| 96% |
Stage #1: 4-bromo-1H-indole; N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃;
Stage #2: With potassium hydroxide In lithium hydroxide monohydrate; N,N-dimethyl-formamide Reflux; |
|
| 96.2% |
With trichlorophosphate at 10 - 40℃; for 2h; Inert atmosphere; |
5.1 1) Preparation of 4-bromo-3-formylindole (II-b)
DMF (20g) was weighed into 100 ml three-port flask. Moving to the water bath, water temperature 10 °C was stirred. The phosphorus oxychloride (9.38g) was slowly added in the course of the reaction, and stirring was continued in the course of the reaction (control temperature 35 °C), stirring was continued, heating was carried out to 40 °C stirring 1h (nitrogen protection reaction), the I-b raw material (10g) was weighed, and then DMF (10g) was added. The solution was then added dropwise to the reaction solution (temperature control 10 - 25 °C, exothermic phenomenon reaction), washed with DMF (5g), warmed to 35 °C, and changed to a three-port flask. The thermometer is inserted and mechanical stirring is used. Reaction 35 °C at a temperature 1 hour, with a large white solid precipitate, sampling TLC plates monitored. After completion of the reaction, ice-water was added to quench the excess phosphorus oxychloride and then adjusted to basic pH value 10-12 with aqueous sodium hydroxide solution and heated to 70 °C, pH value maintained at 10-12. After cooling to room temperature, 4 - bromo -3 -formyl indole (II-b, 11g) was obtained after filtration and drying 96.2%. |
| 95% |
Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.0833333h;
Stage #2: 4-bromo-1H-indole With potassium hydroxide at 65 - 75℃; for 7h; |
1 Example 1:
In a 500-mL three-neck round-bottom flask, 120 mL of dry N,N-dimethylformamide was added and the temperature was lowered to 0°C. Under vigorous stirring, 11 mL (0.12 mol) of phosphorus oxychloride was slowly added dropwise. Stirring was continued for 5 minutes, and 10 g (0.048πο1) dissolved in 20 g of dry N,N-dimethylformamide was slowly added dropwise. 4-Bromoindole (purity 95%), After the addition, the cold bath was removed and the reaction continued for 1 h. At this point, the reaction solution became a viscous suspension. 4.7M potassium hydroxide solution was slowly added dropwise to the reaction suspension (incremental speed to maintain the reaction solution at 65-75°C, If the temperature is too high, the bath can be cooled, and the reaction is continued for 6 hours after the addition. Slowly add 20 mL of saturated sodium bicarbonate solution, continue stirring for 5 min, dilute with ethyl acetate and dry. Concentration under reduced pressure to obtain the crude 4-bromoindole-3-carboxaldehyde 12g; Immediately afterwards, acetone (2.5mL/g crude product) was heated and refluxed and dissolved. After the dissolution, petroleum ether (11mL/g crude product) was added. The boiling range of petroleum ether is 60oC-90oC, and immediately white fine needle crystals are precipitated) and frozen at low temperature for 10 min. The temperature of freezing is -5 DEG C. After freezing, it is filtered through a sand funnel and washed with petroleum ether twice. In the absence of crystals, the filtered filtrate was again evaporated by evaporation to dry the solvent and the above crystallization was repeated. After a total of four crystallizations, the white crystals of 4-bromoindole-3-carbaldehyde were combined and allowed to air dry. (10.3 g, yield 95%); |
| 91% |
With trichlorophosphate Inert atmosphere; |
|
| 91% |
Stage #1: N,N-dimethyl-formamide With trichlorophosphate for 0.0833333h; Inert atmosphere; Cooling with ice;
Stage #2: 4-bromo-1H-indole at 20℃; for 1.5h; Inert atmosphere; Cooling with ice; |
4-bromoindole-3-carbaldehyde (2).
A round-bottom flask was charged with 130 mL of dry DMF, and the flask was cooled in an ice bath. The liquid was magnetically stirred under N2 atmosphere, and POCl3 (10.7 mL, 117 mmol, 2.3 eq.) was added dropwise. The solution was stirred for 5 min, and then a solution of 4-bromoindole1 (10 g, 51 mmol, 1.0 eq.) in 50 mL of DMF was added dropwise. The ice bath was removed, and the reaction mixture was left to stir for 1.5 h at room temperature. The reaction mixture became a heavy suspension, and was slowly quenched with KOH (28.6 g, 510 mmol, 10.0 eq.) in 100 mL of water. The quench was carried out slowly to maintain the reaction mixture at approximately 60 °C. The reaction mixture was left to cool overnight and then partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. Subsequent recrystallization from acetone and petroleum ether afforded a white solid 2, (10.4 g, 91% yield). NMR spectral data matched literature values |
| 90% |
With trichlorophosphate at 0 - 20℃; for 1h; |
|
| 89% |
With trichlorophosphate at 35 - 40℃; for 0.75h; |
|
| 88% |
With trichlorophosphate |
|
| 78% |
Stage #1: N,N-dimethyl-formamide With trichlorophosphate for 0.25h; Heating; cooling;
Stage #2: 4-bromo-1H-indole at 35 - 40℃; for 1h; |
|
| 53% |
With trichlorophosphate for 16h; y; |
|
| 52% |
Stage #1: 4-bromo-1H-indole; N,N-dimethyl-formamide With trichlorophosphate at 0 - 38℃; for 1.25h;
Stage #2: With sodium hydroxide In lithium hydroxide monohydrate at 170℃; for 0.0833333h; |
|
| 49% |
Stage #1: N,N-dimethyl-formamide With trichlorophosphate for 0.333333h; Cooling with ice;
Stage #2: 4-bromo-1H-indole at 20℃; for 1.5h; |
18.1 8.5 General procedure D
General procedure: To a dried two-neck round-bottom flask containing DMF (0.7mL for 1.10mmol of starting material) chilled in an ice bath, POCl3 (1.95 equiv) was added slowly. After stirring for 20min, a solution of an indole derivative (1.0 equiv) in DMF (3mL for 1.10mmol of starting material) was added dropwise. The reaction was allowed to warm to room temperature and allowed to stir for 1.5h. The reaction was quenched by adding ice followed by 1N NaOH (40mL) dropwise in an ice bath. The crude mixture was allowed to stand at room temperature and the precipitate formed was filtered to afford the 3-formyl-indole derivative product. |
|
With trichlorophosphate at 0 - 60℃; |
|
|
Stage #1: 4-bromo-1H-indole; N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; for 1h;
Stage #2: With potassium hydroxide In lithium hydroxide monohydrate |
2.1
A round bottom flask charged with 50 mL of DMF is cooled to 0 0C, and phosphorous oxychloride (8.ImL, 88 mmol) is added dropwise. After stirring for approx. 5 min, a solution of 4-bromoindole (5.0 mL, 40 mmol) in 50 mL of DMF is added dropwise. The ice bath is removed, and the reaction mixture is stirred for 1 h at rt. The reaction becomes a very thick suspension. The mixture is cooled back to 0 0C and carefully quenched with 22 g of KOH in 80 mL of water. The resulting mixture is partitioned between EtOAc (200 mL) and sat. NaHCO3 (100 mL). The EtOAc layer is washed with brine (100 mL) and water (100 mL), dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid, which is triturated with ether to afford the title compound as an off-white solid. |
|
Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.0333333h; Inert atmosphere;
Stage #2: 4-bromo-1H-indole at 20℃; for 1h; Inert atmosphere; |
|
|
With trichlorophosphate |
|
|
Stage #1: 4-bromo-1H-indole; N,N-dimethyl-formamide With pyridine; trichlorophosphate at 35℃; for 0.75h; Inert atmosphere; Cooling with ice;
Stage #2: With sodium hydroxide In lithium hydroxide monohydrate at 100℃; for 0.0333333h; Inert atmosphere; Cooling with ice; |
4.1.6. 4-[(tert-Butyldiphenylsilyloxy)methyl]indole-3-carboxaldehyde 35
General procedure: Phosphorus oxychloride (2.3 mL, 24.0 mmol) was added to ice-cold, stirred, dry dimethylformamide (7.8 mL, 99.0 mmol) followed by dry pyridine (2.0 mL, 26.0 mmol). A solution of the foregoing protected indole-4-methanol 33 (8.50 g, 22.0 mmol) in dimethylformamide (3 mL) was then added dropwise and the resulting solution warmed to 35 °C for 0.75 h before being poured onto ice. Sodium hydroxide (4.00 g) in water (200 mL) was added in portions and the resulting mixture boiled for 2 min then cooled and extracted with dichloromethane (3×50 mL). The combined extracts were dried, filtered and evaporated to give the indole-3-carboxaldehyde35 (7.52 g, 82%) as a brown oil |
|
Stage #1: 4-bromo-1H-indole; N,N-dimethyl-formamide With trichlorophosphate at 0 - 40℃; for 2.5h;
Stage #2: With sodium hydroxide In lithium hydroxide monohydrate at 90℃; for 1h; |
|
|
Stage #1: N,N-dimethyl-formamide With trichlorophosphate Cooling with ice;
Stage #2: 4-bromo-1H-indole In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #3: With sodium hydroxide In lithium hydroxide monohydrate at 100℃; for 0.25h; |
General procedure for the preparation of indolylnitroalkenes
General procedure: Phosphorus oxychloride (0.86 mL) was added dropwise to dimethylformamide (1.0 mL) with ice-bath cooling. The chosen indoles (1.0 g) were added as a dimethylformamide solution for preparation of corresponding indolecarbaldehydes. The resulting mixture was stirred at room temperature for one hour. The reaction mixture was quenched with chilled water, followed by the addition of aq Sodium hydroxide solution and refluxed at 100 °C for 15 min. The reaction mixture was cooled to room temperature and maintained at 0 °C overnight. The precipitates formed were collected and washed with water. After this, the -NH groups of different indolecarbaldehydes were protected with methyl, tosyl, benzyl, or methylsulfonyl by using corresponding halogenides (1.5 equiv) under different basic conditions, such as sodium hydride (1.5 equiv) using acetonitrile as a solvent. Then, the reaction of resulting N-protected indolecarbaldehydes (1.0 g) with nitromethane (5 mL) in the presence of 30 mol % of ammonium acetate as the catalyst to furnish the desired indolylnitroalkenes.9 |
|
With trichlorophosphate In N,N-dimethyl-formamide at 0 - 25℃; for 1h; Inert atmosphere; |
|
|
Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃;
Stage #2: 4-bromo-1H-indole at 20℃;
Stage #3: With potassium hydroxide In lithium hydroxide monohydrate at 0℃; |
2.1
EXAMPLE 2; N-T(I -Pyridin-3 -ylcyclohexyDmethyll - 1 -pyrimidin-2-yl-4-(trifluoromethyl)- 1 H-indole-3 - carboxamide; Step 1. 4-Bromo-lH-indole-3-carbaldehyde; A round bottom flask charged with 50 mL of DMF is cooled to 0 0C, and phosphorous oxychloride (8.ImL, 88 mmol) is added dropwise. After stirring for approx. 5 min, a solution of 4-bromoindole (5.0 mL, 40 mmol) in 50 mL of DMF is added dropwise. The ice bath is removed, and the reaction mixture is stirred for 1 h at rt. The reaction becomes a very thick suspension. The mixture is cooled back to 0 0C and carefully quenched with 22 g of KOH in 80 mL of water. The resulting mixture is partitioned between EtOAc (200 mL) and sat. NaHCO3 (100 mL). The EtOAc layer is washed with brine (100 mL) and water (100 mL), dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid, which is triturated with ether to afford the title compound as an off-white solid. |
|
With trichlorophosphate at 20℃; |
1.a1 (a1) Preparation of Compound 2-6
General procedure: Indole and POCl3 in DMF at room temperature the reaction solvent,Compound 2 was obtained.Compound 2 is dissolved in nitromethane,Compound 3 is produced by ammonium acetate catalysis.Using anhydrous tetrahydrofuran as a solvent,Compound 3 is dissolved therein,Add lithium aluminum hydride,The reaction is carried out under anhydrous conditions to give the compound 4.Compound 4 was reacted with paraformaldehyde in a solution of AcOH:MeOH = 10:1 to give compound 5.Compound 5 is reacted with Boc anhydride in a tetrahydrofuran solvent to give compound 6. |
|
Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.0833333h;
Stage #2: 4-bromo-1H-indole In N,N-dimethyl-formamide at 20℃; for 2h; |
|
|
With trichlorophosphate |
|
|
With trichlorophosphate at 0 - 20℃; for 2h; Inert atmosphere; |
|
|
Stage #1: 4-bromo-1H-indole; N,N-dimethyl-formamide With trichlorophosphate
Stage #2: With potassium hydroxide In lithium hydroxide monohydrate |
|
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