* 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 1,3-bis(3-sulfopropyl)-1H-imidazol-3-ium trifluoromethanesulfonate In water at 100℃; for 0.333333 h; Microwave irradiation; Green chemistry
General procedure: Cyclohexanone (0.91 g, 10.0 mmol) was mixed with [(HSO3- p)2im][CF3SO3] (0.5 mmol) in water (15 mL), and phenylhydrazine hydrochloride (1.44 g, 10.0 mmol) was added. The mixture was then stirred at 100 8C for about 15 min under microwave irradiation. Reaction progress was monitored by GC–MS. After completion, the reaction mixture was cooled to room temperature, and 1,2,3,4-tetrahydrocarbazole was obtained by filtration. The remaining mixture of [(HSO3-p)2im][CF3SO3]/H2O was reused directly.
92%
for 8 h; Reflux
General procedure: A substituted phenyl hydrazine. HCl (4.61 mmol) was added to the mixture of cyclohexanone (4.61 mmol) and acetic acid (15 ml) portion wise for 30 min. The mixture was then refluxed for 8 h and progress of reaction was monitored by thin layer chromatography. The reaction mixture was cooled and poured into crushed ice. The solid product was separated, filtered, dried and recrystallized from the methanol solvent.
87%
With 1-(3-sulfopropyl)pyridinium p-toluenesulfonate In water at 100℃; for 0.25 h;
Sulfonic acid ionic liquid 1b (0.125 mmol), p-chlorophenylhydrazine hydrochloride (25 mmol),Cyclohexanone (25 mmol) water 15 mL sequentially added to the reaction vessel,Placed in a reactor, under mechanical stirring at 100 ° C for 15 minutes,After cooling to room temperature, the mixture was filtered and dried to give 5.01 g, yield 87percent.
Reference：
[1] Journal of Fluorine Chemistry, 2012, vol. 144, p. 45 - 50,6
[2] Tetrahedron Letters, 2018, vol. 59, # 22, p. 2145 - 2149
[3] Heterocyclic Communications, 2003, vol. 9, # 1, p. 9 - 12
[4] Organic and Biomolecular Chemistry, 2016, vol. 14, # 41, p. 9868 - 9873
[5] Patent: CN105968039, 2016, A, . Location in patent: Paragraph 0049-0051
[6] Chemical Communications, 2004, # 2, p. 158 - 159
[7] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1095 - 1102
[8] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 4, p. 807 - 824
[9] Letters in Organic Chemistry, 2009, vol. 6, # 2, p. 159 - 164
[10] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1238 - 1244
[11] Tetrahedron, 2017, vol. 73, # 45, p. 6436 - 6442
[12] Angewandte Chemie - International Edition, 2018, [13] Angew. Chem., 2018, vol. 130, # 48, p. 16118 - 16122,5
2
[ 108-94-1 ]
[ 1073-69-4 ]
[ 36684-65-8 ]
Yield
Reaction Conditions
Operation in experiment
61.28%
for 0.25 h; Reflux
General procedure: The amalgamation of tetrahydrocarbazoles were based on Fischer-indole synthesis method. In general it was carried out by dissolving 8.8 g (0.08 mol) of cyclohexanone in 50 ml of glacial acetic acid, to this 8.8 g (0.08 mol) of substituted phenyl hydrazine was added and boiled under reflux for 15 min. the solution was cooled, crystals formed were isolated by filtration. Crude product was further purified by recrystallization from aqueous ethanol. A total of four derivatives were synthesized by this route and were subjected to characterization.
Reference：
[1] Organic Letters, 2012, vol. 14, # 17, p. 4568 - 4571
[2] Synthesis, 2001, # 3, p. 370 - 372
[3] Green Chemistry, 2009, vol. 11, # 8, p. 1239 - 1246
[4] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 7, p. 713 - 722[5] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 7, p. 898 - 907
[6] Letters in Drug Design and Discovery, 2018, vol. 15, # 4, p. 437 - 449
[7] Angewandte Chemie - International Edition, 2011, vol. 50, # 25, p. 5682 - 5686
3
[ 40594-87-4 ]
[ 108-94-1 ]
[ 36684-65-8 ]
Reference：
[1] Journal of the American Chemical Society, 1998, vol. 120, # 26, p. 6621 - 6622
[2] Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10251 - 10263
4
[ 931-17-9 ]
[ 106-47-8 ]
[ 36684-65-8 ]
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 9, p. 1673 - 1680
[2] RSC Advances, 2013, vol. 3, # 17, p. 6022 - 6029
5
[ 92671-34-6 ]
[ 36684-65-8 ]
Yield
Reaction Conditions
Operation in experiment
20%
With sodium acetate; iron In ethanol; water; acetic acid
B. The reduction can also be carried out using Fe/acetic acid. A mixture of 0.784 g of iron, 1.62 mL of glacial acetic acid, 0.544 g of sodium acetate, and 1 g of 2-(5-chloro-2-nitrophenyl)cyclo-hexanone was refluxed in 80 mL of 4:1 (v/v) ethanol/water for 2 hr. The mixture was cooled, ethanol was evaporated, and the residue was extracted into methylene chloride. Work-up followed by column chromatography on silica yielded 0.160 g (20percent) of the named product.
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 10, p. 1704 - 1712
[2] Patent: US4659862, 1987, A,
6
[ 1073-70-7 ]
[ 36684-65-8 ]
Reference：
[1] Patent: US6018046, 2000, A,
7
[ 106-39-8 ]
[ 36684-65-8 ]
Reference：
[1] Journal of the American Chemical Society, 1999, vol. 121, # 44, p. 10251 - 10263
[2] Journal of the American Chemical Society, 1998, vol. 120, # 26, p. 6621 - 6622
General procedure: The amalgamation of tetrahydrocarbazoles were based on Fischer-indole synthesis method. In general it was carried out by dissolving 8.8 g (0.08 mol) of cyclohexanone in 50 ml of glacial acetic acid, to this 8.8 g (0.08 mol) of substituted phenyl hydrazine was added and boiled under reflux for 15 min. the solution was cooled, crystals formed were isolated by filtration. Crude product was further purified by recrystallization from aqueous ethanol. A total of four derivatives were synthesized by this route and were subjected to characterization.
With sodium acetate; iron; In ethanol; water; acetic acid;
B. The reduction can also be carried out using Fe/acetic acid. A mixture of 0.784 g of iron, 1.62 mL of glacial acetic acid, 0.544 g of sodium acetate, and 1 g of 2-(5-chloro-2-nitrophenyl)cyclo-hexanone was refluxed in 80 mL of 4:1 (v/v) ethanol/water for 2 hr. The mixture was cooled, ethanol was evaporated, and the residue was extracted into methylene chloride. Work-up followed by column chromatography on silica yielded 0.160 g (20%) of the named product.
With potassium tert-butylate; In tetrahydrofuran; for 18h;
A sample of 6-Chloro-2,3,4,9-tetrahydro-l H-carbazole (Example 82), 173mg (0.840 x 10" mol), 4-phenoxybutyl bromide, 289mg (1.26 x 10" mol), were combined in a 15ml round bottom flask with magnetic stirring bar. The flask was capped with a rubber septum, evacuated then back filled with nitrogen. Anhydrous tetrahydrofuran, <n="70"/>2ml, followed by IM in THF potassium tert-butyloxide, 1.3ml (1.3 x 10~3 mol), were added via syringe. After 18 hours TLC with 1 :4 ethyl acetate / hexanes showed a new spot with higher Rf. Diluted mix with water, extracted with ethyl acetate and evaporated organic layer. The resulting residue was dissolved in warm solvent (5% ethyl acetate / 95% hexanes), allowed to cool, collected solids provided 6-Chloro-9-(4- phenoxy-butyl)-2,3 ,4,9-tetrahydro- 1 H-carbazole.NMR 500 MH D6DMSO: 7.42, d, IH, 7.37, d, IH, 7.27, q, 2H, 7.03, dd, IH, 6.91-6.87, m, 3H, 4.13, t, 2H, 3.95, t, 2H, 2.72, t, 2H, 2.61, t, 2H, 1.86, q, 2H, 1.78, t, 4H, 1.72, q, 2H.
[Step 1] Synthesis of 6-chloro-1,2,3,4-tetrahydrocarbazole 4-chlorophenylhydrazine hydrochloride (25 g) was suspended in acetic acid (120 ml), and cyclohexanone (14.5 ml) was added. The mixture was heated under reflux for 2 hours and cooled to 0 C. The precipitated crystals were recovered by filtration, and washed with water and ethanol. The crude product was recrystallized from methanol to obtain the title compound (12.4 g, 43%). m.p.: 146.3-146.4 C. IR spectrum (KBr tab.) nucm-1: 3406, 2939, 1470, 1439, 1057, 800, 592. NMR spectrum (DMSO-d6) delta ppm: 10.84 (1H, s), 7.33 (1H, d, J=2.1 Hz), 7.21 (1H, d, J=8.5 Hz), 6.96 (1H, dd, J=8.5, 2.1 Hz), 2.73-2.57 (4H, m), 1.84-1.76 (4H, m).
EXAMPLE 14 Synthesis of 6-Chloro-1,2,3,4-tetrahydrocarbazole N-(4-Chlorophenyl)benzophenone hydrazone (1.0 equiv., 0.5 mmol, 153 mg), cyclohexanone (1.5 equiv., 0.75 mmol, 0.078 mL), and TsOH.H2O (2 equiv., 1.0 mmol, 190 mg) were dissolved in ethanol (3 mL) and heated to reflux for 41 hours. The reaction mixture was then cooled to room temperature, diluted with Et2O (5 mL), neutralized with a saturated NaHCO3 solution, and extracted with Et2O (3*10 mL). The organic extracts were then dried over K2CO3, filtered and concentrated under vacuum. Purification by flash column chromatography (10% EtOAc/Hex) gave the title product as a white solid (94 mg, 0.46 mmol, 91% yield).
With copper(II) choride dihydrate; In dimethyl sulfoxide; at 100℃; for 7h;
General procedure: A mixture of starting compound (2.69 mmol), CuCl2.2H2O (10 mol %) in DMSO (5 mL) stirred at 100 C. The reaction progress was monitored by thin layer chromatography (PMA was used for stain solution). The reaction mixture was poured into ice cold water. The crude product was purified by column chromatography using ethyl acetate and petroleum ether as eluent to afford carbazoles.
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