* 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 4-methylmorpholine N-oxide In dichloromethane at 20℃; for 1 h; Molecular sieve
Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 A molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80percent): 1H NMR (300 MHz, CDCl3) δ10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H), CI MS m/z=146 [C9H7NO+H]+.
53%
Stage #1: With Dess-Martin periodane In dichloromethane for 1 h; Stage #2: With water In diethyl ether; dichloromethane; water
b) lH-Indole-4-carbaldehyde; Dess-Martin periodane (1.04 g, 2.46 mmol) was dissolved into anhydrous CH2Cl2 (10 ml). (lH-Indol-4-yi)-methanol (449 mg, 3.07 mmol) in anhydrous CH2Cl2 (10 ml) was added and the mixture was stirred for 1 h. Sodium hydroxide (50ml of IN solution) and ether (50 ml) were added and the reaction was stirred for 30 min. The organic layer was separated and washed with water (10 ml), brine (10 ml), dried over MgSO4, filtered and concentrated to a thick brown oil. Purification by column chromatography (silica gel, gradient elution of 2percent MeOH/CH2Cl2 to 5percent MeOH/CH2Cl2) gave lH-indole-4- <n="163"/>carbaldehyde (235 mg, 53percent) as a yellow solid: 1HNMR (300 MHz, DMSOd6) 5 11.59 (bs, IH), 10.18 (s, IH), 7.78-7.75 (m, IH), 7.66-7.60 (m, 2H), 7.33-7.28 (m, IH), 7.08 (d, J = 3.0 Hz, IH).
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 16, p. 3350 - 3352
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 26, p. 5755 - 5775
[3] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 8, p. 983 - 988
[4] Patent: US2006/111385, 2006, A1, . Location in patent: Page/Page column 20
[5] Chemistry Letters, 1980, p. 813 - 816
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 23, p. 3211 - 3218
[7] Patent: WO2007/53131, 2007, A2, . Location in patent: Page/Page column 161-162
[8] Helvetica Chimica Acta, 1954, vol. 37, p. 1826
2
[ 1074-85-7 ]
[ 114615-82-6 ]
[ 1074-86-8 ]
Yield
Reaction Conditions
Operation in experiment
80%
With 4-methylmorpholine N-oxide In dichloromethane
Step B: Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 A molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80percent): 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H); CI MS m/z=146 [C9H7NO+H]+.
Reference：
[1] Patent: US2002/91134, 2002, A1,
3
[ 16136-52-0 ]
[ 1074-86-8 ]
Reference：
[1] Tetrahedron, 1983, vol. 39, # 22, p. 3695 - 3706
[2] Heterocycles, 1987, vol. 26, # 5, p. 1173 - 1176
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 6, p. 2646 - 2650
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 1826
35
[ 52488-36-5 ]
[ 68-12-2 ]
[ 1074-86-8 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5106 - 5110
36
[ 1074-86-8 ]
[ 3468-18-6 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium borohydrid; methylamine In methanol; water
Step C: To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40percent methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0° C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3*) with ether. The combined organic layers were extracted with 2 N HCl (100 mL). The HCl layer was made basic (pH~11) with 2 N NaOH and extracted (3*) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88percent): 1H NMR (300 MHz, CDCl3) δ 8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
Reference：
[1] Patent: US2002/91134, 2002, A1,
37
[ 1074-86-8 ]
[ 74-88-4 ]
[ 133994-99-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.666667 h; Stage #2: at 20℃; for 12 h;
a) 1 -Methyl-lH-indole-4-carbaldehyde; To a solution of lH-indole-4-carbaldehyde (413 mg, 2.85 mmol) in anhydrous DMF (6.5 niL) was added sodium hydride (171 mg of 60percent dispersion in oil, 4.27 mmol). The mixture was stirred for 40 min at room temperature. Methyl iodide (0.36 mL, 5.78 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (25 mL) and the mixture was extracted with ethyl acetate (3x 25 mL). Combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2) gave l-methyl-lH-indole-4-carbaldehyde (452 mg g, 99percent) as a yellow oil: 1H NMR (400 MHz, DMSO-^) δ 10.20 (s, IH), 7.84 (d, J= 8.0 Hz, IH), 7.68 (d, J= 7.2 Hz, IH), 7.58 (d, J= 2.8 Hz, IH), 7.38-7.34 (m, IH), 7.08 (d, J= 3.2 Hz, IH), 3.87 (s, 3H).
89%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333 h; Inert atmosphere Stage #2: for 0.5 h; Inert atmosphere
To the solution of 28 in dimethylformamide (DMF) maintained at 0 °C was added sodium hydride (NaH, 0.36 g, 10.32 mmol) and was stirred for 5 min before adding methylidodide (MeI, 0.44 mL, 8.25 mmol) and the reaction was stirred for 30 min. Reaction was quenched by slow addition of water at 0 °C and extracted using EtOAc (25 mL 3). The combined organic layer was collected, dried over anhydrous MgSO4 andconcentrated under reduced pressure to give a pale yellow residue,which was purified by silica gel chromatography (EtOAc: Hexane,4:1) to give 31 as off white residue in 89percent yield; 1H NMR (300 MHz,CDCl3): δ 3.89 (s, 3H), 7.26-7.28 (m, 2H), 7.38 (t, J=8.1 Hz, 1H), 7.46(t, J=8.1 Hz, 2H), 10.27 (s, 1H).
70%
Stage #1: With caesium carbonate In acetonitrile at 60℃; for 2 h; Stage #2: at 60℃; for 1 h;
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
Reference：
[1] Patent: WO2007/53131, 2007, A2, . Location in patent: Page/Page column 178
[2] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 13 - 23
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2060 - 2079
[4] Journal of Organometallic Chemistry, 2011, vol. 696, # 5, p. 1072 - 1083
[5] Patent: WO2012/47702, 2012, A1, . Location in patent: Page/Page column 32
[6] Organic and Biomolecular Chemistry, 2017, vol. 15, # 35, p. 7404 - 7410
38
[ 1074-86-8 ]
[ 2472-88-0 ]
[ 74-88-4 ]
[ 133994-99-7 ]
Reference：
[1] Patent: US5086070, 1992, A,
39
[ 1074-86-8 ]
[ 75-03-6 ]
[ 894852-86-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 20℃; for 12 h;
a) l-ethyl-lH-indole-4-carbaldehvde; <n="181"/>To a solution of lH-indole-4-carbaldehyde (2.00 g, 13.8 mmol) in anhydrous DMF (6.5 niL) was added sodium hydride (827 mg of 60percent dispersion in oil, 20.7 mmol). The mixture was stirred for 30 min at room temperature. Ethyl iodide (2.22 mL, 27.5 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (100 mL) and the mixture was extracted with ethyl acetate (3x 100 mL). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, gradient elution Of CH2Cl2 to 5percent MeOH/CH2Cl2) gave the title compound (1-ethyl-lH- indole-4-carbaldehyde) (2.43 g, 99percent) as a yellow oil: 1H NMR (300 MHz, OMSOd6) δ 10.19 (s, IH), 7.88 (d, J= 8.1 Hz, IH), 7.68-7.64 (m, 2H), 7.37-7.32 (m, IH), 7.08 (d, J= 3.0, IH), 4.28 (q, J= 7.2 Hz, 2H), 1.36 (t, J= 7.2 Hz, 3H).
78%
Stage #1: With caesium carbonate In acetonitrile at 60℃; for 2 h; Stage #2: at 60℃; for 1 h;
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
Reference：
[1] Patent: WO2007/53131, 2007, A2, . Location in patent: Page/Page column 179-180
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2060 - 2079
With 4-methylmorpholine N-oxide;tetra-n-propylammonium perruthenate.; In dichloromethane; at 20℃; for 1h;Molecular sieve;
Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 A molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80%): 1H NMR (300 MHz, CDCl3) δ10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H), CI MS m/z=146 [C9H7NO+H]+.
53%
b) lH-Indole-4-carbaldehyde; Dess-Martin periodane (1.04 g, 2.46 mmol) was dissolved into anhydrous CH2Cl2 (10 ml). (lH-Indol-4-yi)-methanol (449 mg, 3.07 mmol) in anhydrous CH2Cl2 (10 ml) was added and the mixture was stirred for 1 h. Sodium hydroxide (50ml of IN solution) and ether (50 ml) were added and the reaction was stirred for 30 min. The organic layer was separated and washed with water (10 ml), brine (10 ml), dried over MgSO4, filtered and concentrated to a thick brown oil. Purification by column chromatography (silica gel, gradient elution of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) gave lH-indole-4- <n="163"/>carbaldehyde (235 mg, 53%) as a yellow solid: 1HNMR (300 MHz, DMSOd6) 5 11.59 (bs, IH), 10.18 (s, IH), 7.78-7.75 (m, IH), 7.66-7.60 (m, 2H), 7.33-7.28 (m, IH), 7.08 (d, J = 3.0 Hz, IH).
Ammonium acetate (5.8g, 75mmol) was added to a solution of 4- indolcarboxaldehyde (V) (29g, 200mol) in nitromethane (290mL), which was stirred and refluxed for 3h30min. The reaction mixture obtained was diluted with AcOEt and washed with a saturated solution of NaCi. The organic layer was dried and concentrated to dryness. The resultant residue was washed with cyclohexane and the solid was filtered, washed and dried under vacuum to obtain, 30.8g (82%) of 4-(2-nitrovinyl) indole (II). 1H-RMN (200 MHz, DMSO-d6) δ: 6,90 (m, 1H, 3-H), 7,20 (t, J=7,8Hz, 1H, 2-H), 7,62 (m, 3H, Ar), 8,19 (d, J=14Hz, 1H, Ar-CH=CH-N02), 8,42 (d, J=14Hz, 1H, Ar-CH=CH- NO2), 11,6 (broad, 1H, NH).
With sodium methylate; In methanol; at -25 - 0℃;Inert atmosphere;
Example 6 Compound 2. To a solution of <strong>[1074-86-8]indole-4-carboxaldehyde</strong> (1, 583 mg, 4 mmol) and methyl azidoacetate (460 mg, 40 mmol) in dry methanol (20 mL) was added sodium methoxide in methanol dropwise (6.9 mL of 25% NaOMe, 32 mmol) at -25 C. (dry ice/CCl4) under N2. The reaction mixture was warmed to 0 C. and was stirred 3.5 h. The reaction mixture was poured into water (120 mL) and was extracted with EtOAc (2*60 mL). The combined extracts were washed with saturated aqueous NaCl (60 mL) and were dried (MgSO4). The solvent was removed in vacuo to give 2 (890 mg, 91%). 1H-NMR (CDCl3) δ 8.28 (br s, 1H), 8.06 (d, 1H, J=7.6 Hz), 7.45 (s, 1H), 7.42 (d, 1H, J=7.6 Hz), 7.30 (t, 1H, J=3.2 Hz), 7.26 (s, 1H), 6.73 (br s, 1H), 3.96 (s, 3H).
37% aq. HCHO (38.0 mg, 0.44 mmol, 1.2 mol eq) was added toa solution of 50% aq. NHMe2 (49.8 mg, 0.55 mmol, 1.5 mol eq) in AcOH (1.0 mL) and then a solution of 47 (50.7 mg, 0.35 mmol) in AcOH (2.0 mL) was added with stirring at rt. After making the reactionmixture alkaline by adding 8% NaOH solution, the whole was extracted with CH2Cl2-MeOH (95:5, v/v).The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. Theresultant residue was purified by p-TLC on Al2O3 with CH2Cl2-MeOH (95:5, v/v). Extraction of the bandhaving an Rf value of 0.40-0.03 with CHCl3-MeOH-30% aq. NH3 (46:5:0.5, v/v) afforded 56 (52.3 mg,72%).
Intermediate 77; 4-(Azetidin-l-ylmethyl)-lH-indole; Sodium triacetoxy borohydride (1.46 g, 6.9 mmol) was added to a solution of lH-indole-4- carbaldehyde (0.5 g, 3.4 mmol) and azetidine (0.39 g, 6.87 mmol) in THF (15 ml). The mixture was stirred for Ih and diluted with dichloromethane and NaHCCβ (aq). The organic phase was washed with brine (Ix), dried (MgSO4) and evaporated. The crude product was dissolved in dichloromethane and hexane was added (1:1). The offwhite powder was filtered and washed with a mixture of dichloromethane hexane (1:1). Yield: 400 mg (52%). Offwhite solid. MS (ESI+) for Ci2Hi4N2 m/z 187 (M+H)+.
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water;Product distribution / selectivity;
Intermediate 49; l-(Phenylsulfonyl)-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong>; lH-Indole-4-carbaldehyde (0.300 g, 2.01 mmol), benzensulfonyl chloride (0.47 g, 2.67 mmol) and tetrabutylammonium hydrogen sulfate (0.070 g, 0.21 mmol) were dissolved in dichloromethane (10 mL) and NaOH (413 mg, 10.33 mmol) in water (3 mL) was added. The mixture was stirred overnight and diluted with water and extracted with dichloromethane (Ix). The combined organics were dried (MgSO4) and the crude product was purified with a plug of silica using 1% MeOH in dichloromethane as the eluent. Yield: 541 mg (95%). White solid. MS (electronspray; [M+H]+) m/z 286.3.
89%
After a suspension of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> 5 (2.0g, 14mmol), TBAHS (0.72g, 2.1mmol), and KOH (1.6g, 28mmol) in CH2Cl2 (100mL) was stirred for 20min, benzenesulfonyl chloride (2.6mL, 21mmol) was added, and the mixture was stirred at room temperature for 16h. The reaction was quenched with water, and extracted with CH2Cl2 (50mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was puried by silica gel chromatography (ethyl acetate/petroleum=1:8) to afford the 1-phenylsulfonyl indole (3.5g, 12mmol) as a white solid. Yield: 89%. 1H NMR (400MHz, CDCl3) δ 10.17 (s, 1H), 8.28 (d, J=8.3Hz, 1H), 7.88 (d, J=8.1Hz, 2H), 7.77 (d, J=2.8Hz, 1H), 7.72 (d, J=7.4Hz, 1H), 7.59-7.42 (m, 6H).
Intermediate 5; l-(Phenylsulfonyl)-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> lH-Indole-4-carbaldehyde (24.8 g, 0.17 mol) was dissolved in dry DMF (500 ml), cooled in ice-bath and NaH (7.5 g (60% suspension in oil), 0.19 mol, 1.1 eq.) was added. After stirring for a few minutes, the cold bath was removed and the rxn mixture was stirred at room temperature for 40 min. under Ar. The insoluble NaH clumps were brought in solution by means of sonication for a few minutes. The mixture was cooled in ice-bath and benzenesulfonyl chloride (23.9 ml, 0.188 mol, 1.1 eq.) was added dropwise over 3 min. The reaction mixture was stirred at room temperature for 1 hour, then poured slowly into a mixture of water (1 L) and EtOAc (200 ml). The aqueous phase was extracted with EtOAc (5x100 ml), the organic phase was washed with brine (200 ml), dried over Na2SO4 and evaporated. The residue was purified on silica flash column using petroleumether/EtOAc (1 :1) giving the product as a colorless crystalline solid. Yield: 45.5 g. MS m/z 286 [M + H]+.
(6,7-dimethoxy-3,4-dihydro-2<i>H</i>-isoquinolin-1-ylidene)-acetic acid ethyl ester[ No CAS ]
ethyl 2-(1H-indol-4-yl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With piperidine; In ethanol; isopropyl alcohol; at 80℃;
Example 1 ethyl 2-(1H-indol-4-yl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate A mixture of 500 mg (1.8 mmol) of ethyl (6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (Intermediate 2.1), 523 mg (3.61 mmol) of <strong>[1074-86-8]indole-4-carbaldehyde</strong>, 281 mg (3.61 mmol) of nitroethane and 61.4 mg (0.72 mmol) of piperidine in 10 ML of ethanol/isopropanol (1:1) was stirred at 80 C. overnight. 40 ML of isopropanol were added, the mixture was cooled to 0 C., and the resulting precipitate was filtered off.The solid was washed with ethanol and dried in vacuo to give the title compound as a white solid.The title compound was readily recrystallized from ethyl acetate to furnish white needles. Yield: (487 mg, 63%) Melting point [ C.]: 246-247 _
c) (lH-Indol-4-ylmethyl)-methyl-amine; lH-Indole-4-carbaldehyde (219 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to an orange solid and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.0 mg, 1.53 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, IN) was added and the aqueous layer was extracted with ethyl acetate (3x 20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (lH-indol-4-ylmethyl)-methyl- amine (229 mg, 94%) as a brown solid: 1B. NMR (400 MHz, DMSOd6) δ 11.03 (bs, IH), 7.29-7.24 (m, 2H), 7.03-6.93 (m, 2H), 6.51-6.50 (m, IH), 3.88 (s, 2H), 2.30 (s, 3H).
88%
To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40% methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0 C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3×) with ether. The combined organic layers were extracted with 2 N HCl (100 mL) . The HCl layer was made basic (pH11) with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88%): 1H NMR (300 MHz, CDCl3) δ8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
54.5%
Example 55N2-((lH-Indol-4-yl)methyl)-N4-(5-cyclopropyl-lH-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine (I- 40) step 1 : To a solution of methanamine (536 mg, 17.24 mmol) in MeOH (10 mL) was added lH-indole-4- carbaldehyde (500 mg, 3.45 mmol). The reaction mixture was stirred at RT for 14 h. The reaction was cooled in an ice bath and NaBH4 (130 mg, 3.45 mmol) was added in several portions. The reaction was stirred at 0 C for 5 min then stirred at RT for 4 h. The solvent was removed under reduced pressure to afford 300 mg (54.5%) of (lH-indol-4-yl)-N-methylmethanamine (116) which was used in the next step without further purification: MS (ESI) m/z = 161.3 [M+l] +.
With sodium borohydrid; methylamine; In methanol; water;
Step C: To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40% methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0 C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3*) with ether. The combined organic layers were extracted with 2 N HCl (100 mL). The HCl layer was made basic (pH~11) with 2 N NaOH and extracted (3*) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88%): 1H NMR (300 MHz, CDCl3) delta 8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
With 4-methylmorpholine N-oxide;silica gel; In dichloromethane;
Step B: Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 A molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80%): 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H); CI MS m/z=146 [C9H7NO+H]+.
4,5-dichloro-2-tetrahydropyranyloxy benzylchloride[ No CAS ]
[ 24006-92-6 ]
[ 280134-99-8 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In tetrahydrofuran;
This compound was prepared from 4-formylindole and 4,5-dichloro-2-tetrahydropyranyloxy benzylchloride [prep. from 1,2-dihydroxymethyl-4,5-dichloro benzene acc. W. Y. Lee et al. J. Org. Chem. 57, 1992, 4074-4079] following the general procedure for alkylation of indoles. After treatment of the product with 1N HCl in THF, 4-formyl-1-(4,5-dichloro-2-hydroxymethylbenzyl)-indole was obtained. 1H NMR (CDCl3): delta 4.65 (s, 2H), 5.45 (s, 2H), 6.81 (s, 1H), 7.26 (s, 1H), 7.27 (d, J=3.4 H8 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.36 (d, J=3.8 Hz, 1H), 7.51 (d, J=6.8 Hz, 1H), 7.52 (s, 1H), 7.66 (d, J=7.2 Hz, 1H), 10.25 (s, 1H).
Example 4 N2-((lH-Indol-4-yl)methyl)- N4-(5-cyclopropyl-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (1-38) step 1 : To a solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (2.9 g, 20 mmol) in THF (50 mL) cooled in an ice bath was added NaH (0.96 g, 60% in oil, 24 mmol) with vigorous stirring. After stirring for 30 min, 4- toluenesulfonyl chloride (5.73 g, 30 mmol) was added. The mixture was stirred at RT overnight and the solvent was removed in vacuo. The residue was diluted with DCM (500 mL) and water (50 mL). The organic layer was separated, dried (MgSO i), filtered and concentrated. The crude product was purified by S1O2 chromatography eluting with a petroleum ether/EtOAc gradient (5 to 10% EtOAc) to afford 900 mg (15%) of l-tosyl-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (42) as white solid: MS (ESI) m/z = 300.1 [M+l]+.
EXAMPLE 22 Synthesis of 1-(p-toluenesulfonyl)<strong>[1074-86-8]indole-4-carbaldehyde</strong> STR29 The same procedures used in Example 17 were repeated except for using 1.09 g of <strong>[1074-86-8]indole-4-carbaldehyde</strong> and 1.05 g of p-toluenesulfonyl chloride instead of the benzenesulfonyl chloride used therein to thus give 1.79 g of 1-(p-toluenesulfonyl)<strong>[1074-86-8]indole-4-carbaldehyde</strong> as brown crystals. The yield thereof was found to be 80%. NMR (CDCl3) 2.32 (3H,s), 7.22 (2H,d,J=8.6 Hz), 7.4~7.6 (2H,m), 7.6~7.8 (4H,m), 8.26 (1H,d,J=7.1 Hz), 10.17 (1H,s)
1-(2,3-difluorobenzyl)indole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 53 Synthesis of 1-(2,3-difluorobenzyl)indole-4-carbaldehyde STR60 The same procedures used in Example 1 were repeated except for using 580 mg of indole-4-carbaldehyde and 911 mg of <strong>[113211-94-2]2,3-difluorobenzyl bromide</strong> in place of the benzyl bromide used in Example 1 to give 841 mg of 1-(2,3-difluorobenzyl)indole-4-carbaldehyde as pale brown crystals. The yield thereof was found to be 76%. NMR (CDCl3) delta: 5.46 (2H,s), 6.59 (1H,dd,J=7.0 Hz, 7.0 Hz), 6.8~7.2 (2H,m), 7.2~7.4 (3H,m), 7.59 (1H,d,J=8.1 Hz), 7.65 (1H,dd,J=7.3 Hz, 1.1 Hz), 10.25 (1H,s)
1-(2,6-difluorobenzyl)indole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 63 Synthesis of 1-(2,6-difluorobenzyl)indole-4-carbaldehyde STR70 The same procedures used in Example 1 were repeated except for using 2.35 g of <strong>[697-73-4]2,6-difluorobenzyl chloride</strong> and 2.00 g of indole-4-carbaldehyde as a starting material to give 3.74 g of 1-(2,6-difluorobenzyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 100%. NMR (CDCl3) delta: 5.41 (2H,s), 6.8~6.9 (2H,m), 7.2~7.5 (4H,m), 7.61 (1H,d,J=7.3 Hz), 7.82 (1H,d,J=8.1 Hz), 10.22 (1H,s)
With dmap; In acetonitrile; for 48h;Heating / reflux;
To lH-Indole-4-carbaldehyde (518, 1.57 g, 10.8 mmol) in acetonitrile (20 mL) was added 1- isocyanatobutane (1.81 mL, 16.2 mmol), followed by 4-dimethylaminopyridine (130 mg, 1.1 mmol). The reaction was refluxed for 48 hours. The reaction solution was quenched with 1 M HCl (aq.) and EPO <DP n="140"/>extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to give a light yellow solid (519, 2.62 g,
2-amino-4-(1H-indol-4-yl)-5-oxo-7-(2,4,6-trimethyl-phenyl)-1,5,7,8-tetrahydro-4H-pyrano[4,3-b]pyridine-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate; 1-butyl-3-methylimidazolium Tetrafluoroborate; at 100℃; for 1 - 2h;
Example 109[0407] Preparation of 2-Amino-4-(lH-indol-4-yl)-5-oxo-7-(2,4,6-trimethyI-phenyl)- l,5,7,8-tetrahydro-4H-pyrano[4,3-b]pyridine-3-carboxylic acid ethyl ester. <n="150"/>[0408] Synthesis of 2-Amino-4-(lH-indol-4-yl)-5-oxo-7-(2,4,6-trimethyl-phenyI)- l,5,7,8-tetrahydro-4H-pyrano[4,3-b]pyridine-3-carboxylic acid ethyl ester (13oo): Ethyl amidinoacetate acetic acid salt is added to a 25-mL flask followed by lactone (1 equiv) and indole-4-carboxaldehyde (1 equiv). l-Butyl-3-methylimidazolium tetrafluoroborate (approx 2-3 drops/mmol of substrate) is added and the reaction mixture stirred at 100 0C for 1-2 hours. After completion (determined by LCMS), the reaction slurry is diluted with EtOAc and saturated NaHCO3. The organic layer is collected and the aqueous layer further extracted with 3 x EtOAc. The product is purified in 25-80% EtOAc in hexanes. MS (ES) M+H expect 472.2, found 472.2.
With sodium methylate; In methanol; at -25 - 0℃; for 3.5h;
Synthesis of compound 2: To a solution of <strong>[1074-86-8]indole-4-carboxaldehyde</strong> (1, 583 mg, 4 mmol) and methyl azidoacetate (460 mg, 40 mmol) in dry methanol (20 mL) was added sodium methoxide in methanol dropwise (6.9 mL of 25% NaOMe, 32 mmol) at -250C (dry ice/CCL) under N2. The reaction mixture was warmed to O0C and was stirred 3.5 h. The reaction mixture was poured into water (120 mL) and was extracted with EtOAc (2 x 60 mL). The combined extracts were washed with saturated aqueous NaCl (60 mL) and were dried (MgSO4). The solvent was removed in vacuo to give 2 (890 mg, 91%). 1HNMR (CDCl3) δ 8.28 (br s, IH), 8.06 (d, IH, J=7.6 Hz), 7.45 (s, IH), 7.42 (d, IH, J=7.6 Hz), 7.30 (t, IH, J=3.2 Hz), 7.26 (s, IH), 6.73 (br s, IH), 3.96 (s, 3H).
(6-Amino-quinolin-2-yl)-(R)-indan-1-yl-amine (0.10 g, 0.36 mmol), indol-4-carboxaldehyde (0.063 g, 0.44 mmol) and acetic acid (0.06 mL) were dissolved in methanol (3 mL). After 3 h of stirring at ambient temperature NaBH3CN (0.057 g, 0.91 mmol) was added and the reaction mixture stirred for 16 h at ambient temperature. Saturated sodium bicarbonate solution was added then and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate was evaporated. The residual yellow oil was subjected to column chromatography (silica gel, heptane, ethyl acetate; 9:1=>1:2) to yield the title compound as a yellow foam (34 mg, 23%); MS 405.7 [(M+H)+].
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;
[00313] A reaction vial was charged with N-(quinolin-3-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (20.00 mg, 0.07238 mmol), lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (10.5 mg, 0.0000724 mol), sodium triacetoxyborohydride (76.7 mg, 0.000362 mol) and 1 ,2-dichloroethane (3 mL, 0.04 mol) and the reaction stirred at room temperature over night. The reaction was then quenched with water and extracted with dichloromethane. The solvent was removed and the residue purified by prep HPLC to get the product as light yellow solid. MS (M+H)= 406.4
With potassium hexamethylsilazane; In tetrahydrofuran; at -78℃; for 3h;
Intermediate 2: Preparation of Benzyl 4-(cyanomethyl)-lH-indole-l-carboxylate Step-1 : Preparation of Benzyl 4-formyl-lH-indole-l-carboxylate <n="31"/>To a solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (12g, 82.75 mmol) in dry tetrahydrofuran (THF) (330 ml) was added potassium hexamethyldisilazane (KHMDS) (33.0 g, 165.5 mmol) at -78 0C in portion wise followed by a tetrahydrofuran solution of benzyl chloroformate (17.6 ml, 124.12 mmol) during a period of 1.0 hour at the same temperature. The mixture was stirred for an additional 2 hours at the same temperature, diluted with cold water (100 ml) followed by ethyl acetate (200 ml) and allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using 5% ethyl acetate/hexane as eluant to afford the title compound (12.0 g, 52%) as colorless oil which solidifies when stored in a refrigerator. 1H NMR (300 MHz, CDCl3) δ 5.47 (s, 2 H), 7.28-7.5 (m, 7 H), 7.7 (d, 1 H, J= 0.9 Hz), 7.8 (d,1 H, J= 3.6 Hz), 8.5 (d, 1 H3 J= 8.1 Hz), 10.2 (s, 1 H).
To a solution of 35.01 g (81.6 mmol) of (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in 200 ml of dichloromethane was added at 0 C. 11.01 ml (87.1 mmol) of tetramethyl guanidine and the mixture was warmed to 22 C. The mixture was treated with 7.9 g (54.4 mmol) of 4-formyl-indole and stirring was continued at 40 C. for 16 h. The mixture was treated again with 10.0 g (23.3 mmol) of the Wittig salt and 8.0 ml (24.0 mmol) of tetramethyl guanidine and stirring was continued at 40 C. for 24 h after which time the conversion was complete. The reaction mixture was poured into crashed ice and then extracted twice with MeCl2. The organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, 95:5 to 4:1) to give 15.12 g of the title compound as a light yellow solid. MS: 259.1 (M+).
a) 1 -Methyl-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong>; To a solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (413 mg, 2.85 mmol) in anhydrous DMF (6.5 niL) was added sodium hydride (171 mg of 60% dispersion in oil, 4.27 mmol). The mixture was stirred for 40 min at room temperature. Methyl iodide (0.36 mL, 5.78 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (25 mL) and the mixture was extracted with ethyl acetate (3x 25 mL). Combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2) gave l-methyl-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (452 mg g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-^) δ 10.20 (s, IH), 7.84 (d, J= 8.0 Hz, IH), 7.68 (d, J= 7.2 Hz, IH), 7.58 (d, J= 2.8 Hz, IH), 7.38-7.34 (m, IH), 7.08 (d, J= 3.2 Hz, IH), 3.87 (s, 3H).
89%
To the solution of 28 in dimethylformamide (DMF) maintained at 0 C was added sodium hydride (NaH, 0.36 g, 10.32 mmol) and was stirred for 5 min before adding methylidodide (MeI, 0.44 mL, 8.25 mmol) and the reaction was stirred for 30 min. Reaction was quenched by slow addition of water at 0 C and extracted using EtOAc (25 mL 3). The combined organic layer was collected, dried over anhydrous MgSO4 andconcentrated under reduced pressure to give a pale yellow residue,which was purified by silica gel chromatography (EtOAc: Hexane,4:1) to give 31 as off white residue in 89% yield; 1H NMR (300 MHz,CDCl3): δ 3.89 (s, 3H), 7.26-7.28 (m, 2H), 7.38 (t, J=8.1 Hz, 1H), 7.46(t, J=8.1 Hz, 2H), 10.27 (s, 1H).
82.56%
With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere;
To a stirred solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (1 g, 6.8 mmol, 1 eq) in DMF (10 mL) was added NaH (0.130 g, 7.4 mmol, 1.1 eq) at 0 C under the nitrogen atmosphere followed by addition of methyl iodide (1.06 g, 7.5 mmol, 1.1 eq). The reaction mixture was stirred at 0C for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the titled compound 1- methyl-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (0.90 g, 82.56%). LCMS: 160.07 [M+H]+.
70%
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
70%
Sodium hydride (0.570 g,14.25 mmol) were added portionwise to a stirred solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (1.88 g,12.95 mmol) in THF (30 mL) at rt, under nitrogen. The resulting red mixture wasstirred at 0 C for 15 minutes, iodomethane (0.81 mL,12.95 mmol) was added and the resulting solution was stirred at 0 C for 10minutes and then at rt for 90 minutes. The reaction mixture was quenched withwater (50 mL), diluted with saturated brine (50 mL), extracted with EtOAc (2 x 150 mL), theorganic layer was dried over MgSO4, filtered and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in heptane to afford1-methyl-<strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (1.45 g, 70 %) as a yellow oil. 1HNMR (400 MHz, CDCl3) 3.86 (s, 3H), 7.26 (q, J = 2.9 Hz, 2H), 7.32 - 7.38 (m, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.63 (d, J= 7.3 Hz, 1H), 10.25 (s, 1H); MS (ESI) [M + H]+ m/z160.
To a solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (0.252 g, 1.72 mmol) in 8 mL of DMF was added sodium hydride (0.046 g, 1.9 mmol). After 5 mm, iodomethane (0.13 mL, 2.1 mmol) was added. After 30 min, the reaction was treated with saturated aqueous ammonium chloride, diluted with water, and extracted 2x with dichloromethane. The combined organic fractions were washed 3x with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-40% ethyl acetate in hexanes to provide 1- methyl-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 161.2 for [M+Hf .
a) l-ethyl-lH-indole-4-carbaldehvde; <n="181"/>To a solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (2.00 g, 13.8 mmol) in anhydrous DMF (6.5 niL) was added sodium hydride (827 mg of 60% dispersion in oil, 20.7 mmol). The mixture was stirred for 30 min at room temperature. Ethyl iodide (2.22 mL, 27.5 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (100 mL) and the mixture was extracted with ethyl acetate (3x 100 mL). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, gradient elution Of CH2Cl2 to 5% MeOH/CH2Cl2) gave the title compound (1-ethyl-lH- <strong>[1074-86-8]indole-4-carbaldehyde</strong>) (2.43 g, 99%) as a yellow oil: 1H NMR (300 MHz, OMSOd6) δ 10.19 (s, IH), 7.88 (d, J= 8.1 Hz, IH), 7.68-7.64 (m, 2H), 7.37-7.32 (m, IH), 7.08 (d, J= 3.0, IH), 4.28 (q, J= 7.2 Hz, 2H), 1.36 (t, J= 7.2 Hz, 3H).
78%
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (15 mg, 0.048 mM) in absolute ethanol (2.0 mL), there were added 4-formyl-indole (11 mg, 0.076 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off and then washed with ethanol to thus give the title compound (12 mg, yield: 58%). 1H-NMR (300 MHz, DMSO): δ 3.77 (4H, m), 3.91 (4H, m), 6.39 (1H, s), 6.57 (1H, s), 7.06-7.23 (3H, m), 7.40-7.52 (5H, m), 7.95 (1H, s), 7.97 (1H, s), 8.35 (1H, s), 11.16 (1H, s), 11.34 (1H, s); MS (ESI) m/z (M+H)+ 438
Step A: methyl 2-(4-chlorophenyl)-2-(4-formyl-lH-indol-l-yl)acetateTo a solution of lH-indole-4-carbaldehyde (2.0 g, 13.79 mmol) in DMF (50 mL) was added NaH (0.66 g, 16.55 mmol) at 0 C. After stirring for 30 min at 0 C, a solution of methyl 2-bromo-2-(4-chlorophenyl)-acetate (4.67 g, 17.92 mmol) in DMF (20 mL) was added dropwise. The reaction was allowed to warm to rt and stirred for an additional 1 hr. Then it was diluted with EtOAc (200 mL) and quenched with water. The organic layer was separated and washed with brine (50 mL), dried over Na2S04, filtered and the solvent was removed in vacuo. The residue was purified via column chromatography (0-20 % EtOAc/hexanes) to provide the title compound.
<strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (1.5 g, 10.33 mmol) was added to a solution of tert- butyl piperazine-1-carboxylate (2.89 g, 15.50 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 1 h, and sodium cyanoborohydride (1.948 g, 31.0 mmol) was added and the mixture was stirred at room temperature for 7 days. Water was then added and solid material separated which was collected by filtration. The crude product was fractionated using flash chromatography on silica gel using 35% ethyl acetate in hexanes as eluent. Homogenous fractions were combined and evaporated to give the title compound as a white solid (405 mg, 12.43 % yield). Analytical LC/MS conditions: Phenomenex LUNA C18 column, 50x2, 3 mm particles Mobile Phase A: 5 % acetonitrile: 95% water: 10 mM ammonium acetate; Mobile Phase B: 95 % acetonitrile: 5% water: 10 mM ammonium acetate; Temperature: 40 C; Gradient: 0-100 % B over 4 minutes, then a 1 minute hold at 100% B; Flow: 0.8 mL/min; Detection: UV at 220 nm. LC/MS results: 2.9 min, 316 (M+H)+. 1H NMR (400 MHz, chloroform-d) d 8.23 (br. s., 1H), 7.35 (d, J=8.1 Hz, 1H), 7.23 (br. s., 1H), 7.18 (t, J=7.7 Hz, 1H), 7.13-7.05 (m, 1H), 6.76 (br. s., 1H), 3.83 (s, 2H), 3.51-3.40 (m, 4H), 2.53-2.40 (m, 4H), 1.48 (s, 9H).
With sodium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 8h;
4-formyl-1H-indole (1 g, 6.896 mmol) dissolved in EDC (50 mL) was taken in a 250 mL round bottom flask. N-boc-piperazine (1.54 g, 8.275 mmol) was added to the flask followed by sodium cyanoborohydride (0.65 g, 10.3 mmol). The reaction mass was stirred for 8 h while monitoring the progress of the reaction by TLC. After completion of the reaction (TLC), the reaction mass was quenched in to ice water (25 mL) and basified with lye solution (pH ~10). The separated organic layer was dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain crude thick oil. The compound was purified over silica gel column with hexanes and ethyl acetate as eluent. IR (cm-1): 2985, 1685, 1480, 1278, 714; Mass (m/z): 316 (M+H)+; 1H NMR (400 MHz, CDCl3) δ: 1.44 (9H, s), 2.45 (4H, bs), 3.42 (4H, bs), 3.8 (2H, s), 6.72 - 6.73 (1H, m), 7.06 - 7.08 (1H, d, J = 7.07 Hz), 7.13 - 7.17 (1H, m), 7.20 - 7.22 (1H, m), 7.31 - 7.33 (1H, d, J = 8.04 Hz), 8.22 (1H, bs).
Reference Example 8d 4-(4-methanesulfonylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole 2.92 g of sodium triacetoxyborohydride, 2.26 of <strong>[161357-89-7]1-methanesulfonylpiperazine hydrochloride</strong> and 545 mg of pyridine are successively added to a solution of 1 g of indole-4-carboxaldehyde in 40 ml of tetrahydrofuran under argon. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid cooled to 15 C., and then 1.30 g of sodium cyanoborohydride are added in portions. The reaction medium is stirred for 2 hours while allowing it to rise to ambient temperature, poured into a water/ice mixture, treated with 28% aqueous ammonia until the pH is neutral, and extracted with dichloromethane (4×30 ml). The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate), so as to give 890 mg of 4-(4-methanesulfonylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole in the form of a yellow solid.
Reference Example 9d 4-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole 1.38 g of 1-methylpiperazine and 2.92 g of sodium triacetoxyborohydride are successively added to a solution of 1 g of <strong>[1074-86-8]indole-4-carboxaldehyde</strong> in 40 ml of tetrahydrofuran under argon. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid, cooled to 15 C., and then 1.30 g of sodium cyanoborohydride are added in portions. The reaction medium is stirred for 2 hours while allowing it to rise to ambient temperature, poured into a water/ice mixture, treated with 28% aqueous ammonia until the pH is neutral, and extracted with dichloromethane (4×50 ml). The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 95/05 dichloromethane/7N ammoniacal methanol, so as to give 1.22 g of 4-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole in the form of a yellow solid.
To a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (1) (1.0 g, 6.88 mmol) in dimethylformamide (DMF, 35 mL) was added potassium t-butoxide (KOtBu, 1.16 g, 10.32 mmol) at 0 C. After the resulting solution was stirred for 30 min at 0 C., 2-bromopentane (2) (1.05 ml, 8.27 mmol) was added dropwise, and the reaction solution was warmed up to room temperature gradually and stirred for 12 h at room temperature. Water (5 ml) was added to quench the reaction. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with H2O (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (6:1 hexane/ethyl acetate) recovered <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (1) (500 mg) and gave 1-(pentan-2-yl)-<strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (3) mixed with residual 2-bromopentane (2), which was used in the following step directly.
2-(4-indole)-imidazo[4,5f][1,10] phenanthroline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With ammonium acetate; In acetic acid; for 2h;Reflux; Inert atmosphere;
The ligand was synthesized by using a modified literature procedure. A mixture of 1,10-phenanthroline-5,6-dione (0.525 g, 2.5 mmol), indole-4-benzaldehyde (0.36 g, 2.5 mmol), ammonium acetate (3.88 g, 50 mmol) and glacial acetic acid (20 mL) was refluxed for 2 h under argon then cooled to room temperature and diluted with water (40ml). The cooled deep-red solution was diluted with water (40mL) and neutralized with ammonium hydroxide to give a yellow precipitate. The crude product dissolved in ethanol was purified by filtration on silica gel (60-100 mesh, ethanol). The principal yellow band was collected. Then, evaporation of the solution gave yellow crystals. Yield 0.76 g, 83%.
With potassium carbonate; In N,N-dimethyl-formamide; for 2h;Reflux;
The indole -4 - formaldehyde (10.00g, 68 . 97mmol) dissolved in N, N - dimethyl formamide (150 ml), added to the O-fluoro phenyl nitrile (8.40 ml, 75 . 86mmol) and potassium carbonate (19.03g, 137 . 94mmol). Mixed solution stirring reflux about 2h, TLC monitoring to the reaction is complete. Reacting liquid temperature to normal temperature, filtering, the filter cake is dichloromethane (20 ml × 3) washing three times. In the filtrate by adding 200 ml of methylene chloride and 200 ml water, takes organically. After the dichloromethane (150 ml × 3) extracting the aqueous phase, the combined organic phase, saturated salt water (300 ml × 4) washing the organic phase. Drying the organic phase with anhydrous magnesium sulfate, filter, evaporate the solvent under reduced pressure, to obtain amber solid. The solid weight crystallized to obtain pale white solid product about 16g (yield is about 94.3%).
94.3%
With potassium carbonate; In N,N-dimethyl-formamide; for 2h;Reflux;
A solution of <strong>[1074-86-8]indole-4-carbaldehyde</strong>(10.00 g, 68.97 mmol) was dissolved in N, N-dimethylformamide (150 mL). A solution of o-fluorobenzonitrile (8.40 mL, 75.86 mmol) and potassium carbonate (19.03 g, 137.94 mmol) were added and Stirred under reflux about for 2h, until the reaction was completed by TLC monitoring. After the temperature of the reaction solution was lowered to room temperature, the reaction solution was filtered, and the filter cake was washed three times with dichloromethane (20 mL x 3).The filtrate was combined and 200 mL of dichloromethane and 200 mL of water were added to the filtrate to separate the organic phase and the aqueous phase was extracted with dichloromethane (150ML x 3), and the organic phases were combined. The organic phase was washed with saturated brine (300 mL x 4), dried over anhydrous magnesium sulfate, and filtered., The filtrate was evaporated under reduced pressure to give a tan solid. The solid was recrystallized to give about 16 g of product as an off-white solid product (yield About 94.3%).
Ca. 94.3%
With potassium carbonate; In N,N-dimethyl-formamide; at 160℃; for 2h;
A solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong>(10.00 g, 68.97 mmol) was dissolved in N, N-dimethylformamide (150 mL) and added O-fluorobenzonitrile (8.40 mL, 75.86 mmol) and potassium carbonate (19.03 g, 137.94 mmol). The mixture was stirred at 160 C for about 2 hours and the TLC was monitored until the reaction was complete. After the temperature of the reaction solution was lowered to room temperature, the filter cake was washed three times with dichloromethane (20 mL). To the filtrate was added 200 mL of dichloromethane and 200 mL of water to separate the organic phase. The aqueous phase was extracted with dichloromethane (150 mL x 3) and the organic phases were combined. The organic phase was washed with saturated brine (300 mL x 4), dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a tan solid. The solid was recrystallized to give about 16 g (yield about 94.3%) of the off-white solid product V.
89.1%
With potassium carbonate; In N,N-dimethyl-formamide; for 1h;Reflux;
K2CO3 (19.2 g, 138.93 mmol) and 2-fluorobenzonitrile (9.18 g, 75.87 mmol) were added to a solution of 24 (10 g, 68.97 mmol) in 100 mL DMF. The mixture was stirred and refluxed for 1 h. After cooling to rt, the mixture was added to 100 mL water and extracted with ethyl acetate (100 mL * 3). After that the organic phase was collected and washed with NaCl saturated solution (150 mL * 5) and then dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The residue was recrystallized by ethyl acetate to obtain white solid. Yield: 89.1%. MP: 240-243 C. 1H NMR (400 MHz, CDCl3) δ: 10.32 (s, 1H), 7.91 (d, 1H), 7.81 (t, 1H), 7.76 (d, 1H), 7.61-7.56 (m, 5H), 7.42 (t, 1H). MS (ESI): [M + H]+ calcd 247.1; found 247.2.
70.7%
Step 1 : NaH (60% in mineral oil, 303 mg, 7.58 mmol, Eq: 1.1) was added to a solution of lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (1 g, 6.89 mmol, Eq: 1.00) in DMF (12 mL) at 0 C. After 10 min., the mixture was warmed to RT and treated with sonication for 2 min. 2-Fluorobenzonitrile (918 mg, 822 μ, 7.58 mmol, Eq: 1.1) was added and the mixture was treated with sonication for 3 min. After 3 h the mixture was diluted with sat. NH4C1, extracted with EtOAc, the combined extracts washed with H20 and concentrated. The residue was tritrurated with Hexane/Et20 to give 2-(4-formyl-lH-indol-l-yl)benzonitrile (1.2g, 70.7%) as a grey solid.
Sjp3. Synthesis of (E)-N’-(( 1 H-indol-4-yl)methylene)-2-(2-(trifluoromethyl)phenoxy)acetohydrazide: 2-(2-(trifluoromethyl)phenoxy)acetohydrazide (0.2 g, 0.85 mmol) and <strong>[1074-86-8]1H-indol-4-carbaldehyde</strong> (0.13 g, 0.85 mmol) were dissolved in ethanol, followed by stirring at 100 C for 16 hours. After the completion of the reaction, the reactionmixture was concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain Compound 192 (0.27 g, 88 %).‘H NMR (400 MHz, DMSO-d6): 11.57-11.33 (m, 2H), 8.43-8.25 (m, 1H), 7.64-7.44 (m, 4H), 7.25-6.96 (m, 6H), 5.37-4.84 (m, 2H).
Step 3. Synthesis of (E)-N’-(( 1 H-indol-4-yl)methylene)-2-(2-bromo-4,6-dimethylphenoxy)acetohydrazide: 2-(2-bromo-4,6-dimethylphenoxy)acetohydrazide (85 mg,0.31 mmol) and lH-indol-4-carbaldehyde (45 mg, 0.31 mmol) were dissolved in EtOH 2 mL, followed by stirring at 100 C for 12 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was recrystallized withethanol, and filtered to obtain Compound 259 (50 mg, 40 %).‘H NMR (400 MHz, DMSO-d6): 6 11.47-11.44 (m, 1H), 11.34 (bs, 1H), 8.68 (s, 111), 8.23 (s,1H), 7.47 (m, 2H), 7.25 (m, 2H), 7.17-7.13 (m, 4H), 7.12 (s, 1H), 6.78 (s, 1H), 4.98 (s, 1H),4.48 (s, 2H), 2.32-2.24 (m, 9H).
40%
In ethanol; at 100℃; for 12h;
Step 3. Synthesis of (E)-N’-(( 1 H-indol-4-yl)methylene)-2-(2-bromo-4,6-dimethylphenoxy)acetohydrazide: 2-(2-bromo-4,6-dimethylphenoxy)acetohydrazide (85 mg,0.31 mmol) and lH-indol-4-carbaldehyde (45 mg, 0.31 mmol) were dissolved in EtOH 2 mL, followed by stirring at 100 C for 12 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was recrystallized withethanol, and filtered to obtain Compound 259 (50 mg, 40 %).‘H NMR (400 MHz, DMSO-d6): 6 11.47-11.44 (m, 1H), 11.34 (bs, 1H), 8.68 (s, 111), 8.23 (s,1H), 7.47 (m, 2H), 7.25 (m, 2H), 7.17-7.13 (m, 4H), 7.12 (s, 1H), 6.78 (s, 1H), 4.98 (s, 1H),4.48 (s, 2H), 2.32-2.24 (m, 9H).
Example 69. Synthesis of compound 3192-(2-(furan-3-yl)pyridin-3-yloxy)acetohydrazide (70 mg, 0.30 mmol) and <strong>[1074-86-8]1H-indol-4-carbaldehyde</strong> (48 mg, 0.33 mmol) were dissolved in EtOH 2 mL, followed by stirring at 80 C for 12 hours. After the completion of the reaction, the reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane = 1:1). The resultant wasrecrystallized with tetrahydrofuran / hexane, and filtered to obtain Compound 319 (50 mg,46%).‘H NMR (400 MHz, DMSO-d6): 6 11.62 (m, 1H), 11.39 (m, 1H), 8.74-8.46 (m, 1H), 8.30 (s, 1H), 8.21 (m, 1H), 7.74 (m, 1H), 7.52 (m, 3H), 7.20 (m, 4H), 7.01 (m, 1H), 5.43 (s, 1H), 4.90 (s, ill).
Example 81. Synthesis of compound 3372-(2,6-dimethyl-4-(tetrahydrofuran-3 -yl)phenoxy)acetohydrazide (50 mg, 0.19 mmol) and 1 Hindol-4-carbaldehyde (100 mg, 0.55 mmol) were dissolved in EtOH 1 mL, followed by stirringat 90 C for 3 hours. After the completion of the reaction, the reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain Compound 337 (31 mg, 50 %).1HNMR(400 MHz, DMSO-d6): 6 11.42(bs, 1H), 11.29(m, 1H), 8.55-8.16 (2s, 1H), 7.58 (m,2H), 7.40 (m, 2H), 6.95 (m, 2H), 6.47 (m, 1H), 5.26 (s, 1H), 4.73 (s, 1H), 3.96 (m, 3H), 3.75 (m,2H), 2.32 (s, 3H), 2.21 (s, 3H).
Step 3. Synthesis of (E)-N’-(( 1 H-indol-4-yl)methylene)-2-(mesitylamino)acetohydrazide:2-(mesitylamino)acetohydrazide (0.1 g, 0.48 mmol) and 1 H-indol-4-carbaldehyde (0.084 g,0.58 mmol) were dissolved in ethanol, followed by stirring at 100 C for 16 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. Theobtained concentrate was purified by column chromatography, and then concentrated underreduced pressure. The formed crystalline solid was filtered to obtain Compound 135 (0.089 g,55 %).‘H NMR (400 MHz, DMSO-d6): 11.47-11.34 (m, 2H), 8.41-8.20 (m, 1H), 7.47 (m, 2H), 7.48-7.10 (m, 2H), 6.91 (s, 0.6H), 6.74 (m, 2H), 4.36-3.60 (m, 3H), 2.25-2.12 (m, 9H).
With sodium hydride; benzenesulfonyl chloride; In tetrahydrofuran; at 20℃; for 12h;
Step 1. Synthesis of 1-(phenylsulfonyl)-1H-indol-6-carbaldehyde: IH-indol-4-carbaldehyde (1000 mg, 6.89 mmol), sodium hydride (360 mg, 8.26 mmol) and benzylsulfonyl chloride (1 mL, 6.89 mmol) were dissolved in tetrahydrofuran 10 mL, followed by stirring at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by columnchromatography (ethyl acetate:hexane = 1:3) to obtain 1-(phenylsulfonyl)-1H-indol-6- carbaldehyde (500 mg, 25 %).
1-(3-fluorobenzyl)-1H-indole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
General procedure: To a solution of indole-aldehyde (435mg 3mmol) in CH3CN (30mL) was added Cs2CO3 (829mg, 6mmol), and the mixture was refluxed for 2h. To this solution, alkyl halide (3.3mmol) was added, and the mixture was heated under reflux for 1h. After the completion of the reaction, the solvent was evaporated under reduced pressure and water was added to the reaction mixture and extracted 3 times for ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;
General procedure: 3-Ethyl-1-(piperidin-4-yl)indolin-2-one 612 (1 equiv), requisite aldehyde or ketone (1.3 equiv), acetic acid (3 equiv) and NaBH(OAc)3 (2.6 equiv) were dissolved in 1,2-dichloroethane (0.1-0.2 M) and stirred at rt for 3-29 h. The mixture was adjusted to pH = 9 by addition of satd. NaHCO3 (aq), and extracted in DCM. The organic layers were collected, washed with satd. NaCl(aq), dried over Na2SO4, filtered and concentrated. The residue was purified via flash chromatography using hexanes/diethyl ether 100:0→5:5 or hexanes/EtOAc 100:0→ 5:5 as the eluent to afford the title material. For 7f-7j, the title material was converted to the HCl salt by addition of 2 M HCl/ether.
With 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate); acetic acid; In acetonitrile; at 0℃; for 3h;
EXAMPLE 206 <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> (2.26 g, 15.5 mmol) was added to Acetonitrile (20 mL) followed by acetic acid (2.25 mL, 39 mmol). The reaction mixture was cooled to 0 C and Selectfluor (2.5 g, 17.1 mmol) was added portion-wise over the course of 15 mm. The reaction was aged for 3 hours then diluted with 15 mL of EtOAc and washed with water (25 mL) 3 times. The organics were then stripped in vacuo and the crude product purified via normal phase MPLC (100% DCM).
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Step A: lH-Indole-4-carbaldehyde (10 g, 69.0 mmol) was added to a suspension of NaH (2.0 g, 82.6 mmol) in anhydrous THF (150 mL) at 0 C. The resultant suspension was stirred at 0 C for 30 minutes, followed by addition of 2-(trimethylsilyl) ethoxymethyl chloride (13.8 g, 82.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water, dried over anhydrous Na2S04 and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with a gradient of 10% - 30% EtOAc/hexanes to afford l-((2-(trimethylsilyl)ethoxy)methyl)-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (817 g, 61.4 mmol, 89%> yield) as dark yellow solid.
89%
1H-Indole-4-carbaldehyde (10 g, 69.0 nimol) was added to a suspension of NaH (2.0 g, 82.6 nimol) in anhydrous THF (150 111L) at 0 C. The resultant suspension was stirred at 0 C for 30 minutes, followed by addition of 2-(trimethylsilyl) ethoxymethyl chloride (13.8 g, 82.6 nimol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water, dried over anhydrous Na2S04 and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with a gradient of 10% - 30% EtOAc/hexanes to afford l-((2-(trimethylsilyl)ethoxy)methyl)-lH-<strong>[1074-86-8]indole-4-carbaldehyde</strong> (817 g, 61.4 mmol, 89% yield) as dark yellow solid.
2-(furan-2-yl)cyclopropanecarbohydrazide[ No CAS ]
(E)-N'-((1H-indol-4-yl)methylene)-2-(furan-2-yl)cyclopropanecarbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With zinc(II) oxide; In ethanol; at 20℃;Green chemistry;
General procedure: A mixture of appropriate aldehyde (10 mmol) from the list a-t, compound 4 (10 mmol), ZnO Nano particles (2 mmol) and ethanol (25 mL) was stirred at rt for 30 min to 1 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through a nanofiltration membrane (Make: Synder, Model: NFS 100-250Da). The filtrate was evaporated under reduced pressure and dried to obtain crude product 5a-t which was further purified by recrystallization in ethanol to afford pure compounds.
3-[(4-nitrophenyl)sulfonyl]-1H-indole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In dimethyl sulfoxide; at 70℃; for 6h;
General procedure: Indole 1 (0.3 mmol), sodium sulfinate 2 (0.6 mmol), CuI (0.06 mmol), 1,10-phenanthroline (0.06 mmol), K2CO3 (0.6 mmol) and DMSO(2 mL) were added to a 25 mL round bottom flask equipped witha condenser and stirring bar. The mixture was stirred at 70 C for6 h. Upon completion (TLC), the mixture was allowed to cool to room temperature and water (10 mL) was added. The resultingsuspension was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over Na2SO4. After filtration, the acquired solution was collected and the solvent was removed under reduced pressure at ca. 50 C. The residue was subjected to silica gel column chromatography to give pure products by using mixed petroleum ether(60-90 C) and ethyl acetate (v/v = 2:1) as eluent.
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In dimethyl sulfoxide; at 70℃; for 6h;
General procedure: Indole 1 (0.3 mmol), sodium sulfinate 2 (0.6 mmol), CuI (0.06 mmol), 1,10-phenanthroline (0.06 mmol), K2CO3 (0.6 mmol) and DMSO(2 mL) were added to a 25 mL round bottom flask equipped witha condenser and stirring bar. The mixture was stirred at 70 C for6 h. Upon completion (TLC), the mixture was allowed to cool to room temperature and water (10 mL) was added. The resultingsuspension was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over Na2SO4. After filtration, the acquired solution was collected and the solvent was removed under reduced pressure at ca. 50 C. The residue was subjected to silica gel column chromatography to give pure products by using mixed petroleum ether(60-90 C) and ethyl acetate (v/v = 2:1) as eluent.
(E)-4-(2-(1H-indol-4-yl)vinyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.2%
General procedure: To a solution of t-BuOK (3.0 equiv) in dry DMF was added 1a or 1b (1.1 equiv). After the mixture was stirred at 0C under nitrogen for 0.5h, a substituted benzaldehyde (1.0 equiv) in dry DMF was added dropwise to the solution. The reaction mixture was slowly warmed to room temperature and stirred for 2-5h. Ice-water was added, and the precipitate was filtered to give the crude product. Purification of the crude product by recrystallization from ethyl acetate provided the target product.
4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile[ No CAS ]
6-fluoro-4-(4-formyl-1H-indol-1-yl)-2,3-dihydro-3-methylbenzofuran-7-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.9%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; for 2h;Inert atmosphere; Cooling with ice;
A 25 ml reaction flask was filled with nitrogen and charged with 4,6-difluoro-2,3-dihydro-3- methylbenzofuran-7-carbonitrile (195.2 mg, 1 mmol), <strong>[1074-86-8]indole-4-carboxaldehyde</strong> (159.7 mg, 1.1 mmol) and anhydrous DMF (1 ml). After the mixture was cooled in an ice-water bath, NaH (60% in mineral oil, 48 mg, 1.2 mmol) was slowly added. The reaction was stirred under nitrogen for 2 hours. The desired product was less polar and separated from its isomer through RPLC (50 g, 5 to 75 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation and further dried in high vacuum to afford the title compound as a white solid (188.6 mg, 58.9 %).1H NMR (CDCl3, 300 MHz): δ = 10.30 (s, 1 H), 7.78-7.75 (dd, J = 0.81, 7.17 Hz, 1 H), 7.59-7.56 (m, 2 H), 7.48-7.46 (m, 1 H), 7.43- 7.42 (d, J = 3.21 Hz, 1 H), 6.83 (d, J = 9.66 Hz, 1 H), 5.02-4.96 (t, J = 9.12 Hz, 1 H), 4.42-4.37 (q, J = 5.73, 9.12 Hz, 1 H), 3.78-3.65 (m, 1 H), 0.71-0.69 (d, J = 6.8 Hz, 3 H); LCMS: C19H13FN2O2 [M + H]+ =321.
1-(4-methoxybenzenesulfonyl)-1H-indole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
To the solution of 28 (1 g, 6.89 mmol) in dichloromethane(DCM) was added tetrabutylammonium hydrogen sulfate (TBAHS,0.35 g, 1.03 mmol), potassium hydroxide (KOH, 0.77 g, 13.78 mmol) and stirred for 20 min before adding 4-Methoxybenzenesulfonylchloride (2.14 g, 10.33 mmol) and the reaction was stirred for 12 h at room temperature. Reaction was quenched by addition of water and neutralized with 3 N HCl and extracted using EtOAc(25 mL 3). The combined organic layer was collected, dried overanhydrous MgSO4 and concentrated under reduced pressure to give a pale yellow residue, which was purified by silica gel chromatography (EtOAc: Hexane, 4:1) to give 32 as off-white residue in 45%yield; 1H NMR (300 MHz, CDCl3): δ 3.81 (s, 3H), 6.90 (d, J=9.0 Hz,2H), 7.46-7.51 (m, 2H), 7.72-7.77 (m, 2H), 7.82-7.85 (m, 2H), 8.28(t, J=8.1 Hz, 1H), 10.91 (s, 1H).
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 9h;
(22a) 10 parts by mole of bromine-n-butane was slowly added to 400 parts by mole of DMSO, and then 15 parts by mole of indoledehyde 4a and 15 parts by mole of KOH were added to the DMSO to form a mixed solution; (22b) The mixture was stirred at room temperature for 9h, then 5000 molar parts of water were added and extracted with dichloromethane; (22c) The combined methylene chloride layers were washed sequentially with water and brine and dried over anhydrous Na2SO4. The dichloromethane was evaporated to dryness under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel with a volume ratio of 2: 1 petroleum ether / ethyl acetate to give indoledehyde 4b.
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 15h;
(22a) 30 molar parts of bromoisobutane are slowly added to 400 to 500 molar parts of DMSO, and then 20 molar parts of indoledehyde 4a and 50 molar parts of KOH are added to the DMSO to form a mixed solution; (22b) The mixture was stirred at room temperature for 15h, then 6000 molar parts of water were added and extracted with dichloromethane; (22c) The combined methylene chloride layers were washed sequentially with water and brine and dried over anhydrous Na2SO4. The methylene chloride was evaporated to dryness under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel with a volume ratio of 20: 1 petroleum ether / ethyl acetate to give indole aldehyde 4c.
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 12h;
(22a) 20 molar parts of bromododecane was slowly added to 423 molar parts of DMSO, and then 17 molar parts of indoledehyde 4a and 25.6 molar parts of KOH were added to the DMSO to form a mixed solution; (22b) The mixture was stirred at room temperature for 12 h, then 5555 molar parts of water were added and extracted with dichloromethane; (22c) The combined methylene chloride layers were washed sequentially with water and brine and dried over anhydrous Na2SO4. The methylene chloride was evaporated to dryness under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel with a volume ratio of 4: 1 petroleum ether / ethyl acetate to give indole aldehyde 4d.
General procedure: General operating procedure: To a suspension of dry NaH (240 mg, 10 mmol, 2 equiv) in DMF (10ml) with stirring was added with pyrrole-2-carboxyaldehyde or indole-carboxyaldehyde (5 mmol, 1 equiv) under Nitrogen at 0 C. After 20 minutes, the reaction mixture was added with alkyl halide (6mmol, 1.2 equiv). The reaction was slowly warmed up to room temperature stirred for 30 minutes. TLC analysis (25% ethyl acetate in petroleum ether) showed no starting material. The reaction mixture was diluted with dichloromethane and washed three times with water, once with brine. The organic solution was dried over Na2SO4, filtered and concentrated. The solvent was removed under reduced pressure to afford the title compound a1-a23 and b1-b35. The residue was directly used for subsequent reaction.
General procedure: General operating procedure: To a suspension of dry NaH (240 mg, 10 mmol, 2 equiv) in DMF (10ml) with stirring was added with pyrrole-2-carboxyaldehyde or indole-carboxyaldehyde (5 mmol, 1 equiv) under Nitrogen at 0 C. After 20 minutes, the reaction mixture was added with alkyl halide (6mmol, 1.2 equiv). The reaction was slowly warmed up to room temperature stirred for 30 minutes. TLC analysis (25% ethyl acetate in petroleum ether) showed no starting material. The reaction mixture was diluted with dichloromethane and washed three times with water, once with brine. The organic solution was dried over Na2SO4, filtered and concentrated. The solvent was removed under reduced pressure to afford the title compound a1-a23 and b1-b35. The residue was directly used for subsequent reaction.
General procedure: General operating procedure: To a suspension of dry NaH (240 mg, 10 mmol, 2 equiv) in DMF (10ml) with stirring was added with pyrrole-2-carboxyaldehyde or indole-carboxyaldehyde (5 mmol, 1 equiv) under Nitrogen at 0 C. After 20 minutes, the reaction mixture was added with alkyl halide (6mmol, 1.2 equiv). The reaction was slowly warmed up to room temperature stirred for 30 minutes. TLC analysis (25% ethyl acetate in petroleum ether) showed no starting material. The reaction mixture was diluted with dichloromethane and washed three times with water, once with brine. The organic solution was dried over Na2SO4, filtered and concentrated. The solvent was removed under reduced pressure to afford the title compound a1-a23 and b1-b35. The residue was directly used for subsequent reaction.
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
(1H-indol-4-yl)(2-methoxyphenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
In tetrahydrofuran; at 70℃;Schlenk technique; Inert atmosphere;
General procedure: In a flame-dried Schlenk bottle under argon atmosphere, Grignard reagent B (10.2 mol) was added to the Schlenk bottle. Then, in an ice-water bath, a solution of <strong>[1074-86-8]1H-<strong>[1074-86-8]indole-4-carbaldehyde</strong></strong> A (10 mmol) in anhydrous THF (10 mL) was added to the Schlenk bottle. Subsequently, the reaction mixture was moved to an oil bath, which was refluxed at 70 o C overnight. After the completion of the reaction indicated by TLC, the reaction mixture was quenched by saturated ammonium chloride solution and was extracted by ethyl acetate for three times. The combined organic layer was dried by anhydrous sodium sulfate, which was concentrated under the reduced pressure. The resulted residue was purified through flash chromatography on silica gel to afford the pure 4-indolylmethanols 1.
(E)-3-(3-(1H-indol-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.85%
With piperidine; In chloroform; at 60℃; for 12h;Inert atmosphere;
The dehydroacetic acid (500mg, 2.97mmol)And 4-indolecarboxaldehyde (431.64 mg, 2.97 mmol) was dissolved in CHCl3 (4 ml).Piperidine (2d) was added dropwise,Nitrogen protection,The reaction was carried out at 60 C for 12 h.Using the same post-treatment step in Example 1,A yellow solid 514 mg (yield: 57.85%) was obtained.
General procedure: To a solution of 5 (0.2 mmol) in anhydrous THF, NaH (60%,0.24 mmol) was added at 0 C under N2 atmosphere. After stirring for15 min, aromatic aldehyde (0.24 mmol) was added into the mixture andthe reaction was stirred for another 1 h. The reaction mixture was thenextracted with EtOAc (3×20 mL). The combined organic layers werethen washed with saturated brine, dried over anhydrous Na2SO4, andconcentrated in vacuo. The residue was purified by flash columnchromatography using PE/EA (5/1, V/V) as an eluent to afford thecompounds 7a-n, 8a-d.
General procedure: To a solution of 5 (0.2 mmol) in anhydrous THF, NaH (60%,0.24 mmol) was added at 0 C under N2 atmosphere. After stirring for15 min, aromatic aldehyde (0.24 mmol) was added into the mixture andthe reaction was stirred for another 1 h. The reaction mixture was thenextracted with EtOAc (3×20 mL). The combined organic layers werethen washed with saturated brine, dried over anhydrous Na2SO4, andconcentrated in vacuo. The residue was purified by flash columnchromatography using PE/EA (5/1, V/V) as an eluent to afford thecompounds 7a-n, 8a-d.
General procedure: To a solution of 5 (0.2 mmol) in anhydrous THF, NaH (60%,0.24 mmol) was added at 0 C under N2 atmosphere. After stirring for15 min, aromatic aldehyde (0.24 mmol) was added into the mixture andthe reaction was stirred for another 1 h. The reaction mixture was thenextracted with EtOAc (3×20 mL). The combined organic layers werethen washed with saturated brine, dried over anhydrous Na2SO4, andconcentrated in vacuo. The residue was purified by flash columnchromatography using PE/EA (5/1, V/V) as an eluent to afford thecompounds 7a-n, 8a-d.
General procedure: To a solution of 5 (0.2 mmol) in anhydrous THF, NaH (60%,0.24 mmol) was added at 0 C under N2 atmosphere. After stirring for15 min, aromatic aldehyde (0.24 mmol) was added into the mixture andthe reaction was stirred for another 1 h. The reaction mixture was thenextracted with EtOAc (3×20 mL). The combined organic layers werethen washed with saturated brine, dried over anhydrous Na2SO4, andconcentrated in vacuo. The residue was purified by flash columnchromatography using PE/EA (5/1, V/V) as an eluent to afford thecompounds 7a-n, 8a-d.
General procedure: To a solution of 5 (0.2 mmol) in anhydrous THF, NaH (60%,0.24 mmol) was added at 0 C under N2 atmosphere. After stirring for15 min, aromatic aldehyde (0.24 mmol) was added into the mixture andthe reaction was stirred for another 1 h. The reaction mixture was thenextracted with EtOAc (3×20 mL). The combined organic layers werethen washed with saturated brine, dried over anhydrous Na2SO4, andconcentrated in vacuo. The residue was purified by flash columnchromatography using PE/EA (5/1, V/V) as an eluent to afford thecompounds 7a-n, 8a-d.
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