* 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.
With tetrabutylammomium bromide; potassium hydroxide In dimethyl sulfoxide at 20℃; Inert atmosphere
Weigh carbazole (1.67g, 10mmol) and tetrabutylammonium bromide (0.322 g) to the reaction flask using an oil pump vacuum - filled with nitrogen - cycle three times after evacuation, nitrogen protection reaction system,Dimethylsulfoxide (40 mL) and 8.0 g of 50percent KOH were added to the system. Bromopropane (6.15 g, 50 mmol) was added dropwise with stirring and stirred at room temperature overnight.After the reaction was complete, the mixture was extracted with a large amount of water and methylene chloride. The organic phase was washed with saturated brine and dried over anhydrous MgSO4. The filtrate was filtered to remove most of the solvent with a rotary evaporator.And then with petroleum ether as the eluent, over the column. To give 9-propylcarbazole in 90percent yield.
86%
Stage #1: With sodium hydroxide In dimethyl sulfoxide for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 4 h; Inert atmosphere
Carbazole was added to a suspension of sodium hydroxide(1.2 mol ratio) in DMSO (13 V) under nitrogen atmosphere. The mixture was stirred for 30 min and then 1-bromopropane(1.1 mol ratio) was added. The reaction was stirred at room temperatureand monitored by TLC. Water was added, the mixturewas extracted with CHCl3 and dried with anhydrous sodium sulfate,and evaporated. The residue was purified by column chromatographywith Petroleum ether/ethyl acetate as the eluent to giveCrANA. Yield – 86percent, Color: Colorless solid, 1H NMR, (400 MHz,CDCl3): d (ppm), 0.9–0.99 (t, 3H), 1.87–1.96 (m, 2H), 4.26–4.29(t,2H), 7.2–7.3 (m, 2H), 7.4–7.5 (m, 4H), 8.1 (t, 2H).
80%
Stage #1: With tetrabutylammomium bromide; potassium hydroxide In acetone for 0.666667 h; Stage #2: for 1 h; Reflux
General procedure: Carbazole (1.67 g, 10 mmol), tetrabutyl ammoniumbromide (0.32 g, 1 mmol) and potassium hydroxide (2.24 g, 40 mmol) dissolved in acetone (20 mL) were added to a 100 mL three-necked flask, the mixture solution was stirred for 40 minutes. Alkyl bromide(12 mmol) was added dropwise to the solution with constant stirring. The mixture was refluxed for 1 h.The reaction mixture was then poured into ice water (300 mL) with vigorous stirring to obtain a great deal of deposit. The mixture was filtered, washed with water and the filter cake obtained was then recrystallized from alcohol and water to give N-alkyl carbazole (1a–1c).12
74%
With caesium carbonate In N,N-dimethyl-formamide for 16 h; Inert atmosphere
General procedure: Under Ar, a solution of carbazole (5.0g, 29.9mmol), bromoethane (4.45mL, 35.9mmol), and Cs2CO3 (14.6g, 44.8mmol) in DMF (20mL) was stirred at 80°C for 16h. The reaction mixture was cooled, diluted with EtOAc (50mL), and filtered. The organic solvents were evaporated in vacuo. The resultant dark oil was purified by column chromatography on silica gel using heptanes/EtOAc in different proportions to afford the title compound as a light-yellow oil (5.075g, 87percent).
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 12, p. 3898 - 3904
[2] Patent: CN106188152, 2016, A, . Location in patent: Paragraph 0075
[3] Journal of Molecular Structure, 2014, vol. 1060, # 1, p. 191 - 196
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 39, p. 12727 - 12732[5] Angew. Chem., 2018, vol. 130, # 39, p. 12909 - 12914,6
[6] Bulletin of the Chemical Society of Japan, 1981, vol. 54, # 6, p. 1897 - 1898
[7] Croatica Chemica Acta, 2015, vol. 88, # 1, p. 1 - 6
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 43, p. 11458 - 11462[9] Angew. Chem., 2014, vol. 126, # 43, p. 11851,1
[10] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 74 - 89
[11] MedChemComm, 2016, vol. 7, # 10, p. 1988 - 1994
2
[ 86-74-8 ]
[ 107-08-4 ]
[ 1484-10-2 ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydroxide In acetone for 16 h; Reflux; Inert atmosphere
General procedure: A mixture of carbazole (10g, 59.81mmol), n-pentyl bromide (11mL, 88.92mmol), and finely ground NaOH (4g, 100mmol) in dry acetone (100mL) was refluxed for 16h under nitrogen. After all volatile components were removed by rotary evaporation in vacuo, the residue was extracted with tert-butyl methyl ether (150mL). The organic phase was washed with water, brine, dried (MgSO4), filtered, and evaporated in vacuo. The obtained residue was crystallized from ice-cold ethanol. Yield: 12.72g (90percent).
Reference：
[1] Synthetic Communications, 2010, vol. 40, # 15, p. 2291 - 2301
[2] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 881 - 907
[3] ChemMedChem, 2011, vol. 6, # 8, p. 1518 - 1529
3
[ 107-10-8 ]
[ 189999-35-7 ]
[ 1484-10-2 ]
Reference：
[1] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1202 - 1209
4
[ 696-59-3 ]
[ 556-53-6 ]
[ 1484-10-2 ]
Reference：
[1] Tetrahedron Letters, 1986, vol. 27, # 19, p. 2131 - 2134
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 913 - 916
5
[ 2113-51-1 ]
[ 1484-10-2 ]
Reference：
[1] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1202 - 1209
6
[ 6510-71-0 ]
[ 1484-10-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1946, vol. 16, p. 1471,1473[2] Chem.Abstr., 1949, p. 3819
Stage #1: 9H-carbazole With sodium hydroxide In water; toluene for 0.166667h;
Stage #2: propyl bromide With tetra-(n-butyl)ammonium iodide In water; toluene for 16h; Reflux;
90%
With tetrabutylammomium bromide; potassium hydroxide In dimethyl sulfoxide at 20℃; Inert atmosphere;
2.S1.4.a
Weigh carbazole (1.67g, 10mmol) and tetrabutylammonium bromide (0.322 g) to the reaction flask using an oil pump vacuum - filled with nitrogen - cycle three times after evacuation, nitrogen protection reaction system,Dimethylsulfoxide (40 mL) and 8.0 g of 50% KOH were added to the system. Bromopropane (6.15 g, 50 mmol) was added dropwise with stirring and stirred at room temperature overnight.After the reaction was complete, the mixture was extracted with a large amount of water and methylene chloride. The organic phase was washed with saturated brine and dried over anhydrous MgSO4. The filtrate was filtered to remove most of the solvent with a rotary evaporator.And then with petroleum ether as the eluent, over the column. To give 9-propylcarbazole in 90% yield.
86%
Stage #1: 9H-carbazole With sodium hydroxide In dimethyl sulfoxide for 0.5h; Inert atmosphere;
Stage #2: propyl bromide In dimethyl sulfoxide at 20℃; for 4h; Inert atmosphere;
2.2.1. Preparation of 9-propyl 9H-carbazole (Cr-NA)
Carbazole was added to a suspension of sodium hydroxide(1.2 mol ratio) in DMSO (13 V) under nitrogen atmosphere. The mixture was stirred for 30 min and then 1-bromopropane(1.1 mol ratio) was added. The reaction was stirred at room temperatureand monitored by TLC. Water was added, the mixturewas extracted with CHCl3 and dried with anhydrous sodium sulfate,and evaporated. The residue was purified by column chromatographywith Petroleum ether/ethyl acetate as the eluent to giveCrANA. Yield - 86%, Color: Colorless solid, 1H NMR, (400 MHz,CDCl3): d (ppm), 0.9-0.99 (t, 3H), 1.87-1.96 (m, 2H), 4.26-4.29(t,2H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 4H), 8.1 (t, 2H).
82%
Stage #1: 9H-carbazole With sodium hydride In tetrahydrofuran for 0.25h; Inert atmosphere;
Stage #2: propyl bromide In tetrahydrofuran at 80℃; for 6h; Inert atmosphere;
81%
With sodium hydroxide In benzene at 55 - 60℃; for 1h;
80%
Stage #1: 9H-carbazole With tetrabutylammomium bromide; potassium hydroxide In acetone for 0.666667h;
Stage #2: propyl bromide In acetone for 1h; Reflux;
General Synthetic Procedure of N-alkyl Carbazole (1a-c)
General procedure: Carbazole (1.67 g, 10 mmol), tetrabutyl ammoniumbromide (0.32 g, 1 mmol) and potassium hydroxide (2.24 g, 40 mmol) dissolved in acetone (20 mL) were added to a 100 mL three-necked flask, the mixture solution was stirred for 40 minutes. Alkyl bromide(12 mmol) was added dropwise to the solution with constant stirring. The mixture was refluxed for 1 h.The reaction mixture was then poured into ice water (300 mL) with vigorous stirring to obtain a great deal of deposit. The mixture was filtered, washed with water and the filter cake obtained was then recrystallized from alcohol and water to give N-alkyl carbazole (1a-1c).12
80%
With tetra-(n-butyl)ammonium iodide; sodium hydroxide In water; toluene at 80℃; for 2h;
74%
With caesium carbonate In N,N-dimethyl-formamide for 16h; Inert atmosphere;
9-ethyl-9H-carbazole (5)
General procedure: Under Ar, a solution of carbazole (5.0g, 29.9mmol), bromoethane (4.45mL, 35.9mmol), and Cs2CO3 (14.6g, 44.8mmol) in DMF (20mL) was stirred at 80°C for 16h. The reaction mixture was cooled, diluted with EtOAc (50mL), and filtered. The organic solvents were evaporated in vacuo. The resultant dark oil was purified by column chromatography on silica gel using heptanes/EtOAc in different proportions to afford the title compound as a light-yellow oil (5.075g, 87%).
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere;
With caesium carbonate In N,N-dimethyl-formamide at 26℃; for 28.8h;
96%
Stage #1: 9H-carbazole With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 1-iodo-propane In N,N-dimethyl-formamide at 20℃; for 12h;
83%
With sodium hydroxide In acetone for 16h; Reflux; Inert atmosphere;
Method B:
General procedure: A mixture of carbazole (10g, 59.81mmol), n-pentyl bromide (11mL, 88.92mmol), and finely ground NaOH (4g, 100mmol) in dry acetone (100mL) was refluxed for 16h under nitrogen. After all volatile components were removed by rotary evaporation in vacuo, the residue was extracted with tert-butyl methyl ether (150mL). The organic phase was washed with water, brine, dried (MgSO4), filtered, and evaporated in vacuo. The obtained residue was crystallized from ice-cold ethanol. Yield: 12.72g (90%).
With potassium hydroxide In dimethyl sulfoxide for 0.5h; Cooling;
With trichlorophosphate In 1,2-dichloro-ethane at 0 - 90℃; for 12h;
2.2.2. Preparation of 9-propyl-9H-carbazole-3-carbaldehyde (Cr-CHO)
A round bottom flask was charged with a solution of DMF(2.01 mol ratio) and 1,2-dichloroethane (3 ml) at 0 C. POCl3(1.25 mol ratio) was slowly added to the mixture. Then, CrANA(1 mol ratio) in 1,2-dichloroethane (3 ml) was added dropwise tothe mixture. The mixture was stirred for 12 h at 90 C. Next, itwas poured into ice water and the compound was filtered anddried. Yield - 94%, Color: yellow solid. 1H NMR, (400 MHz, DMSO):d (ppm), 0.82-0.88 (t, 3H), 1.77-1.86 (m, 2H), 4.41-4.45 (t, 2H), 8.7(m, 2H), 8.3 (d, 1H), 7.9 (d, 1H), 7.8 (d, 1H) 7.8 (d, 1H), 7.6 (t, 1H),7.5 (t, 1H), 7.3 (d, 1H), 10 (s, 1H), IR, (KBr, cm1): CAN - 1339, CO- 1685 cm1.
76.2%
With trichlorophosphate In 1,2-dichloro-ethane at 0 - 90℃; Inert atmosphere;
1 Synthesis of Compound 2:
General procedure: DMF, (1.4 mL, 17.7 mmol) and POCl 3, (0.8 mL, 8 mmol) were added to a two-necked flask filled with nitrogenunder ice bath conditions .Compound 3 (6.0 mmol) dissolved in 15 mL of dichloroethane was then added to the above system.The mixed system was reacted at 0 °C for 1 h, and then at 90 °C overnight.After the reaction was completed, the mixed system was cooled to room temperature naturally, poured into ice water, and then extracted with dichloromethane.Then washed with saturated brine, collected the organic layer, dried over anhydrous Na2SO4, filtered, and removed the solvent under reduced pressure to obtain the crude product, which was purified by flash column chromatography (EA/PE, 1/4, v/v) , a yellow solid was obtained.
With trichlorophosphate at 80℃; for 6h; Inert atmosphere; Cooling with ice;
With aluminum (III) chloride In 1,2-dichloro-ethane at 20℃; for 40h;
12.1 [0159] Step 1. Compound 12a-1 . 2-Bromo-1-(9-propyl-9H-carbazol-3-yl)-ethanone.
To a mixture of 9-propyl-9H-carbazole (Compound 1-5, 500 mg, 2.29 mmol) and aluminum chloride (350 mg, 2.63 mmol) in dichloroethane (7.15 mL) was added a solution of bromoacetyl chloride (328 L, 3.94 mmol) in dichloroethane (3.90 mL) dropwise and the reaction mixture was stirred at room temperature for 40 h. The mixture was poured onto a mixture of 3 N hydrochloric acid and crushed ice (15 mL, 1 : 1) and extracted with dichloromethane (3 x 25 mL). The organic layer was washed with 1 M aqueous sodium carbonate, dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with hexane:ethyl acetate (98:2- 85: 15) to give the title compound (517 mg, 1.56 mmol, 65%) as a pale brown powder. LCMS: 89%, Rt 1.889, ESMS m/z 330 (M+H)+.
With aluminum (III) chloride In dichloromethane at 20℃; for 50h; Cooling with ice;
General Synthetic Procedure of 3,6-Diacetyl-9-alkyl Carbazole (2a-c)
General procedure: Aluminium chloride powder (1.10 g, 8 mmol) was dissolved partly in dichloromethane (10 mL) in a 100 mL three-necked flask with constant stirring until the solution became orange-yellow. To the solution acetyl chloride (1 mL, 10 mmol) in dichloromethane and compound 1 (2 mmol) in dichloromethane was added dropwise to it in an ice bath. The reaction was carried out in the ice bath for 2 h and further stirred at room temperature for 48h. The reaction mixture was then poured into ice water (400 mL) with vigorous stirring to get a pale-yellow precipitate. The crude products were filtered, washed with water, dried, and then recrystallized from alcohol to get compound 2.13
84%
Stage #1: acetyl chloride With aluminum (III) chloride In dichloromethane
Stage #2: 9-propyl 9H-carbazole In dichloromethane at 20℃; for 4h;
With N-Bromosuccinimide In chloroform at 0 - 20℃; Inert atmosphere;
2.S1.4.a A) Preparation of 9-propylcarbazole-3-borate:
Weigh 9- propyl carbazole (4.18g, 20.0mmol) to the reaction flask using an oil pump vacuum - filled with nitrogen - vacuum cycle three times, the system nitrogen atmosphere was added CHCl3 (100mL) added to the system, the dark reaction apparatus .The reaction system was reduced to 0 ° C and N-bromosuccinimide (3.56 g, 20.0 mmol) was slowly added dropwise. The reaction temperature was returned to room temperature and stirred overnight. After the reaction was complete, the CHCl3 was removed by rotary evaporator and the crude product was extracted with water and dichloromethane,With petroleum ether and ethyl acetate = 9: 1 column. To give 9-propyl-3-bromocarbazole.
Stage #1: 9-propyl 9H-carbazole With aluminum (III) chloride In benzene for 0.333333h; Inert atmosphere; Cooling with ice;
Stage #2: 4-methyl-1-naphthalenecarbonyl chloride In benzene at 100℃; for 1h; Inert atmosphere; Microwave irradiation;
3-(4-chlorobenzoyl)-9-ethyl-9H-carbazole (10)
General procedure: Under Ar, AlCl3 (1.13g, 8.44mmol) was added to a solution of 5 (1.5g, 7.68mmol) in anhydrous benzene (20mL), and the solution was cooled by an ice bath for 20min. 4-chlorobenzoic acid (1.12mL, 8.83mmol) was added dropwise via a syringe to the solution, which was tightly capped in a microwave vessel and subjected to microwave irradiation at 100°C for 1h and then cooled to room temperature. The reaction mixture was cooled on an ice-water bath, then poured onto a mixture of ice and a 4M NaOH solution (50mL) and extracted with ethyl acetate (150mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc/heptanes in different proportions to yield the target product (1.374g, 54%) as a white solid:
52%
Stage #1: 9-propyl 9H-carbazole With aluminum (III) chloride In benzene for 0.333333h; Inert atmosphere; Cooling with ice;
Stage #2: 4-methyl-1-naphthalenecarbonyl chloride In benzene at 100℃; for 1h; Inert atmosphere; Microwave irradiation;
12 Example 6: 3-(4-chlorobenzoyl)-9-ethyl-9/-/-carbazole (10)
General procedure: Under argon, AICI3 (1.13 g, 8.44 mmol) was added to a solution of 5 (1.5 g, 7.68 mmol) in anhydrous benzene (20 ml_), and the solution was cooled by an ice bath for 20 min. 4-chlorobenzoic acid (1.12 ml_, 8.83 mmol) was added dropwise via a syringe to the solution, which was tightly capped in a microwave vessel and subjected to microwave irradiation at 100 °C for 1 hour and then cooled to room temperature. The reaction mixture was cooled on an ice-water bath, then poured onto a mixture of ice and a 4 M NaOH solution (50 ml_) and extracted with ethyl acetate (150 ml_). The organic phase was washed with saturated aqueous NaHC03 and brine, dried (MgS04), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/heptanes in different proportions to yield the target product (1.374 g, 54%) as a white solid
With sodium ethanolate In ethanol; dimethyl sulfoxide for 0.05h;
3 Example 3 Preparation of 3-hydroxymethyl-9-propylcarbazole
In a dry 100 mL three-necked flask,Under ice-cold bath cooling, add 20 mL of DMSO, 72 mg (2.4 mmol) of paraformaldehyde, 245 mg (3.6 mmol) of sodium ethoxide, 2 mL of absolute ethanol, stir to dissolve, and dissolve 500 mg (2.4 mmol) of N-propylcarbazole in 5 mL of DMSO. In the middle, it was quickly dropped into the reaction system, and after reacting for 3 min, 3 drops of concentrated hydrochloric acid was added dropwise to terminate the reaction. Then, 30 mL of distilled water was added, and a solid was precipitated, suctioned, washed with water, and dried to obtain a crude product. The crude product was recrystallized from absolute ethanol to give a pure yellow solid.of 3-hydroxymethyl-9-propylcarbazole. Yield 77.5%,
With silver hexafluoroantimonate; tris(2,4-di-tert-butylphenyl)phosphite gold(I) chloride In tetrahydrofuran at 20℃; for 0.25h; regioselective reaction;
With 6-phenyl-12-(p-tolyl)-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine; sodium t-butanolate In toluene at 100℃; for 12h;
27 Preparation Example 27
Add 0.3mmol 2,2'-bisbromobiphenyl, 0.36mmol n-propylamine, 0.015mmol palladium chloride, 0.03mmol organoantimony ligand IV, 0.6mmol sodium tert-butoxide and 2mL toluene in a 25mL reaction tube. React for 12 h at 100°C. After the reaction, the solvent was removed under reduced pressure, and the pure compound was separated by column chromatography with a yield of 85%.
59.7 mg
With <i>L</i>-proline; copper(l) chloride; potassium hydroxide In N,N-dimethyl-formamide at 140℃; for 24h;
General procedure A for the synthesis of N-substituted 9H-carbazole as examplified by thePreparation of 9-benzyl-9H-carbazole1
General procedure: Benzylamine (16.49 mg, 0.154 mmol, 1.2 equiv.) was added to a pressure tube that was chargedwith 2,2'-dibromo-1,1'-biphenyl 1 (40 mg, 0.128 mmol, 1 equiv.), CuCl (1.269 mg, 0.013 mmol,0.1 equiv.), L-Proline (1.771 mg, 0.015 μmol, 0.12 equiv.) and potassium hydroxide (21.58 mg,0.385 mmol, 3 equiv.) under air. The anhydrous DMF (0.5 mL) was added. The reaction mixturethen heated at 140 °C for 24 h. After cooling, the reaction mixture was diluted withdichloromethane (10 mL), and the resulting mixture was filtered through a pad of Celite, whichwas washed three times with dichloromethane (30 mL). The filtrate was concentrated in vacuo.The crude product was purified by preparative thin layer chromatography (silica gel; hexane) toyield 3a (25.7 mg, 78%) as a white solid;
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