99% |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 2h; |
EXAMPLE 6 (E)-2-cyano-3-(1H-indol-2-yl)acrylic Acid Sulfuric acid (248 pL) was added to a solution of indole-2-carboxylic acid (2.48 mmol) in absolute ethanol (8 mL). The reaction mixture was refluxed for 15 h, and sulfuric acid (248 pL) was added. The reaction mixture was heated for a further 3 h. After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in 10 mL of DCM, and the resulting solution was washed with a saturated sodium carbonate aqueous solution (3*20 mL), water (10 mL) and brine (10 mL). The organic phase is dried with magnesium sulfate, filtered, evaporated under reduced pressure in order to obtain a white powder (365.8 mg, 77%). 1H NMR (400 MHz, CDCl3): delta 8.93 (s, 1H), 7.70 and 7.43 (2*d, J=8.1 Hz, 2H), 7.36-7.24 (m, 2H), 7.16 (t, J=7.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H). A solution of ethyl 1H-indole-2-carboxylate (2.65 mmol) in anhydrous tetrahydrofurane (10 mL) was added dropwise to a cooled solution (0 C.), a lithium aluminium hydride (3.98 mmol) suspension in anhydrous tetrahydrofurane (10 mL) and the mixture was stirred for 2 h. The reaction was stopped by dropwise addition of (5 mL) and washed with water (20 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 40% ethyl acetate cyclohexane) in order to obtain a white powder (386.7 mg, 99%). 1H NMR (400 MHz, CDCl3): delta 8.38 (se, 1H), 7.61 and 7.37 (2*d, J=8.0 Hz, 2H), 7.21 and 7.13 (m, 2H), 6.43 (t, J=7.3 Hz, 1H), 4.84 (se, 2H), 1.93 (se, 1H). |
98% |
With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃; for 1h; |
(a) Indole-2-carbinol (31). To a solution of ester 30 (7.5 g, 39.64 mmol) in ether (100 mL) was added LiAIH4 (2.3 g, 60.6 mmol) slowly at 0 C. under argon and warmed to room temperature for 1 h. The suspension was quenched with water and white precipitate was removed by filtration. The filtrate was dried (MgSO4) and concentrated to afford 31 as a solid (5.75 g, 98%): 1H NMR (300 MHz, CDCl3) delta 4.82 (s, 2, CH2OH), 6.41 (s,1, PyH), 7.11 (m, 1, ArH), 7.20 (m, 1, ArH), 7.35 (d, J=7.8 Hz, 1, ArH), 7.59 (d, J=7.7 Hz, 1, ArH), 8.35 (br.s, 1, NH). |
98% |
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To a solution of ethyl 1H-indole-2-carboxylate (7.5 g, 39.64 mmol) in ether (100 mL) was added LiAlH4 (2.3 g, 60.6 mmol) slowly at 0 C. under argon and warmed to room temperature for 1 h. The suspension was quenched slowly with water and white precipitate was removed by filtration. The filtrate was dried (MgSO4) and concentrated to afford Indole-2-carbinol as a solid (5.75 g, 98%): 1H NMR (300 MHz, CDCl3) delta 4.82 (s, 2, C2OH), 6.41 (s, 1, PyH), 7.11 (m, 1, ArH), 7.20 (m, 1, ArH), 7.35 (d, J=7.8 Hz, 1, ArH), 7.59 (d, J=7.7 Hz, 1, ArH), 8.35 (br. s, 1, NH). |
98% |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 0.5h; |
For the synthesis of 6, lithium aluminium hydride (2mmol) was stirred in dry THF at 0C. Then 1 (1mmol) was dissolved in THF and added drop wise to the solution of lithium aluminium hydride at 0C. Then, the mixture was slowly warmed to room temperature till the completion (0.5h) of reaction as monitored by TLC. It was then cooled to 0C, 10% aqueous sodium hydroxide (20mL) and 40mL of water was added successively. Then reaction mixture was allowed to stir for 0.5h, filtered through celite and washed with dry ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by isocratic flash column chromatography (petroleum ether: ethyl acetate=8: 2, v/v) on silica gel (200-400) to get pure compound 6 with 98% yield. |
98% |
With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 100℃; under 38002.6 - 76005.1 Torr; for 10h;Glovebox; Autoclave; |
General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5. |
96% |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3.5h; |
General procedure: To ethyl 1H-indole-2-carboxylate (1.3 g, 6.89 mmol) in THF at 0 .was added lithium aluminumhydride solution (1M, in THF 0.29 g, 1.54 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at0 . The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed withTHF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 1.1 g (96% yield) of thecrude (1H-indol-2-yl)methanol which was used directly in the next step. |
92% |
With lithium aluminium tetrahydride; In tetrahydrofuran; |
General procedure: In round-bottom flask94 containing the correspondent indole ester (1 eq.) in THF, LiAlH4 (4 eq.) was added in an95 ice bath under stirring. The ice bath was removed and the reaction was kept under96 magnetic stirring until the completion of the reaction was detected by TLC (1 hour). Then, in an ice bath, the reaction was quenched with distilled water diluted in THF, followed 97 by 4 eq. of 1 M NaOH solution and finally three times this volume of distilled water. The 98 suspension was stirred for 10 min, when the white precipitate was filtered off and washed 99 with THF. The filtrate was partially evaporated under reduced pressure and the remaining 100 solution was extracted with 2 x 20 mL AcOEt. The organic layer was collected, dried 101 with Na2SO4, filtered and the solvent evaporated under reduced pressure. 102(1H-Indol-2-yl)methanol (12) (2). Obtained from the general procedure as a yellow 103 solid, 92% yield; mp 71.9 - 73.3 C; IR (neat, cm-1) 3393, 3373, 3236, 1453, 1415, 1054; 104 1H NMR (200 MHz, CDCl3) delta 8.41 (broad s, 1H), 7.61 (d, 1H, J = 7.3), 7.62-7.10 (m, 105 3H), 6.39 (s, 1H), 4.72 (s, 2H), 2.55 (broad s, 1H); 13C NMR (50 MHz, CDCl3) delta 137.5, 106 136.3, 127.9, 122.1, 120.6, 119.9, 111.0, 100.5, 58.5. |
92% |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2.5h;Inert atmosphere; |
The solution of ethyl indole-2-carboxylate (4.73 g; 25 mmol) dissolved in dry THF (25 mL) was added dropwise to a stirredsuspension of LiAlH4 (1.23 g; 32.3 mmol) in dry THF (40 mL). The mixture was stirred 2.5 h at room temperature and cautiously quenched by adding dropwise: water (1.2 mL), 15% NaOH (1.2 mL) and again water (3.7 mL). The solution was stirred for 1 h andthe white precipitate was filtered out. The filter cake was washed with Et2O (4 × 25 mL). The combined organic phases were driedover Na2SO4 and the solvents were evaporated in vacuo. The crude product was crystallized from EtOAc-hexane 1:2 and washedwith EtOAc-hexane 1:20. The product that remained in the filtrate was separated by column chromatography (silica gel, EtOAchexane1:4, then 1:2).White solid, overall yield 3.39 g (92%); mp 74-75.5 C (EtOAc-hexane).1H NMR (Bruker 500 MHz, CDCl3) delta 2.16 (s 1H), 4.73 (s, 2H), 6.37 (s, 1H), 7.10 (t, J = 7.4 Hz; 1H), 7.17 (t, J = 7.6 Hz; 1H), 7.27 (d, J= 8.1 Hz; 1H), 7.57 (t, J = 7.7 Hz; 1H), 8.32 (s, 1H).13C NMR (Bruker 125 MHz, CDCl3) delta = 58.62, 100.54, 110.96, 119.92, 120.60, 122.17, 128.05, 136.36, 137.50.MS (EI): m/z (%) = 148 (15), 147 (98), 146 (25), 131 (26), 130 (98), 129 (100), 128 (25), 119 (11), 118 (35), 117 (23), 103 (15), 102(20), 91 (24), 90 (16), 89 (26), 84 (24), 77 (19), 73 (10), 69 (10), 66 (28), 65 (11), 63 (16), 57 (15), 51 (12), 43 (26), 39 (11).HRMS (EI) m/z calcd for C9H9NO*+: 147.0684; found: 147.0678. |
83% |
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[1185] To a suspension of lithium aluminum hydride (10.6 g, 264 mmol) in THF (200 mL) is added dropwise a solution of ethyl indole-2-carboxylate (50.0 g, 256 mmol) in THF (250 mL) over 25 minutes. After 3 h, water (10.6 mL) is carefully added, followed by 15% NaOH (10.6 mL), followed by additional portion of water (31.8 mL). The resulting suspension is dried (Na2SO4) and filtered through celite. After concentration under reduced pressure, the white solid (34.0 g) is crystallized from EtOAc/hexanes to give white needles for 1H-indol-2-ylmethanol. Yield 83%. HRMS (FAB) calcd for C9H9NO+H 148.0762, found 148.0771. |
75% |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1.5h; |
Compound 1a (100.00 g, 528.51 mmol) was dissolved in tetrahydrofuran (1000 mL), and lithium aluminum hydride (24.07 g, 634.21 mmol) was slowly added in batch at 0 C. The reaction mixture was stirred at this temperature for 1.5 hr, and then water (24 mL), 10% sodium hydroxide solution (24 mL), and water (72 mL) were successively added dropwise. The resulting mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness to obtain an oil crude product. The oil crude product was then slurried in a mixed solvent of ethyl acetate and petroleum ether (300 mL, v/v=50/1) to give Compound 1b (59.00 g, yield: 75%). 1H NMR (400 MHz, CDCl3) delta8.37 (br. s., 1H), 7.59 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.22-7.16 (m, 1H), 7.15-7.07 (m, 1H), 6.41-6.40 (m, 1H), 4.81 (s, 2H), 1.97 (br. s., 1H). MS-ESI calculated value [M+ H]+ 148, measured value 148. |
1.76 g (99%) |
With hydrogenchloride; diisobutylaluminium hydride; In tetrahydrofuran; |
2-Indolemethanol: In a 50-mL round-bottom flask, a total of 2.28 g (12 mmol) of ethyl 2-indolecarboxylate was dissolved in 15 mL of dry THF under N2. The solution was cooled to -78 C. (acetone-dry ice bath) and 24 mL (24 mmol) of 1.0M DIBAL in THF was added over a period of 1 h. The mixture was stirred for 2 h at -78 C., quenched with 10 mL of 1N HCl, then allowed to warm to room temperature. The reaction mixture was then extracted with ether (4*100 mL) and the ether layer was washed with 1N HCL (2*100 mL), dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by flash chromatography (1:1 ethyl acetate:petroleum ether). Yield: 1.76 g (99%). 1 H NMR (CDCl3): delta1.86 (t, 1H, J=6, OH), 4.82 (d, 2H, J=6), 6.40 (s, 1H), 7.0-7.3 (m, 2H), 7.34 (d, 1H, J=7.8), 7.58 (d, 1H, J=7.8), 8.36 (br s, 1H) MS (EI): m/z 147 (M+). |
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To a solution of ethyl indole-2-carboxylate (20 g) in 200 mL of TEtaF cooled at -78 0C was added 1 10 mL of 1 M solution LiAlEta4 in THF. The reaction mixture was stirred between -78 0C and 0 0C for 1 h, and then quenched by slow addition of 125 mL of 4N HCl followed by 150 mL of water. The reaction mixture was extracted with 1 L of 1 : 1 EtOAc/hexane and the extract was dried over Na2Stheta4. Filtration and concentration provided the crude alcohol, which was dissoled in 1.2 L of CH2CI2 and treated with 100 g of Mntheta2- After stirring for 2 h, the mixture was filtered through celite and the filtrate was used for the next step without further purification. |
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Stepl : 1 //-indole-2-carbaldehyde; To a -780C solution of ethyl indole-2-carboxylate in THF (0.5 M) was added 1.04 equiv. LiAlH4 as a IM solution in THF. The reaction was stirred for Ih with warming to O0C and then quenched by the slow addition of 5 equiv. HCl as a 4 N aqueous solution followed by an equal volume of water. The reaction mixture was extracted twice with excess EtO Ac/Hex (1 :1) and the combined organic layers were dried over Na2SO4. Filtration and evaporation of the volatiles provided the crude alcohol, which was dissolved in CH2Cl2 (0.1 M) and treated with 11 equiv. OfMnO2. After stirring for 2h, the mixture was filtered through Celite and the filtrate was used for the next step without further purification. |
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Description 1; 2-HydroxymethyI-lH-Indole (Dl); lH-Indole-2-carboxylic acid ethyl ester (20 gm, 0.105 M) in THF (50 mL) was treated with cooled and stirred suspension of Lithium Aluminum Hydride (6.21 gm, 0.163 M) in THF (15 mL) slowly over the period of lhour. The reaction mixture was heated at reflux for 3 hours. After the completion of reaction, the reaction mixture was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes and poured on to the ice water and compound was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to afford the compound, which was identified by IR, NMR Mass Spectral analyses as the title compound.Mass: 148 (M+H)+; NMR : 4.82 (2H, s), 6.40 - 6.40 (IH, d), 7.08 - 7.12 (IH, m), 7.16 - 7.25 (IH, m), 7.33 - 7.35 (IH, m), 7. 57 - 7.59 (IH, m), 8.35 (IH, bs). |
1.5 g |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; |
To a slurry of lithium aluminum hydride (1.00 g, 26.3 mmol) in anhydrous tetrahydrofuran (50 mL) which was cooled to 0 C was added a solution of ethyl 1H-indole-2-carboxylate (3.80 g, 20.0 mmol) in tetrahydrofuran (50 mL) dropwise at 0 C while stirring. The temperature of the mixture was then warmed naturally to room temperature and the mixture was stirred at room temperature overnight. The resulting mixture was quenched with methanol, and then filtered through a celite pad. The filtrate was concentrated in vacuo to afford 1.5 g of 1H-indol-2- ylmethanol. |
2.3 g |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h;Cooling with ice; |
In a 100 ml reaction flask, lithium aluminumhydride (902.63 mg, 23.78 mmol) and THF (30 ml) were added successively, stirred at room temperature for 5 min, then ice-cooled and slowly added. indole-2-carboxylic acid ethyl ester (3 g, 15.86 mmol) was added and the mixture was warmed to room temperature for 2 h.After completion of the reaction, the system was cooled to 0 C, then 20 ml of THF and 1.7 ml of 20% KOH were added thereto, stirred for 10 min, filtered, and the filter cake was washed with 20 ml of THF.The filtrate was washed once with saturated NaCl (10 ml), dried over anhydrous sodium sulfate and filtered.It was concentrated to dryness to give the title compound (2.3 g). |