62 °C) mixtures (10:90 to 20:80) as eluent to afford the pure diindolylmethane derivatives. |
85% | With triphenyl bismuth(V) bisperfluorooctanesulfonate In tetrahydrofuran at 20℃; for 2h; | |
85% | With triphenylbismuth(V) bis(perfluorooctanesulfonate) In tetrahydrofuran at 20℃; for 2h; | 18 Preparation Example 18 In a 50 ml round bottom flask, 0.5 mmol of benzaldehyde, 1.0 mmol of 5-methylindole, 1.05 mmol of catalyst Ph3BiX2 (X=OSO2C8F17), 0.5 ml of THF were added, and the reaction was carried out at room temperature. The reaction was carried out by TLC. reactionCompletely, the solvent was removed, diluted with diethyl ether, filtered, and the ruthenium catalyst was recovered. The filtrate is spun dry to obtain a crude product, which is separated by column chromatography.3,3'-bis(5-methylindenyl)phenylmethane in a yield of 85%. |
83% | Stage #1: benzaldehyde With ferric(III) chloride; 2,2-dimethyl-1,3-dioxane-4,6-dione; ethanol at 80℃; for 7h; Green chemistry; Stage #2: 5-methyl-1H-indole In ethanol at 80℃; for 5h; Green chemistry; | General procedure for the synthesis of bis(indolyl)methanes 3 General procedure: Aromatic aldehydes 1 (0.2 mmol), Meldrum’s acid (0.2 mmol) and Anhydrous FeCl3 (0.02 mmol) were dissolved in ethanol (2 mL). Subsequently, the mixture was stirred in a preheated oil bath at 80 °C for 7 h. Indoles 2 (0.4 mmol) was then added to the reaction system quickly and was stirred at 80 °C for another 5 h. Upon completion, the mixture was cooled to room temperature, diluted with CH2Cl2 (310 mL), and washed with brine. The organic layers were combined, dried over Na2SO4, filtered, and then evaporated in vacuum. The residue was purified by flash column chromatography on silica gel (200-300 mesh), with ethyl acetate and petroleum ether (1:5, v:v) as the elution solvent to give the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran at 0℃; Stage #2: benzenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; | |
92% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In dichloromethane at 0 - 20℃; for 1.5h; | |
88% | Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.5h; Stage #2: benzenesulfonyl chloride In tetrahydrofuran; mineral oil at 20℃; | 68.1 Stage 1: 1-Benzenesulfonyl-5-methyl-1H-indoleA 60% dispersion of sodium hydride in mineral oil (1.55 g, 38.9 mmol) was added at 0° C. within 30 min to a solution of 5-methylindole (5.0 g, 38 mmol) in anhydrous tetrahydrofuran (60 ml). The suspension formed was stirred for 1 h at room temperature, then benzenesulfonyl chloride (6.89 g, 5.0 ml, 38.9 mmol) was added dropwise and the mixture was stirred overnight at room temperature. 5% sodium hydrogen carbonate solution (200 ml) was then added to the reaction mixture and it was extracted with diethyl ether (3×80 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. The crude product (10.4 g) was purified by flash chromatography with ethyl acetate/cyclohexane (1:9).Yield: 9.1 g (88%), light brown oil1H-NMR (DMSO-d6): 2.34 (s, 3H); 6.76 (dd, 1H, J=0.8, 3.7 Hz); 7.13-7.18 (m, 1H); 7.37 (m, 1H); 7.53-7.71 (m, 3H); 7.74 (d, 1H, J=3.7 Hz); 7.81 (d, 1H, J=8.5 Hz); 7.91-7.96 (m, 2H). |
80% | Stage #1: 5-methyl-1H-indole With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: benzenesulfonyl chloride In tetrahydrofuran for 1h; | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: benzenesulfonyl chloride for 2h; | ||
With sodium hydride In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-Methylindole-3-carboxaldehyde 5-Methylindole-3-carboxaldehyde was prepared from 5-methylindole according to the method described in Example 1 to give 2.06 (42%) of the product as a pink solid: mp 148-149 C.; IR numax (Nujol)/cm-13145, 2924, 1639, 1523, 1450, 1133, 805 and 616; NMR deltaH (400 MHz, DMSO-d6) 2.41 (3H, s), 3.32 (3H, s), 7.08 (1H, d, J 6.7 Hz), 7.39 (1H, d, J 8.2 Hz), 7.90 (1H, s), 8.22 (1H, s), 9.90 (1H, s) and 12.01 (1H, br. s); Found: C, 75.24; H, 5.67; N, 8.83%. C10H9NO requires: C, 75.45; H, 5.70; N, 8.97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
a 5-methyl-indole-3-carboxylic acid methyl ester The sub-title compound was prepared in a manner analogous to Example 1a) from 5-methyl-1H-indole. 1H NMR (400 MHz, DMSO-d6): delta11.80 (1H, bs); 8.00 (1H, s); 7.79 (1H, t, J 0.8 Hz); 7.35 (1H, d, J 8.4 Hz); 7.02 (1H, dd, J 8.4 and 1.5 Hz); 3.79 (3H, s); 2.40 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: diethyl benzalmalonate With 1,1-bis[(S)-4-benzyloxazolin-2-yl]-2,2-diphenylethene; copper(II) bis(trifluoromethanesulfonate) In ethanol at 20℃; for 0.5h; Inert atmosphere; Stage #2: 5-methyl-1H-indole In ethanol at 20℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | 4.4. General procedure for asymmetric F-C alkylation of indoles with alkylidene malonates General procedure: To a Schlenk tube Cu(OTf)2 (0.025 mmol) was added, followed by ligand 4b (0.0275 mmol) in the solvent ethanol (1.0 mL) under N2, the solution was stirred for 1.5 h at room temperature, a mixture of diethyl arylidenemalonate (0.25 mmol) in the above solvent (1.0 mL) was added. After stirring for 30 min, indole (0.25 mmol) was added. After stirring for 24-72 h at room temperature, the solution was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel [eluted with ethyl acetate/petroleum ether (1:5, v/v)] to afford the (S)-ethyl 2-ethoxycarbonyl 3-(3-indolyl)-3-arylpropanoate as a white solid. The enantiomeric excesses were determined by HPLC with a chiral column (Daicel Chiralcel OD-H; hexane/iso-propanol 90:10; flow rate 0.8 mL/min; 254 nm). |
99% | With C46H50N4O4S2; copper(II) bis(trifluoromethanesulfonate) In 2-methyl-propan-1-ol at 0℃; Inert atmosphere; Schlenk technique; enantioselective reaction; | |
98% | Stage #1: diethyl benzalmalonate With bis[(S)-4-(isopropyl)oxazoline-2-yl]-2-(thienyl)-ethene; copper(II) bis(trifluoromethanesulfonate) In 2-methyl-propan-1-ol at 0 - 20℃; Inert atmosphere; Stage #2: 5-methyl-1H-indole In 2-methyl-propan-1-ol at 0℃; for 12h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; |
98% | Stage #1: diethyl benzalmalonate With (3aR,8aS)-2-(3-(3,5-di-tert-butylphenyl)-2,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)propyl)-8,8a-dihydro-3aH-indeno[1,2-d]oxazole; copper(II) bis(trifluoromethanesulfonate) In iso-butanol at -25℃; for 0.25h; Stage #2: 5-methyl-1H-indole In iso-butanol at -25℃; optical yield given as %ee; enantioselective reaction; | |
91% | With copper(II) trifluoromethanesulfonate complex with 4-[(4S,4'S)-2,2'-bis(4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl)propyl]-1H-1,2,3-triazol-1-ylmethylpolystyrene In tetrahydrofuran; ethanol at -30℃; for 504h; enantioselective reaction; | Reaction of indoles with benzylidenemalonates (general procedure). General procedure: A solution of 1 mmol of benzylidenemalonate 2a-2d and 2 mmol of indole 1a-1f in 4 mL of THF-EtOH (1 : 1) was cooled to -30°C, 200 mg (10 mol %) of Cu(OTf)2*L3 was added, and the mixture was stirred for 21 days at -30°C. When the reaction was complete (TLC, CH2Cl2-petroleum ether, 1 : 1), the catalyst was filtered off and washed with THF (5 × 10 mL) and methylene chloride (2 × 10 mL). The filtrate was evaporated, and the product was isolated by column chromatography using methylene chloride-petroleum ether (1 : 3 to 1 : 1) and then pure methylene chloride as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With perchloric acid adsorbed on silica gel; anthranilic acid amide; In acetonitrile; at 80℃; for 6h; | General procedure: Solid acid catalyst (50% w/w) was added to the solution of indole-3-carboxaldehydes 1a-1h or azaindole-3-carboxaldehyde 6 (1 mmol) and anthranilamide 2a (1 mmol) in acetonitrile (6 mL). The reaction mixture was allowed to stir for 6-24 h at room temperature or at reflux temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, it was allowed to cool and catalyst was recovered by filtration. The filtrate was concentrated to get crude products which after silica gel (No.100-200) column chromatography gave deformylated products 4a-4h or 5 in 25-90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dodecacarbonyl-triangulo-triruthenium; In toluene; at 120℃; for 12h;Schlenk technique; Inert atmosphere; | General procedure: Condition A: A mixture of 33 indole (1) (0.2mmol, 1 equiv), hydrosilane (2) (0.3mmol, 1.5 equiv), 16 Ru3(CO)12 (1.9mg, 0.003mmol, 1.5mol %), were weighted in a Schlenk tube equipped with a stir bar. Dry 11 toluene (2.0mL) was added and the mixture was stirred at 120C for 12h under Ar atmosphere. Afterwards, it was diluted with CH2Cl2 and transferred to a 50mL round bottom flask. Silica was added to the flask and solvents were evaporated under reduced pressure. Flash column chromatography on silica gel with EtOAc:petroleum ether=1:100 as eluent afforded the 47 N-silylated indole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20%; 30% | With iodine; In 1,2-dichloro-ethane; at 80℃; for 18h; | General procedure: To a mixture of piplartine (1 mmol) and Indole (3 mmol), Iodine (10 mol %) was added. The contents were refluxed in dichloroethane (5 mL) for an appropriate time (12-48 h) and reaction was monitored by thin-layer chromatography (TLC). After complete conversion, the solvent was evaporated, and the product was washed with hypo solution (10 mL), and then extracted with chloroform. The combined organic layers was dried over anhydrous sodium sulphate and evaporated under reduced pressure, purified by silica-gel column chromatography to afford pure product mono-adduct (2a-2k) and di-adduct (3a-3k). |
With iodine; In 1,2-dichloro-ethane; for 38h;Reflux; | Experimental Procedure for (2k & 3k); To a mixture of piplartine (0.317 g, 1 mmol) and 5-methylindole (0.393 g, 3 mmol), Iodine (0.0127 g, 10 mol %) was added. The contents were refluxed in 1,2-dichloroethane (5 ml) for an appropriate time (38 h). The reaction was monitored by thin-layer chromatography (TLC). After complete conversion, the solvent was evaporated, and the product was washed with saturated hypo solution (10 ml), and then extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulphate and evaporated using rotary evaporator, purified by silica-gel (60-120 mesh) column chromatography by Ethylacetate:Hexane (4:6) to afford pure product mono adduct (2k) and di adduct (3k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With iodine In ethanol at 20℃; for 12h; | Typical experimental procedure for the iodine-promoteddirect 3-selanyl- and 3-sulfenylation of indoles withdichalcogenides General procedure: indole (0.5 mmol), disulfide (0.28 mmol), I2 (0.25 mmol), and EtOH (3 mL) were added to a Schlenk tube or round-bottomed flask and stirred at room temperature for 12 h. After the reaction was finished, the reaction mixture was washed with sodium thiosulfate. Then the mixture was extracted with ethyl acetate.The combined organic extracts were dried over Na2SO4, concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to afford the desired product. Complete characterization of the products and selected 1Hand 13C NMR spectra for 3, 4, and 5 are presented in the Supplemental Materials (Figures S1-S6) |
95% | With sodium tetrafluoroborate; potassium iodide In acetonitrile at 60℃; for 12h; Electrolysis; | Electrosynthesis of 3-sulfenylindoles General procedure: The electrochemical experiment was performed on 263A Potentiostat/Galvanostat (PrincetonApplied Research, USA) in a 25 mL undivided cell. Two graphite rods(6mmin diameter, 1 cm in length) were employed as the working electrode and the counter electrode respectively. The reference electrode was Ag/Ag+ electrode (0.1 mol/L AgNO3 in CH3CN). 2-Methylindole(1a, 1.0 mmol), diphenyl disulfide (2a, 0.5 mmol) and KI (0.05 mmol) were added into 0.1 mol/L of NaBF4/CH3CN solution (15 mL)with stirring at 60°C. The electrolysis reactions were operated at 0.4V. After completion of the reaction (monitored by GC or TLC), the resulting mixture was concentrated under reduced pressure and purified by column chromatography on silica gel using hexanes/EtOAc(100:1) as eluent to afford 2-methyl-3-(phenylthio)-indole (3aa) as a white solid in 94% yield. |
95% | With sodium tetrafluoroborate; potassium iodide In acetonitrile at 60℃; for 12h; Electrochemical reaction; | 36 Example 36: Preparation of 5-methyl-3-phenylthio-1H-indole (Formula 21) Add in a 30ml beaker 0.1 mol/L sodium tetrafluoroborate in acetonitrile (15 mL), 5-methyl-1H-indole (1 mmol), diphenyl disulfide (0.5 mmol) and potassium iodide (0.05 mmol). Constant potential electrolysis at 60 ° C, 0.4 V, and the reaction was completed after 12 h. The solvent is distilled off under reduced pressure, and then subjected to column chromatography, and the mixture of ethyl acetate/n-hexane volume ratio of 1:100 is used as an eluent, and the eluent containing the target compound is collected, and the solvent is distilled off to obtain the product 5-Methyl-3-phenylthio-1H-indole. The isolated yield was 95%. |
93% | With potassium carbonate In dimethyl sulfoxide at 100℃; for 9h; Green chemistry; | |
92% | With N-Bromosuccinimide In N,N-dimethyl-formamide at -10℃; for 2h; regioselective reaction; | |
64% | With sodium iodide In acetonitrile at 20℃; for 18h; Irradiation; | Preparation of the benzothiazole 3a General procedure: To a 20 mL glass tube with a stir bar was charged 2-methyl-1H-indole 1a (39.35 mg, 0.3 mmol), diphenyldisulfide 2a (65.50 mg, 0.3 mmol), NaI (0.06 mmol, 9 mg) and MeCN (2 mL). The solution was stirred at room temperature with the irradiation of a 12 W blue LED for 18 h. The solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate = 15/1) to give the product 3a (60 mg, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97%Spectr. | With lithium tert-butoxide; In N,N-dimethyl-formamide; at 100℃; under 760.051 Torr; for 24.0h; | General procedure: In a dried two-necked test tube was charged with LiOtBu (160 mg, 2.00 mmol) and indole 1a (23.4 mg, 0.4 mmol). The reaction vessel was evacuated under high vacuum and the atmosphere was replace with a balloon of CO2. Then DMF (2 mL) was added and the mixture was stirred for 24 h at 100C. Then the result mixture was cooled and carefully quenched with a solution of HCl (2 N) and extracted with EtOAc (5x). The combined organic layers were washed with water (2x), brine (1x) and dry over MgSO4. The dried organics were concentrated under reduce pressure and the residue was purified by preparative TLC (hexane:acetone = 1:1) to afford the desired product 2a (153.0 mg, 95%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 5h; | 49 Synthesis of compound (III-8): 0.131g (1mmol) of 5-methylindole (purchased from Beijing Bailingwei Technology Co., Ltd.) was dissolved in 2ml of anhydrous DMF, and 0.044g (1.1mmol) was added at 0°C for hydrogenation Sodium (60%, dispersed in mineral oil). The reaction was warmed to room temperature and stirred for 30 minutes. After 30 minutes, 0.137g (1.2mmol) of 2-chloropyrimidine was added, and the reaction was heated to 130°C for 5.0 hours. The reaction was followed by TLC. The indole spot disappeared and the reaction was complete. 10ml of saturated aqueous sodium chloride solution was added, the solid was separated out, the solid was collected by suction filtration, and dried to obtain 0.199 g of compound (III-8) with a yield of 95.2%. |
90% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Sealed tube; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 0 - 130℃; for 24h; Inert atmosphere; Sealed tube; | |
84% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide at 0 - 130℃; | 3.1 1.Synthetic compound (3-1) Add 5-methylindole (5mmol), DMF (10mL) and NaH (5mmol) into a 25mL reaction flask.The reaction mixture was stirred at 0°C for 10 minutes, and then 2-chloropyrimidine (6 mmol) was added, and then the temperature was raised to room temperature to 130°C for reaction. TLC detected until the reaction was complete.Perform post-treatment and purification: add water (20 mL) for quenching, extract with EA (20 mL×3), combine the organic phases, and wash with saturated NaCl (20 mL×2).After separation, dry with anhydrous magnesium sulfate, remove the organic solvent under reduced pressure, and separate and purify by silica gel column chromatography [V (petroleum ether): V (ethyl acetate) = 15:1] to obtain a pure product, a white solid , Yield: 84%. |
76% | Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 100℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; Schlenk technique; | General procedure for synthesis of N-pyrimidyl indoles1 General procedure: NaH(60% dispersion in mineral oil, 3.6 mmol) was added in portions at 0 °C to a stirred solution of indole (3.0 mmol) in DMF (10 mL). After stirring for 30 min at 0°C, chloropyrimidine(3.6 mmol) was added and the mixture was stirred at 130 °C for 4-24 h. Then,the reaction mixture was cooled to ambient temperature, poured into H2O(20 mL) and extracted with EtOAc (25 mL×2). The combined organic phase was dried over Na2SO4. After filtration and evaporation ofthe solvents under reduced pressure, the crude product was purified by column chromatography on silica gel to afford the corresponding product. | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.666667h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 0 - 130℃; for 24h; | 2. General procedure for synthesis of the starting materials (1a-m) General procedure: NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was added in portions at 0 °C to a stirred solution of indole (5.0 mmol) in DMF (8.0 mL). After stirring for 40 min at 0 °C, 2-chloropyrimidine (687.18 g, 6.0 mmol) was added and the mixture was stirred at 130 °C for 24 h. The reaction mixture was cooled to ambient temperature, quenched with H2O (90 mL) and then extracted with EtOAc (3×30 mL). The combined organic phase was dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was directly purified by column chromatography on silica gel (with EtOAc/petroleum) to get the corresponding product.1 | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.666667h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | 6 In the reaction vessel, 5-methyl indole (6mmol, 787.08mg), NaH (content 60%, 9mmol, 360mg) for 40 minutes, DMF solvent, low temperature; then 2-chloropyrimidine (7.2mmol , 824.616g), after the mixture was reacted at 130 24 hours, cooled to room temperature, the solvent was removed by extraction, separation by column to give compound 5-methyl-1- (pyrimidin-2-yl) lH-indole reactants | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 20℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | 3 Take 100 ml round-bottom flask and moderate in magnitude of the magneton, weighing 5 - methyl - 1H - indole (5mmol, 755 mg) is dissolved in N, N - dimethyl formamide (DMF) in, and placed in the ice water bath slowly adding NaH (mass fraction of 60%, 7 . 5mmol, 300 mg) to pulls out the hydrogen reaction, under low temperature conditions the reaction 1 hours, then adding 2 - chloro pyrimidine (7.5mmol, 855 mg), the mixture 130 °C reaction under 24 hours, 24h through the TLC monitoring completion of the reaction, ethyl acetate after dilution for transfer to 250 ml separatory funnel, water washing three times, after cleaning DMF, collecting the organic phase with anhydrous sodium sulfate removal, pressure reducing and steaming and removing the organic solvent to obtain the crude product, through the column chromatography (ethyl acetate: petroleum ether=2:95) to obtain the product 5 - methyl - 1H - (pyrimidine -2 - yl) - 1H - indole reactants. For thousand electronic balance accurate weighing 5 - methyl - 1H - (pyrimidine -2 - yl) - 1H - indole reactant (0.2mmol, 41.8 mg), transfer to the 25 ml pressure tube, to the reaction in the container adding PdCl2(CH3CN)2(20 µM %, 10.4 mg), Cs2CO3(0.04mmol,13mg), AgSbF6(0.02mmol,7mg), Al2O3(0.2mmol, 20.4 mg), dropping 2 ml 1, 4 - dioxane solvent in thick-walled pressure tube, and finally adding three ISO propyl silicon-based acetylene bromine (0.3mmol, 73 μl), the reaction of the reaction system is screwed plug sealing, heating to 120 °C, oil bath under the stirring condition of reaction 15h. After the reaction, the reaction is cooled down to the room temperature, using a short silica gel column to remove some of the metal impurities in the preliminary purification, steaming and the solvent is removed under reduced pressure to get the crude product, the crude product is carried out column chromatography (eluant: ethyl acetate/petroleum ether=1:99), get the pure dry product, yield 61%. | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; Inert atmosphere; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide at 130℃; for 26h; | 3 A 100 mL round-bottomed flask and a magnet of moderate size were taken and 5-methyl-1H-indole (5 mmol, 755 mg) was dissolved in N, N-dimethylformamide (DMF) Slowly add NaH (mass fraction 60%, 7.5 mmol, 300 mg) for hydrogen extraction reaction in an ice-water bath. After 1 hour of reaction, transfer to a 130 °C. oil bath. After 26 h, the reaction was completed by TLC. After dilution with ethyl acetate Transferred to a 250 mL separatory funnel and washed three times with water. After washing the DMF, the organic phase was collected and washed with anhydrous sodium sulfate. The crude product was removed by rotary evaporation under reduced pressure and the residue was purified by column chromatography (ethyl acetate: petroleum Ether = 2:95) to give the product 5-methyl-1H- (pyrimidin-2-yl) -1H-indole. The 5-methyl-1H- (pyrimidin-2-yl) -1H-indole reactant (0.31 mmol, 62.7 mg) was accurately weighed with a one-thousandth electronic balance and transferred to a thick-walled pressure- , Adding PhI (OAc) 2 (3eq, 289.5mg) to the reaction vessel dropwise with acetic acid / acetic anhydride = 7/3 mixed solvent, tightening the reaction tube stopper to make the reaction system sealed, heating to 60 °C, Reaction 36h. After the reaction was completed, the reaction solution was cooled to room temperature, a short silica gel column was used to remove some metal impurities for preliminary purification, the solvent was extracted and the solvent was removed, and the solvent was distilled off under reduced pressure to give a crude product. The crude product was subjected to column chromatography Demulsifier: ethyl acetate / petroleum ether = 15: 75) to give pure and dry product in 70% yield. | |
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; Inert atmosphere; Schlenk technique; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 0 - 130℃; for 24h; | ||
Stage #1: 5-methyl-1H-indole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide for 24h; Inert atmosphere; Schlenk technique; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydroxide In water; isopropyl alcohol at 130℃; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium iodide In acetonitrile at 20℃; for 0.666667h; Electrolysis; | |
91% | With Graphene oxide In 1,2-dichloro-ethane at 20℃; for 12h; Irradiation; Schlenk technique; Green chemistry; | 3.2. General Procedure of the Products 6 General procedure: In a 10 mL Schlenk tube, indole (0.3 mmol), GO (17.6 mg), and thiol (0.36 mmol) werestirred in DCE (1 mL) for 12 h at room temperature under an air atmosphere irradiated byblue LEDs. The reaction mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:10) to yield thecorresponding product. |
88% | With iridium(III) bis[2-(4,6-difluorophenyl)pyridinato]picolinate In acetonitrile at 25℃; Irradiation; Green chemistry; |
83% | With Rose Bengal lactone In acetonitrile at 20℃; for 6h; Schlenk technique; Irradiation; | |
76% | With iodine; dimethyl sulfoxide In neat (no solvent) at 80℃; for 0.0833333h; Microwave irradiation; Sealed tube; Green chemistry; | |
61% | With 3-chloro-benzenecarboperoxoic acid; sodium bromide In acetonitrile at 20℃; for 24h; regioselective reaction; | A typical procedure for the preparation of 3-selenylindoles General procedure: Indoles 1 (0.2 mmol), diselenides 2 (0.11 mmol), NaBr (0.1 mmol) and mCPBA (0.24 mmol) were added successivelyto MeCN (3 mL). The suspension was vigorously stirred at r. t. for 24 h. Upon completion, the reaction was quenched by additionof sat. aq. Na2S2O3 (2 mL), and then sat. aq. Na2CO3 (8 mL) and H2O (5 mL) were added, respectively. The mixture was extracted with CH2Cl2 (3 × 5 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was finally purified on a silica gel plate (5:1 petroleum ether-ethyl acetate) to furnish products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis(1,5-cyclooctadiene)diiridium(I) dichloride; sulfuric acid; In water; acetonitrile; at 50℃; for 5h;Inert atmosphere; Schlenk technique; | General procedure: A N2 purged flame-dried Schlenk tube containing indole 1(0.200 mmol), [Ir(COD)Cl]2 (0.004mmol), were added successively CH3CN (1 mL), allylic alcohol 2(0.200 mmol) and H2SO4(1 M inH2O)(0.010 mmol) via syringe. The reaction mixture was stirred at 50 C for 5 h. After thereaction was complete, the solvent was removed under reduced pressure. The ratio ofregioisomers(branched/linear) was determined by 1H NMR of the crude reaction mixture. Thecrude residue was purified by flash column silica gel chromatography (petroleum ether/ ethylacetate: 95:5 to 90:10) to yield the product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2,2'-iminobis[ethanol]; In water; at 20℃;Green chemistry; | General procedure: To the reaction mixture containing isatin (0.5mmol) in water (2mL), indole (0.5mmol), diethanolamine (20mol %) was slowly added at room temperature. After thecompletion of reaction as monitored by TLC, the reaction mixture was washed with brine solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the product was purified by flash chromatography on the silica gel column using a gradient of petroleum ether/ethyl acetate, as eluent to afford pure products 1-41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With water; iodine; oxygen; sodium carbonate; In 1,4-dioxane; at 100℃; under 760.051 Torr; for 36h;Schlenk technique; Sealed tube; | General procedure: Under air, a 20 mL of Schlenk tube equipped with a stir bar was charged with indole 1 (0.2 mmol, 1 equiv),TMEDA (75 muL, 0.5 mmol, 2.5 equiv), Na2CO3 (42.4 mg, 0.4mmol, 2.0 equiv), 1,4-dioxane (0.5 mL) and H2O (100 muL). Then I2 (101.5 mg, 0.4 mmol, 2.0 equiv) was added and the tube was sealed with a rubber plug and charged with O2. The reaction mixture was stirred at 100 C for 36 h in oil bath. After cooling to room temperature, the resultant mixture was evaporated with EtOAc (20 mL) under reduced pressure and the residue was purified by flash column chromatography on a silica gel to give the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; chloropyridinecobaloxime(III) In acetonitrile at 20℃; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 3h; | |
52% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: A heterogeneous mixture of <strong>[521-73-3]isoquinoline-1,3,4-trione</strong>(17.5 mg, 0.1 mmol), indole (14.0 mg, 0.12 mmol) and alginic acid (1.76 mg,0.01 mmol, purchased from Sigma Aldrich) in H2O (0.2 mL) was stirred for 24 h(monitored by TLC). Afterwards, the reaction mixture was concentrated under reduced pressure to leave the crude residue which was purified by column chromatography over silica-gel using ethyl acetate/hexane as a mixture of solvent to give the pure compound 3aa in75% yield (21.9 mg) as a white solid.4-Hydroxy-4-(1H-indol-3-yl)isoquinoline-1,3(2H,4H)-dione (3aa): yield 75%; mp:188-190 C; Rf = 0.25 (EtOAc/hexane = 1:3); 1H NMR (400 MHz, acetone-d6) d10.24 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.14 (d, J = 7.8 Hz, 1H), 7.89 (d,J = 7.8 Hz, 1H), 7.76-7.79 (m, 2H), 7.59-7.63 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H),7.06-7.10 (m, 1H), 6.96-7.00 (m, 1H), 6.65-6.66 (m, 1H), 5.66 (br s, 1H, OH); 13CNMR (100 MHz, acetone-d6) d 175.0 (CO), 164.7 (CO), 144.3, 138.0, 134.7,129.2, 128.2, 127.9, 125.8, 125.8, 124.8, 122.6, 122.4, 121.7, 120.1, 112.4, 74.7(C-4, quaternary); HRMS (ESI) m/z calcd For C17H12N2O3 [M+Na]+: 315.0897.Found 315.0953. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With manganese(IV) oxide; iodine; oxygen at 80℃; for 16h; Schlenk technique; | |
89% | With Graphene oxide In 1,2-dichloro-ethane at 20℃; for 12h; Irradiation; Schlenk technique; Green chemistry; | 3.2. General Procedure of the Products 6 General procedure: In a 10 mL Schlenk tube, indole (0.3 mmol), GO (17.6 mg), and thiol (0.36 mmol) werestirred in DCE (1 mL) for 12 h at room temperature under an air atmosphere irradiated byblue LEDs. The reaction mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:10) to yield thecorresponding product. |
85% | With tetrasodium cobalt(II) 4,4',4'',4'''-tetrasulphophthalocyanine; oxygen In water at 100℃; for 15h; Schlenk technique; |
63% | With iodine In acetonitrile at 80℃; for 16h; regioselective reaction; | 2.2 General Procedure for Regioselective Synthesisof 3-Thioindoles Under Air General procedure: Acetonitrile (2 mL) was added into a mixture of indoles 1 (0.25 mmol), thiols 2 (0.375 mmol) and I2 (5 mol %) in a 25 mL round-bottomed flask at room temperature under air. The reaction vessel was allowed to stir at 80 °C for 16 h. After the reaction, the solvent was then removed under vacuum. The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to give the desired 3-thioindoles 3. The characterization of the corresponding products wasshown in Supporting Materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tin(II) trifluoromethanesulfonate In acetonitrile at 20℃; for 2h; | Typical Experimental Procedure for 4aa General procedure: A mixture of indole 1a (50 mg, 0.427 mmol), pentafulvene 3a(147 mg, 0.640 mmol), aldehyde 2a (70 mg, 0.640 mmol), andSn(OTf)2 (4 mg, 0.008 mmol) were weighed in to a reaction tubeand dry MeCN (2 mL) was added and allowed to stir at r.t. for 2h. The solvent was evaporated in vacuo and the residue on silicagel (100-200 mesh) column chromatography with mixture ofhexane-EtOAc yielded the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iodine; oxygen; pyrographite; In N,N-dimethyl-formamide; at 120℃; for 0.8h; | General procedure: A 50 mL round bottom flask equipped with a magnetic stirring bar was charged with substituted indole 1 (1.0 mmol, 1.0 equiv), HMTA (2.0 mmol, 0.2803 g, 2.0 equiv), activated carbon (0.1 g) and DMF (2 mL). Then I2 (0.2 mmol, 0.0507g, 20 mol%) was added and the flask was equipped with a reflux condenser. The reaction mixture was stirred at 120 oC under open air and monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The resultant mixture was filtered through a pad of celite and the filter cake was washed thoroughly with EtOAc (4 × 6 mL). The filtrate was washed with 0.5 M aqueous HCl (10 mL), saturated NaHCO3 solution (10 mL) and saturated NaCl solution ( 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with hexane and ethyl acetate to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With bis(trichloromethyl) carbonate; In acetonitrile;Schlenk technique; Inert atmosphere; | General procedure: A 10 mL Schlenk tube equipped with a magnetic stirring barwas charged with RSO2Na (0.4 mmol) and the appropriateindole or N-methylpyrrole (0.2 mmol). The tube was then evacuatedand backfilled with dry N2 (this operation was repeatedthree times), and the mixture was stirred at -78 C for theinitial time. A solution of triphosgene (0.4 mmol) in MeCN (1mL) was added slowly from a syringe, and the mixture wasstirred at -78 C for 1 h. When the reaction was complete, themixture was warmed to rt and diluted with CH2Cl2 (20 mL). Themixture was then washed with 5% aq NaHCO3 (10 mL), and thecombined organic phase was dried (Na2SO4) and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(II) bis(trifluoromethanesulfonate); 2,2'-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] In dichloromethane at -30 - 0℃; for 168h; Overall yield = 44 %; Overall yield = 77 mg; Optical yield = 60 %ee; enantioselective reaction; | Reaction of Indole with Coumarin-3-carboxylate; General Procedure General procedure: A solution of t-Bu-BOX ligand (14.7 mg, 0.05 mmol, 10 mol%) and Cu(OTf)2 (18.1 mg, 0.05 mmol, 10 mol%) in CH2Cl2 (0.5 mL) was stirred for 1 h and was cooled to -30 °C. A mixture of coumarin-3-carboxylate (0.5 mmol) and indole (1 mmol) was added and the mixture was kept at -30 °C for 2 days and at 0 °C for 5 days. The mixture was diluted in EtOAc (50 mL), washed with NH4Claq (2 × 10 mL), and dried over Na2SO4. The mixture was filtered and concentrated in vacuo. The products were purified by column chromatography (petroleum ether/CH2Cl2, 1:1 then CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iron(III) chloride; ammonia; In water; N,N-dimethyl-formamide; at 130℃; for 1h; | General procedure: A 50 mL round-bottomed flask equipped with a magnetic stirringbar was charged with the appropriate indole 1 (0.5 mmol,1.0 equiv), 37% aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25% aqNH3 (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl3 (0.01 mmol, 0.0016 g,2 mol%), and DMF (2 mL). The flask was fitted with a reflux condenser,and the mixture was stirred at 130 C under open air.When the reaction was complete (TLC), the mixture was cooledto r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL),and extracted with EtOAc (3 x 7 mL). The organic layers werecombined, washed with sat. aq NaHCO3 (10 mL) and sat. aq NaCl(10 mL), dried (Na2SO4), and concentrated under reduced pressure.The residue was purified by flash column chromatography(silica gel, hexane-EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 3,4-dihydroisoquinoline With methanesulfonic acid In water for 0.166667h; Green chemistry; Stage #2: 5-methyl-1H-indole With tetra-(n-butyl)ammonium iodide In water at 60℃; for 18h; Green chemistry; | 2. General procedure for the Mannich reaction General procedure: To a solution of methanesulfonic acid (0.33 mmol) in water (5 mL) was added imine 1 (0.4 mmol) under vigorous stirring. After stirring for 10 min, TBAI (0.1 mmol) and the corresponding indole (0.33 mmol) were added. The reaction mixture was stirred at 60 °C to complete the transformation (TLC monitoring). After that the reaction mixture was quenched with saturated NaHCO3 (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography silica gel plate to afford target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34%Chromat. | With triethylamine; In dimethyl sulfoxide; at 80℃; for 0.75h;Microwave irradiation; Green chemistry; | General procedure: Indole (0.35 mmol, 1 eq.), trifluoroacetaldehyde methylhemiacetal (270 μL, 7eq.), triethylamine (7 μL, 10 mol %), and DMSO (0.5 mL) were mixed together in a microwave vial (10 mL). Thesolution was irradiated in the microwave reactor at 80C for 45 min. After cooling to room temperature thereaction mixture was diluted with 2 mL of dichloromethane and washed with water (3x 5 mL). The solvent wasevaporated under vacuum and the crude product was purified by preparative thin layer chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With water; In hexane; dichloromethane; at 60℃; for 8h;Inert atmosphere; Sealed tube; | General procedure: A microwave vial was charged with the indole (0.25 mmol, 1 eq.) and the correspondingvinyl boronic acid (0.625 mmol, 2.5 eq.). The flask was flushed with argon and sealed.The degassed solvent was added (2.5 mL) followed by the addition of water (3 mmol, 1.2eq.). Next, a 2 M TMSCHN2 solution in n-hexanes was added (1.25 mmol, 5 eq.) undervigorous agitation. The final mixture was heated at 60 C for 8 h in a Biotage Initiatormicrowave reactor, or in a sand-bath at 60 C when specified. The reactions wheremonitored by TLC analysis and quenched in methanol when the reaction was completedor when no more conversion was observed. The volatiles were removed under reduced pressure and the residue obtained was purified by flash column chromatography usingpetroleum ether/ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide; at 100℃; for 6h;Sealed tube; | The preparation method of the compound e29 comprises the steps of: taking about 1 mmol of 7-chloro-5-methyl-[1,2,4]triazole and[1,5-a]pyrimidine and about 3 mmol5-methyl-1H-indole was added to a 10 mL microwave reaction tube,Further, 2 mL of hexafluoroisopropanol solvent and about 0.1 mmol of bistrifluoromethanesulfonimide catalyst were added, sealed and heated to 100 C with stirring and reacted for about 6 h.Then, the reaction system was monitored by TLC, and after the reaction system was cooled to room temperature, it was separated and purified by column chromatography to obtain pure compound e29.The compound e29 is a brown solid with a yield of 65%. |
65% | With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide; at 100℃; for 6h;Microwave irradiation; Sealed tube; | Adding 85 mg (about 0.5 mmol) to a 10 mL microwave reaction tube.<strong>[24415-66-5]7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine</strong> and 197 mg (about 1.5 mmol) of 5-methylindole,14 mg (about 10 mol%) of the catalyst bistrifluoromethylsulfonimide and 1 mL of the solvent HFIP, and then the microwave reaction tube was sealed.Then, the reactant in the microwave reaction tube was stirred at 100 C for 6 hours, and the solvent was distilled off under reduced pressure.And purified by column chromatography using DCM/MeOH as eluent to give about 86 mg of pure product e10 as a brown solid, yield 65%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With toluene-4-sulfonic acid; In ethanol; for 24h;Reflux; | o-Methylaminobenzaldehyde (0.5 mmol) was dissolved in an appropriate amount of ethanol, followed by 5-methylindole (0.5 mmol) and p-toluenesulfonic acid (0.5 mmol), and heated to reflux for 24 h.After cooling to room temperature, the pH was adjusted to basic with a NaOH (1 M) solution, followed by extraction with dichloromethane for 3 times.The organic phase was collected and dried over anhydrous magnesium sulfate.An orange-red solid is obtained, the target compound ZXD1 (for synthesis, see literature: Chemical Science, 2011, 2, 2178-2181).Orange-red solid; Yield: 62%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With trifluorormethanesulfonic acid; 1,1,1,3',3',3'-hexafluoro-propanol; at 60℃; for 24h; | General procedure: To a stirred solution of chloropurine 1 (0.50 mmol) in hexafluoroisopropanol (5 mL), aromaticnucleophile 2 (0.55 mmol, 1.1 equiv) and trifluoromethanesulfonic acid (TfOH, 44 L, 0.5 mmol, 1 equiv)were successively added. The resulting mixture was stirred at 60 C for 24 h. After completion of thereaction checked by TLC, the reaction mixture was poured into sat. NaHCO3 aqueous. The resultantsolution was extracted with ethyl acetate, dried with solid sodium sulfate, and then concentrated. Theresidue was puried by short-column chromatography on silica gel using hexane-ethyl acetate as theeluent to give the purine aromatic-linked compound 3 in the indicated yield in Table 2 or Scheme 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With bis(trimethylsilyl)amide yttrium(III); 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; In toluene; at 120℃; for 36h;Inert atmosphere; | Under nitrogen protection, 0.5 mmol of raw <strong>[3484-35-3]5-methyl-2-indolinone</strong>, 1.2 mmol of pinacol borane and catalyst Y [N(SiMe3) 2] 30.05 mmol, 3 mL of toluene, reacted at 120 C for 36 h, and the product isolation yield was 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N,N’-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea at 20℃; | 2.2 General procedure for Thiourea catalyzed 1,6-conjugate addition of indoles to p-QMs General procedure: To a magnetically stirred solution of corresponding p-QMs 1 (0.2 mmol, 1.0 eq.) and corresponding indole 2 compound in anhydrous CH2Cl2 or THF (2 mL) was added thiourea catalyst C1 (10 mol% ) and stirred at room temperature for 24-60 h until the reaction was completed (monitored by TLC). Evaporation of the solvent under reduced pressure and further purification of the residue by flash chromatography on silica gel (petro ether / EtOAc) furnished the corresponding product 3. |
91% | With phosphoric acid In water monomer at 100℃; for 9h; Schlenk technique; Inert atmosphere; | 3 Example 3 26.2 mg (0.2 mmol) 5-methylindole, 58.8 mg (0.2 mmol) 4-phenylmethylene-2,6-di-tert-butyl-2,5-cyclohexadien-1-one,Phosphoric acid (0.04 mmol) and 1.0 mL of water were added to the Schlenk tube under a nitrogen atmosphere, and the reaction was stirred at 100 oC for 9 hours.After the completion of the reaction, it was separated and purified by column chromatography, and the yield of the target product was 91%. |
91% | With phosphoric acid In water monomer at 100℃; for 9h; Green chemistry; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With caesium carbonate In acetonitrile at 20℃; |
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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