* 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.
Stage #1: for 0.5 h; Cooling with ice Stage #2: at 20℃; for 4.5 h;
Step 1. 5-Bromo-2-methyl-7H-indoleTo a solution of 2-methyl-iH-indole (5.0 g, 38.12 mmol) in sulfuric acid (80 mL) was added Ag2S04 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Br2 (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room temperature, the reaction was then quenched by the addition of water/ice (300 mL). The reaction mixture was extracted with dichloromethane (3 x 200 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-2-methyl-7H-indole as a light brown solid (6 g, 75percent).LC/MS (ES, m/z): [M+H]+ 211.0'H-NMR (300 MHz, CDC13): δ 11.23 (s, 1Η), 7.56 (s, 1Η), 7.21 (d, / = 8.7 Hz, 1H), 7.07 - 7.09 (m, 1H), 6.11 (s, 1H), 2.38 (s, 3H)
59%
Stage #1: for 0.5 h; Cooling with ice Stage #2: With bromine In sulfuric acid at 20℃; for 4 h; Stage #3: With water In sulfuric acid
EXAMPLE 24 2,2,2-Trifluoro-1-(5-(3-(isopropyl(methyl)amino)-6-(1H-tetrazol-5-yl)quinoxalin-2-yl)-2-methyl-1H-indol-3-yl)ethanone Step 1. 5-Bromo-2-methyl-1H-indole To a solution of 2-methyl-1H-indole (5.0 g, 38.12 mmol) in sulfuric acid (80 ml) was added Ag2SO4 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Br2 (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room temperature, the reaction was quenched by the addition of water/ice (300 ml). The reaction mixture was extracted with dichloromethane (3.x.200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-2-methyl-1H-indole as a light brown solid (4.7 g, 59percent).LC/MS (ES, m/z): [M+H]+ 211.01H-NMR (300 MHz, CDCl3): δ 11.23 (s, 1H), 7.56 (s, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.07-7.09 (m, 1H), 6.11 (s, 1H), 2.38 (s, 3H)
Stage #1: at 1 - 5℃; for 0.333333 h; Stage #2: at 35℃; for 0.666667 h; Stage #3: at 95℃; for 0.5 h; Cooling with ice
General procedure: POCl3 (1.73 mL, 18.6 mmol) was slowly added dropwise into stirred and ice-cooled DMF (5.0 mL). The reaction mixture was stirred at 1-5 °C for 20 min, then a solution of corresponding substituted 2-methylindole 6 (15.5 mmol) in DMF (5.0 mL) was slowly added. The resulting reaction mixture was slowly warmed to 35 °C and kept at this temperature for 40 min. It was then allowed to cool down to room temperature. To this mixture, ice (~10 g) was added followed by 5 M NaOH solution (31 mL, 155 mmol). The reaction mixture was heated at 95 °C for 30 min, and then it was allowed to cool down to room temperature. To this mixture, ice (~10 g) was again added, and the resulting reaction mixture was stirred for 30 min. The desired product was collected by filtration and washed several times with water.
90%
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).
87%
Stage #1: at 0℃; for 0.666667 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1.33333 h; Stage #3: With water; sodium hydroxide In N,N-dimethyl-formamide at 100℃; for 0.5 h;
Anhydrous N,N-dimethylformamide (DMF) (12.6 mL, 163.4 mmol) was placed in an N2-purged 250 ml 3-neck round bottom flask and cooled to 0° C. in an ice bath. Phosphorus oxychloride (POCl3, 3.9 mL, 41.84 mmol) was slowly added thereto and stirred at 0° C. for 40 minutes. A solution of 2-methyl-1H-indole (4) (4.8 g, 36.5 mmol) in DMF (7.5 mL) was slowly added thereto while maintaining the temperature at 5° C. or lower. The resulting solution was stirred at 0° C. for 40 minutes, warmed at room temperature, and further stirred for 40 minutes. Then, a few pieces of ice were added to the flask, and a sodium hydroxide (NaOH) solution (16.5 g, 412.5 mmol dissolved in 50 mL of water) was added as droplet form through a dropping funnel while the mixture was vigorously stirred. The resulting solution was heated at 100° C., stirred for 30 minutes, and cooled at room temperature. The resulting pale yellow precipitate was filtered, washed with water, and dried. Then, the product was recrystallized from diethyl ether and hexane to yield a purified product of 2-methyl-1H-indole-3-carbaldehyde (5) as a pale yellow solid (5.0 g, yield 87percent). The 1H NMR spectrum of the resulting 2-methyl-1H-indole-3-carbaldehyde (5) is shown in FIG. 7, and the mass spectrum is shown in FIG. 8. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.962 (1H, s, —NH), 10.058 (1H, s, —CHO), 8.054-80.33 (1H, dd, J=8.4, 2.0, Ar—H), 7.396-7.373 (1H, dd, J=6.6, 2.4, Ar—H), 7.188-7.130 (2H, m, Ar—H), 2.681 (3H, s, —CH3); ESIMS found: m/z 158.4 [M−H]−, 160.4 [M+H]+, 182.3 [M+Na]+; Rf=0.29 (hexane:ethyl acetate=1:1).
79%
Stage #1: for 2.5 h; Cooling with ice Stage #2: at 5℃; for 3 h; Stage #3: With sodium hydroxide In water; N,N-dimethyl-formamide for 1 h; Cooling with ice; Reflux
Formylation of 2-methy-indole was carried out according to McNab462-Methyl-indole-3-carboxaldchyde. Phosphorus oxychloride (1.44 g. 0.88 ml. 9.4 mmol) was added to ice cooled N, N- dimethyl formamide (2.74 g, 2.88 ml, 37.4 mmol) at 0-5 °C and stirred for 2.5 h. A solution of 2-methylindole (1.12 g. 8.5 mmol) in N,N-dimethylformamide (5 ml) was added drop wise keeping the reaction temperature below 5 °C. Upon completion of the addition, ice (7 g) was added followed by drop wise addition of a solution of sodium hydroxide (3.75 g) in water (10 ml) to give a dull yellow precipitate. The reaction was then heated under reflux for 1 h and refrigerated overnight, during which time precipitation of crude product occurred. The product was filtered, washed with water (450 cm3) and re-filtered to give 2-methyl-N-indole-3- carboxaldehyde.Yield:79percent; 'H NMR (300MHz, DMSO) δ: 12.01 (s, 1H), 10.06 (s, 1H), 8.07 (m, 1H), 7.40 (m, 1H), 7.21-7.13 (m, 2H), 2.69 (s, 3H)
79%
Stage #1: at 0 - 5℃; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide for 1 h; Reflux
Formylation of 2-methy-indole was carried out according to McNab47 . 2-Methyl-indole-3-carboxaldehyde. Phosphorus oxychloride (1.44 g. 0.88 ml. 9.4 mmol) was added to ice cooled N, N- dimethyl formamide (2.74 g, 2.88 ml, 37.4 mmol) at 0-5 °C and stirred for 2.5 h. A solution of 2-methylindole (1.12 g. 8.5 mmol) in N,N-dimethylformamide (5 ml) was added drop wise keeping the reaction temperature below 5 °C. Upon completion of the addition, ice (7 g) was added followed by drop wise addition of a solution of sodium hydroxide (3.75 g) in water (10 ml) to give a dull yellow precipitate. The reaction was then heated under reflux for 1 h and refrigerated overnight, during which timeprecipitation of crude product occurred. The product was filtered, washed withwater (450 cm3) and re-filtered to give 2-methyl-N-indole-3-carboxaldehyde. Yield: 79 percent; 'H NMR (300MHz, DMSO) δ: 12.01 (s, 1H), 10.06 (s,1H), 8.07 (m, 1H), 7.40 (m, 1H), 7.21-7.13 (m, 2H), 2.69 (s, 3H)
63%
Stage #1: for 0.333333 h; Cooling with ice Stage #2: at 20℃; for 1.5 h;
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.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 12, p. 2895 - 2901
[2] Tetrahedron Letters, 2018, vol. 59, # 11, p. 1014 - 1018
[3] Chemical Biology and Drug Design, 2011, vol. 78, # 5, p. 864 - 868
[4] European Journal of Medicinal Chemistry, 2003, vol. 38, # 1, p. 75 - 87
[5] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 158 - 167
[6] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 1940 - 1956
[7] Patent: US2016/102078, 2016, A1, . Location in patent: Paragraph 0072-0075
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[15] Tetrahedron, 1993, vol. 49, # 19, p. 4015 - 4034
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[27] Green Chemistry, 2017, vol. 19, # 13, p. 2952 - 2956
3
[ 95-20-5 ]
[ 110-18-9 ]
[ 5416-80-8 ]
Yield
Reaction Conditions
Operation in experiment
63%
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.
Reference：
[1] Chemical Communications, 2012, vol. 48, # 42, p. 5187 - 5189
[2] Journal of the American Chemical Society, 2011, vol. 133, # 31, p. 11924 - 11927
Reference：
[1] Chemische Berichte, 1923, vol. 56, p. 2317
[2] Chemische Berichte, 1923, vol. 56, p. 2060
[3] Biochemical Journal, 1917, vol. 11, p. 60
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 518
7
[ 95-20-5 ]
[ 67-66-3 ]
[ 5416-80-8 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 I, p. 131
[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 I, p. 131
[3] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1914, vol. 91, p. 50
[4] Biochemical Journal, 1935, vol. 29, p. 546,549
8
[ 95-20-5 ]
[ 64-18-6 ]
[ 5416-80-8 ]
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1983, vol. 31, # 8, p. 2892 - 2894
9
[ 95-20-5 ]
[ 110-45-2 ]
[ 5416-80-8 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 I, p. 382[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 II, p. 792
Reference：
[1] Chemische Berichte, 1923, vol. 56, p. 2317
[2] Chemische Berichte, 1923, vol. 56, p. 2060
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 518
12
[ 95-20-5 ]
[ 7647-01-0 ]
[ 74-90-8 ]
[ 67-66-3 ]
[ 5416-80-8 ]
Reference：
[1] Chemische Berichte, 1923, vol. 56, p. 2317
[2] Chemische Berichte, 1923, vol. 56, p. 2060
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 518
13
[ 95-20-5 ]
[ 67-66-3 ]
[ 141-52-6 ]
[ 5416-80-8 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 I, p. 131
14
[ 95-20-5 ]
[ 60-29-7 ]
[ 638-49-3 ]
[ 141-52-6 ]
[ 5416-80-8 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 I, p. 382[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1907, vol. <5> 16 II, p. 792
15
[ 95-20-5 ]
[ 75-03-6 ]
[ 40876-94-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium hydroxide In dimethyl sulfoxide at 20℃; for 12 h;
Example 1Synthesis of JWH4511 -Ethyl-2-methylindole[0150] To a mixture of 0.20 g (1.52 mmol) of 2-methylindole, 0.38 g (6.89 mmol) of KOH in DMSO (6 mL) was added 0.24 mL (3.04 mmol) of iodoethane. The mixture was stirred at room temperature for 12 hours, quenched by the addition of 15 mL of H20, and extracted with ethyl acetate (2 X 15 mL). The combined organic extracts were washed with water (10 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by column chromatography (ether/ petroleum ether 0.5:9.5) to give 0.20g (83 percent) of the desired product as a red oil.
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 1, p. 280 - 284
[2] Chemical Communications, 2012, vol. 48, # 47, p. 5928 - 5930
17
[ 95-20-5 ]
[ 64-67-5 ]
[ 40876-94-6 ]
Reference：
[1] Patent: US2460745, 1944, ,
18
[ 95-20-5 ]
[ 2731-06-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1301 - 1305
[2] Organic Letters, 2002, vol. 4, # 23, p. 4033 - 4035
[3] Helvetica Chimica Acta, 1990, vol. 73, p. 439 - 454
[4] Justus Liebigs Annalen der Chemie, 1933, vol. 500, p. 42,45
[5] Journal of the American Chemical Society, 1959, vol. 81, p. 1203,1206
[6] ChemMedChem, 2012, vol. 7, # 7, p. 1286 - 1294
[7] Journal of Organic Chemistry, 2015, vol. 80, # 6, p. 3217 - 3222
[8] Green Chemistry, 2017, vol. 19, # 13, p. 2952 - 2956
[9] Patent: CN106674079, 2017, A,
19
[ 95-20-5 ]
[ 32588-36-6 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, # 21, p. 6808 - 6809
20
[ 95-20-5 ]
[ 1912-43-2 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1080,1084
[2] Justus Liebigs Annalen der Chemie, 1933, vol. 500, p. 42,45
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1899, vol. <5> 8 I, p. 316
23
[ 95-20-5 ]
[ 73430-27-0 ]
[ 2826-91-7 ]
Reference：
[1] Archiv der Pharmazie, 1994, vol. 327, # 2, p. 105 - 114
[2] European Journal of Organic Chemistry, 2012, # 6, p. 1230 - 1236
5-(2-Ethylindol-3-ylmethylene)thiazolidine-2,4-dione 2-Methylindole (1.0 g, 7.6 mmol) dissolved in diethyl ether (100 mL) under nitrogen was treated with n-Butyl lithium (2 M in pentane, 22.8 mmol) and potassium tert-butoxide (15.2 mmol) with stirring at RT for 30 min. The temperature was lowered to -70 C and methyl Iodide (15.2 mmol) was added and the resulting mixture was stirred at -70 for 2 h. Then 5 drops of water was added and the mixture allowed to warm up to RT. Subsequently, the mixture was poured into water (300 mL), pH was adjusted to 6 by means of 1N hydrochloric acid and the mixture was extracted with diethyl ether. The organic phase was dried with Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel using heptane/ether(4/1) as eluent. This afforded 720 mg (69percent) of 2-ethylindole. 1H NMR (DMSO-d6): delta=10.85 (1H,s); 7.39 (1H,d); 7.25 (1H,d); 6.98(1H,t); 6.90(1H,t); 6.10 (1H,s); 2.71 (2H,q); 1.28 (3H,t).
69%
2-Methyltndote (1.0 g, 7.6mmol) dissolved in diethyl ether (100 mL) under nitrogen was treated with n-Butyl lithium (2 M in pentane, 22.8 mmol) and potassium ferf-butoxide (15.2 mmol) with stirring at RT for 30 min. The temperature was lowered to -70 C and methyl Io.not. dide (15.2 mmol) was added and the resulting mixture was stirred at -70 for 2 h. Then 5 drops of water was added and the mixture allowed to warm up to RT. Subsequently, the mix- ture was poured into water (300 mL), pH was adjusted to 6 by means of 1N hydrochloric acid and the mixture was extracted with diethyl ether. The organic phase was dried with Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel using heptane/ether( 4/1) as eluent. This afforded 720 mg (69 percent) of 2-ethylindole.1H NMR (DMSO-rfbeta): delta = 10.85 (1H,S); 7.39 (1H,d); 7.25 (1H,d); 6.98(1 H,t); 6.90(1 H,t); 6.10 (1H,s); 2.71 (2H,q); 1.28 (3H,t).
69%
2-Methylindole (1.0 g, 7.6 mmol) dissolved in diethyl ether (100 mL) under nitrogen was treated with n-Butyl lithium (2 M in pentane, 22.8 mmol) and potassium tert-butoxide (15.2 mmol) with stirring at RT for 30 min. The temperature was lowered to -70 C. and methyl Iodide (15.2 mmol) was added and the resulting mixture was stirred at -70 for 2 h. Then 5 drops of water was added and the mixture allowed to warm up to RT. Subsequently, the mixture was poured into water (300 mL), pH was adjusted to 6 by means of 1N hydrochloric acid and the mixture was extracted with diethyl ether. The organic phase was dried with Na2SO4 and evaporated to dryness. The residur was purified by column chromatography on silica gel using heptane/ether (4/1) as eluent. This afforded 720 mg (69percent) of 2-ethylindole. 1H NMR (DMSO-d6): delta=10.85 (1H,s); 7.39 (1H,d); 7.25 (1H,d); 6.98(1H,t); 6.90(1H,t); 6.10 (1H,s); 2.71 (2H,q); 1.28 (3H,t).
67.7%
In an ice water bath, 2-methylindole (5 g, 38.1 mmol), 300 mL anhydrous diethyl ether, 2.4 M n-BuLi 47.5 mL (114 mmol), tert-butanol (8.5 g, 75.8 mmol) were added into a reaction vessel. Upon completion of addition, under protection of nitrogen, the reaction was stirred at room temperature for 0.5 h. Then the system was cooled to -70 °C, and iodomethane (10.245 g, 72.2 mmol) was added dropwise. Upon completion of addition, it was reacted for 2 h maintaining this temperature. Then it was warmed up to -40 °C. 2 mL water was added, and then warmed up to room temperature. The system was poured into water, adjusted to pH=6, extracted with diethyl ether, dried and rotate evaporated to dryness to obtain the product 3.74 g, at a yield of 67.7percent.
67.7%
In an ice water bath, 2-methylindole (5 g, 38.1 mmol), 300 mL anhydrous diethyl ether, 2.4 M n-BuLi 47.5 mL (114 mmol), tert-butanol (8.5 g, 75.8 mmol) were added into a reaction vessel. Upon completion of addition, under protection of nitrogen, the reaction was stirred at room temperature for 0.5 h. Then the system was cooled to -70° C., and iodomethane (10.245 g, 72.2 mmol) was added dropwise. Upon completion of addition, it was reacted for 2 h maintaining this temperature. Then it was warmed up to -40° C. 2 mL water was added, and then warmed up to room temperature. The system was poured into water, adjusted to pH=6, extracted with diethyl ether, dried and rotate evaporated to dryness to obtain the product 3.74 g, at a yield of 67.7percent.
Example 10 To a solution of 2-methylindole (1.0 g, 8.82 mmol) dissolved in THF (10 mL) was added 0.95M ethylmagnesium bromide (9.3 mL, 8.82 mmol) at 40 C., and the whole was stirred at 40 C. for 45 minutes. Successively, a solution of <strong>[1122-10-7]2,3-<strong>[1122-10-7]dibromomaleimide</strong></strong> (500 mg, 1.96 mmol) dissolved in THF (4 mL) was added thereto, followed by stirring under heating and refluxing for 3 hours. After addition of 20% aqueous citric acid solution (9 mL) to the reaction mixture under ice cooling and successive stirring, THF was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:2) to obtain N-methyl-2,3-bis(2-methyl-1H-indol-3-yl)maleimide (452 mg, 62.4%) as red solids. mp: >290 C.; 1H-NMR(CDCl3): delta 2.06(s, 6H), 3.22(s, 3H), 6.92(t, J=7.6 Hz, 2H), 7.08(t, J=7.6 Hz, 2H), 7.15-7.24(m, 4H), 8.04(br s, 2H). IR(KBr)3380, 3310, 1705, 1460, 1440, 1380 cm-1. MS m/z: 369(M+).
With caesium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;
5-(2-Methyl-indol-l-yl)-thiophene-2-carboxylic acid ethyl ester A screw cap reaction tube was charged with <strong>[5751-83-7]5-bromo-thiophene-2-carboxylic acid ethyl ester</strong> (0.941 g, 4.00 mmol), 2-methylindole (0.525 g, 4.00 mmol), CuI (76 mg, 0.040 mmol), Cs2CO3 (2.6 g, 8.0 mmol), N,lambdaT-dimethylethylenediamine (35 mg, 0.40 mmol) and toluene (4 mL). The tube was capped and the mixture stirred at 110 0C for 20 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite (1 cm) and silica (2 cm) (pad eluted with 10 mL of isohexane/ethyl acetate 1 :1) and the combined filtrate was concentrated under reduced pressure. The residue was purified by reversed phase column chromatog- raphy (C18-silica, manual gradient of 50-100% acetonitrile in water). Product containing fractions were concentrated and the residue further purified by silica chromatography (5-10% ethyl acetate in isohexane). Pure fractions were concentrated and dried under vacuum to give the sub-title compound (515 mg, 45%).
Step 1. 5-Bromo-2-methyl-7H-indoleTo a solution of 2-methyl-iH-indole (5.0 g, 38.12 mmol) in sulfuric acid (80 mL) was added Ag2S04 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Br2 (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room temperature, the reaction was then quenched by the addition of water/ice (300 mL). The reaction mixture was extracted with dichloromethane (3 x 200 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-2-methyl-7H-indole as a light brown solid (6 g, 75percent).LC/MS (ES, m/z): [M+H]+ 211.0'H-NMR (300 MHz, CDC13): delta 11.23 (s, 1Eta), 7.56 (s, 1Eta), 7.21 (d, / = 8.7 Hz, 1H), 7.07 - 7.09 (m, 1H), 6.11 (s, 1H), 2.38 (s, 3H)
59%
EXAMPLE 24 2,2,2-Trifluoro-1-(5-(3-(isopropyl(methyl)amino)-6-(1H-tetrazol-5-yl)quinoxalin-2-yl)-2-methyl-1H-indol-3-yl)ethanone Step 1. 5-Bromo-2-methyl-1H-indole To a solution of 2-methyl-1H-indole (5.0 g, 38.12 mmol) in sulfuric acid (80 ml) was added Ag2SO4 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Br2 (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room temperature, the reaction was quenched by the addition of water/ice (300 ml). The reaction mixture was extracted with dichloromethane (3.x.200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-2-methyl-1H-indole as a light brown solid (4.7 g, 59percent).LC/MS (ES, m/z): [M+H]+ 211.01H-NMR (300 MHz, CDCl3): delta 11.23 (s, 1H), 7.56 (s, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.07-7.09 (m, 1H), 6.11 (s, 1H), 2.38 (s, 3H)
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 36h;Reflux;
Experimental Procedure for (3d); To a mixture of piplartine (0.317 g, 1 mmol) and 2-methylindole (0.655 g, 5 mmol), Iodine (0.0152 g, 12 mol %) was added. The contents were refluxed in 1,2-dichloroethane (5 ml) for an appropriate time (36 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 di adduct (3d). Compound 2d (mono adduct) was not observed in this reaction.
With water; iodine; In acetonitrile; for 30h;Reflux;
Experimental Procedure for Compound (4); To a mixture of piplartine (1 mmol) and Indole (3 mmol), Iodine (10 mol %) was added. The contents were refluxed in methanol (5 ml) for an appropriate time (30 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 (1.0 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 column chromatography to afford pure product (4).
General procedure: 2-Methyl-1H-indole derivatives (0.5-6 mmol, 1 equiv) were stirred at 80 C in acetic acid (2 mL/1 mmol), <strong>[40064-34-4]4-piperidone hydrochloride hydrate</strong> (1.5-18 mmol, 3 equiv) and 1 M phosphoric acid (1 mL/1 mmol) were added. After 1-2 h, the mixture was poured into ice/ammonia, and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water and brine, dried, and evaporated in vacuo to give the title compounds. The crude products were purified by silica gel column chromatography (ethylacetate-methanol, gradient) and most of them were converted to the corresponding salts by dissolving the free base in methanol or ethanol and adding one equivalent of oxalic acid or ethanolic HCl solution. The solvent was removed and azeotroped with absolute ethanol in vacuo followed by recrystallization from appropriate solvents.
2-methyl-3-(5,6-dimethylbenzothiazol-2-yldiazenyl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
General procedure: 2-Aminobenzothiazole (0.30 g, 2.0 mmol) was dissolved in hot glacial acetic acid/propionic acid mixture (2:1, 6.0 ml) and was rapidly cooled in an ice-salt bath to -5 C. The mixture was then stirred for 2 h. at 0-5 C. The liquor was then added in portions during 30 min to a cold solution of nitrosyl sulfuric acid [prepared from sodium nitrite (0.15 g) and concentrated sulfuric acid (3 ml at 50 C)]. The mixture was stirred for an additional 2 h at 0 C. Excess nitrous acid was destroyed by the addition of urea. The resulting diazonium salt was cooled in salt/ice mixture. 2-methlyindole(0.26 g, 2.0 mmol) was dissolved in mixture of acetic acid/propionic acid solution (3:1, 8.0 ml) and cooled in salt/ice bath and then cold diazonium solution was added to this cooled solution by stirring in a dropwise manner. The solution was stirred at 0-5 C for 2 h. and pH of the reaction mixture was maintained at 4-6 by simultaneous addition of saturated sodium carbonate solution.The mixture was stirred for a further 1 h at 5 C. The resulting product was filtered, washed with water, dried and crystallized from ethanol mixture gave brown powder (yield: 0.29 g, 51%; m.p: 168-170 C), FT-IR (KBr) numax: 3345 (indole -NH), 3059 (aromatic C-H), 2969, 2920 (aliphatic C-H), 1605 (C=C) cm-1; 1HNMR (DMSO-d6/CDCl3): d 9.71 (b, indole -NH), 7.98 (1H,m), 7.37(1H,m), 7.30-7.15 (4H,m), 6.82 (2H,m), 2.36 (3H,s).Anal. Calcd. For C16H12N4S: C, 65.73; H, 4.14; N, 19.16; S, 10.97Found: C, 65.68; H, 4.19; N, 19.11; S, 10.92%.MS (m/z, 70 eV): 292.0 (M+), 277.0, 158.0, 130.0.
3-fluoro-4-((2-methyl-1H-indol-3-yl)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
In water; at 150℃; for 0.116667h;Microwave irradiation;
2-methylindole (1.000 g, 7.62 mmol) and <strong>[105942-09-4]4-(bromomethyl)-3-fluorobenzonitrile</strong> (1.632 g, 7.62 mmol) were added to water (10 mL) and allowed to react in a microwave reactor at 150 for 7 minutes. After completion of the reaction, the reaction solution was extracted with ethyl acetate and a saturated aqueous solution of sodium hydride carbonate, and the organic layer was dried with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the filtrate was purified by column chromatography (SiO2; ethyl acetate/hexane = 1 / 4) to afford the title compound (1.610 g, 80%) as a yellow solid.
3,4-di-(2-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
A solution of ethylmagnesium bromide in ethyl ether (7 ml) was prepared from magnesiumturnings (0.52 g, 19.5 mmol) and bromoethane (1.5 ml, 19.5 mmol). Under nitrogen atmosphere,the ethylmagnesium bromide solution was added to a solution of 2-methylindole(2.6 g, 19.5 mmol) in 35 ml toluene. After heating to 60C for 1h, a solution of <strong>[1122-10-7]dibromomaleimide</strong>(1.0 g, 3.9 mmol) in THF (7 ml) was added. The mixture was heated to refluxfor 24h, then cooled to room temperature and diluted with EtOAc (100 ml). The organiclayer was washed with aq. 1N HCl (50 ml), water (50 ml) and brine (50 ml) in succession,and was dehydrated over anhydrous MgSO4. The residue after evaporation of the solventwas purified by chromatography with EtOAc/hexane (2:1) afforded 1.2 g (86%). Meltingpoint: 184-186C.1H NMR(400 MHz, DMSO-d6): delta (ppm) 11.29 (1H, s), 10.94 (1H, s), 10.87 (1H, s),7.21 (2H, d, J = 8.0 Hz), 6.99 (2H, d, J = 8.0 Hz), 6.94 (2H, t, J = 8.0 Hz), 6.73 (2H, t,J = 8.0 Hz), 1.95 (6H, s); 13C NMR(100 MHz, DMSO-d6): delta (ppm): 172.3, 135.3, 135.2,134.8, 131.8, 126.8, 126.5, 120.7, 119.9, 119.2, 119.0, 118.7, 118.3, 110.5, 12.9; MS(EI,70 eV) m/z 355 (M+); HRMS calcd for C22H17N2O3 355.1321, found 355.1319.
86%
General procedure: A solution of ethylmagnesium bromide in ethyl ether (7 ml) was prepared from magnesiumturnings (0.52 g, 19.5 mmol) and bromoethane (1.5 ml, 19.5 mmol). Under nitrogen atmosphere,the ethylmagnesium bromide solution was added to a solution of 2-methylindole(2.6 g, 19.5 mmol) in 35 ml toluene. After heating to 60C for 1h, a solution of <strong>[1122-10-7]dibromomaleimide</strong>(1.0 g, 3.9 mmol) in THF (7 ml) was added. The mixture was heated to refluxfor 24h, then cooled to room temperature and diluted with EtOAc (100 ml). The organiclayer was washed with aq. 1N HCl (50 ml), water (50 ml) and brine (50 ml) in succession,and was dehydrated over anhydrous MgSO4. The residue after evaporation of the solventwas purified by chromatography with EtOAc/hexane (2:1) afforded 1.2 g (86%). Meltingpoint: 184-186C.1H NMR(400 MHz, DMSO-d6): delta (ppm) 11.29 (1H, s), 10.94 (1H, s), 10.87 (1H, s),7.21 (2H, d, J = 8.0 Hz), 6.99 (2H, d, J = 8.0 Hz), 6.94 (2H, t, J = 8.0 Hz), 6.73 (2H, t,J = 8.0 Hz), 1.95 (6H, s); 13C NMR(100MHz, DMSO-d6): delta (ppm): 172.3, 135.3, 135.2,134.8, 131.8, 126.8, 126.5, 120.7, 119.9, 119.2, 119.0, 118.7, 118.3, 110.5, 12.9; MS(EI,70 eV) m/z 355 (M+); HRMS calcd for C22H17N2O3 355.1321, found 355.1319.
With sodium iodide; In acetonitrile; at 20℃; for 18h;Irradiation;
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, 83percent).
With sodium tetrafluoroborate; potassium iodide; In acetonitrile; at 60℃; for 8h;Electrolysis;
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 94percent yield.
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