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With sodium t-butanolate In toluene at 140℃; for 24 h; sealed tube
EXAMPLE 14; N'-(3,4-Dimethoxybenzylidene)-3-(3-methyl-lH-pyrrolo[2,3-b]pyridin-l- yl)propanehydrazide; [0516] (a) 3-Methyl-lH-pyrrolo[2,3-b]pyridine: This intermediate was prepared using a similar method to that described by Jensen et. al., Angew. Chem. Int. Ed. 2008, 47, 888-890. To a reaction tube was added toluene (5 mL), 2,3-dichloropyridine (300 mg, 2.03 mmol), Pd2dba3 (2 mg, 0.0025 mmol), dppf (6 mg, 0.01 mmol), NaOtBu (487 mg, 5.07 mmol), and allylamine (0.15 mL, 2.03 mmol). The reaction tube was sealed and heated at 140 0C for 20 hours followed by stirring at room temperature for 24 hours. The reaction mixture was washed with water, brine and dried (Na2SO4) and absorbed onto silica gel. Purification on silica gel using DCM-hexane (0 to 60percent), followed by EtOAc-hexane (80percent) provided a orange solid (100 mg, 37percent).
67 mg
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In toluene at 140℃; for 44.3 h; Inert atmosphere; Sealed tube
A mixture of 2,3-dichloropyridine (500mg), allylamine (0.254mL), NaOtBu (1.19g), Pd2dba3 (37.9mg), dppf (91.8mg) in toluene (15mL) was prepared under argon and divided into three vials. The vials were sealed and evacuated and backfilled with argon three times. The resulting green-brown suspensions were heated up to 140°C for 19.3h. Pd2dba3 (0.0125eq) and dppf (0.05eq) were added and the reaction mixture was further stirred at 140°C for 25h. After cooling down, the combined reaction mixtures were diluted with EAand washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgS04, filtrated off and evaporated to dryness. CC of the crude (Biotage, SNAP 25g cartridge, solvent A: Hept; solvent B: EA; gradient in percentB: 50 for 6CV, 50 to 70 over 3CV, 70 for 5CV, 70 to 100 over 3CV, 100 for 3CV) afforded 67mg of brown solid. LC-MS (B): tR = 0.44min; [M+H]+: 133.22.
67 mg
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In toluene at 140℃; for 44.3 h; Inert atmosphere; Sealed tube
A mixture of 2,3-dichloropyridine (500 mg), allylamine (0.254 mL), NaOtBu (1.19 g), Pd2dba3 (37.9 mg), dppf (91.8 mg) in toluene (15 mL) was prepared under argon and divided into three vials. The vials were sealed and evacuated and backfilled with argon three times. The resulting green-brown suspensions were heated up to 140° C. for 19.3 h. Pd2dba3 (0.0125 eq) and dppf (0.05 eq) were added and the reaction mixture was further stirred at 140° C. for 25 h. After cooling down, the combined reaction mixtures were diluted with EA and washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgSO4, filtrated off and evaporated to dryness. CC of the crude (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in percent B: 50 for 6CV, 50 to 70 over 3CV, 70 for 5CV, 70 to 100 over 3CV, 100 for 3CV) afforded 67 mg of brown solid. LC-MS (B): tR=0.44 min; [M+H]+: 133.22
Stage #1: With n-butyllithium In tetrahydrofuran at -30 - 0℃; for 0.5 h; Stage #2: at -40 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water at 60℃; for 2 h;
Example 40(2)3-Methyl-1H-pyrrolo[2,3-b]pyridine (40b)Normal-butyllithium (2.69 M, 118.7 mL) was dropwise added to a solution of compound (40a) (32.4 g) in THF (500 mL) at an internal temperature of -30 to -10° C., followed by stirring at 0° C. for 30 min. Subsequently, a solution of DMF (11.18 g) in THF (50 mL) was added to the reaction solution at an internal temperature of -40° C., followed by increasing the temperature to room temperature. Then, 6 N hydrochloric acid (200 mL) was added to the reaction solution, followed by stirring at 60° C. for 2 hr. After cooling, ethyl acetate (200 mL) and water (100 mL) were added to the reaction solution for distribution. The aqueous layer was added to sodium hydroxide (4 M, 300 mL), and pH was adjusted to 12, followed by stirring for 1 hr. The precipitate was collected by filtration, washed by sprinkling water, and dried under reduced pressure to obtain compound (40b) (16.52 g, 86percent) as a white solid.1H-NMR (CDCl3) δ 9.56 (1H, brs), 8.30 (1H, dd, J=4.6, 1.2 Hz), 7.89 (1H, dd, J=7.8, 1.5 Hz), 7.09-7.06 (2H, m), 2.33 (3H, s); LRMS (ESI) m/z 133 [M+H]+.
Example VI Preparation of 2-chloro-<strong>[5654-93-3]3-methylpyrrolo[2,3-b]pyridine</strong> <strong>[5654-93-3]3-methylpyrrolo[2,3-b]pyridine</strong> (0,5 g 0.0038 mol) was treated in 2 ml acetic acid with an equimolecular amount of sulfuryl chloride at 0 C. for 5 min. The mixture was allowed to warm to room temperature and was stirred for 5 min. After evaporation the residue was dissolved in methylene chloride and was treated with bicarbonate. The organic layer was separated, dried and removed under reduced pressure. Chromatography on silica gel eluding with ethyl acetate gave the desired product. (0,18 g 29%). (1 H-NMR, 300 MHz, CDCl3). 2.25(s,3H), 7.05(dd,1H), 7.75(dd,1H), 8.25(dd, 1H).
With sodium t-butanolate;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 140℃; for 24h;sealed tube;
EXAMPLE 14; N'-(3,4-Dimethoxybenzylidene)-3-(3-methyl-lH-pyrrolo[2,3-b]pyridin-l- yl)propanehydrazide; [0516] (a) 3-Methyl-lH-pyrrolo[2,3-b]pyridine: This intermediate was prepared using a similar method to that described by Jensen et. al., Angew. Chem. Int. Ed. 2008, 47, 888-890. To a reaction tube was added toluene (5 mL), 2,3-dichloropyridine (300 mg, 2.03 mmol), Pd2dba3 (2 mg, 0.0025 mmol), dppf (6 mg, 0.01 mmol), NaOtBu (487 mg, 5.07 mmol), and allylamine (0.15 mL, 2.03 mmol). The reaction tube was sealed and heated at 140 0C for 20 hours followed by stirring at room temperature for 24 hours. The reaction mixture was washed with water, brine and dried (Na2SO4) and absorbed onto silica gel. Purification on silica gel using DCM-hexane (0 to 60%), followed by EtOAc-hexane (80%) provided a orange solid (100 mg, 37%).
67 mg
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; In toluene; at 140℃; for 44.3h;Inert atmosphere; Sealed tube;
A mixture of 2,3-dichloropyridine (500mg), allylamine (0.254mL), NaOtBu (1.19g), Pd2dba3 (37.9mg), dppf (91.8mg) in toluene (15mL) was prepared under argon and divided into three vials. The vials were sealed and evacuated and backfilled with argon three times. The resulting green-brown suspensions were heated up to 140C for 19.3h. Pd2dba3 (0.0125eq) and dppf (0.05eq) were added and the reaction mixture was further stirred at 140C for 25h. After cooling down, the combined reaction mixtures were diluted with EAand washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgS04, filtrated off and evaporated to dryness. CC of the crude (Biotage, SNAP 25g cartridge, solvent A: Hept; solvent B: EA; gradient in %B: 50 for 6CV, 50 to 70 over 3CV, 70 for 5CV, 70 to 100 over 3CV, 100 for 3CV) afforded 67mg of brown solid. LC-MS (B): tR = 0.44min; [M+H]+: 133.22.
67 mg
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; In toluene; at 140℃; for 44.3h;Inert atmosphere; Sealed tube;
A mixture of 2,3-dichloropyridine (500 mg), allylamine (0.254 mL), NaOtBu (1.19 g), Pd2dba3 (37.9 mg), dppf (91.8 mg) in toluene (15 mL) was prepared under argon and divided into three vials. The vials were sealed and evacuated and backfilled with argon three times. The resulting green-brown suspensions were heated up to 140 C. for 19.3 h. Pd2dba3 (0.0125 eq) and dppf (0.05 eq) were added and the reaction mixture was further stirred at 140 C. for 25 h. After cooling down, the combined reaction mixtures were diluted with EA and washed with water and brine. The aq. layers were extracted with EA. The combined org. layers were dried over MgSO4, filtrated off and evaporated to dryness. CC of the crude (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 50 for 6CV, 50 to 70 over 3CV, 70 for 5CV, 70 to 100 over 3CV, 100 for 3CV) afforded 67 mg of brown solid. LC-MS (B): tR=0.44 min; [M+H]+: 133.22
Example 19A 3-Methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide A little at a time, 3.00 g (22.70 mmol) of <strong>[5654-93-3]3-methyl-1H-pyrrolo[2,3-b]pyridine</strong> (Hands, David; Bishop, Brian; Cameron, Mark; Edwards, John S.; Cottrell, Ian F.; Wright, Stanley H. B.; Synthesis 1996, 877-882.) are added to a solution of 10.45 g (45.40 mmol) of meta-chloroperoxybenzoic acid in 250 ml of dichloromethane, and the mixture is stirred at 10 C. for 2 h. Addition of methanol gives a clear solution which is subjected directly to column chromatography on silica gel (mobile phase: dichloromethane/methanol 100:4 to 3:1). A further purification step by preparative HPLC yields the target compound. Yield: 1.4 g (42% of theory) LC-MS (Method 3): Rt=1.22 min. MS (ESI pos.): m/z=149 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz): delta=2.25 (s, 3H), 7.05 (dd, 1H), 7.22 (s, 1H), 7.60 (d, 1H), 8.10 (d, 1H), 11.97 (br. s, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
[0517] (b) Ethyl 3-(3-methyl-lH-pyrrolo[2,3-b]pyridin-l-yl)propanoate: To a stirred solution of 3-methyl-lH-pyrrolo[2,3-b]pyridine (95 mg, 0.72 mmol), Cs2CO3 (468 mg, 1.44 mmol) in DMF (2 mL) was added ethyl acrylate (0.078 mL, 0.72 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc and washed with water, brine and dried (Na2SO4). Concentration provided a viscous orange oil (150 mg) which was used without additional purification.
Example 40(2)3-Methyl-1H-pyrrolo[2,3-b]pyridine (40b)Normal-butyllithium (2.69 M, 118.7 mL) was dropwise added to a solution of compound (40a) (32.4 g) in THF (500 mL) at an internal temperature of -30 to -10 C., followed by stirring at 0 C. for 30 min. Subsequently, a solution of DMF (11.18 g) in THF (50 mL) was added to the reaction solution at an internal temperature of -40 C., followed by increasing the temperature to room temperature. Then, 6 N hydrochloric acid (200 mL) was added to the reaction solution, followed by stirring at 60 C. for 2 hr. After cooling, ethyl acetate (200 mL) and water (100 mL) were added to the reaction solution for distribution. The aqueous layer was added to sodium hydroxide (4 M, 300 mL), and pH was adjusted to 12, followed by stirring for 1 hr. The precipitate was collected by filtration, washed by sprinkling water, and dried under reduced pressure to obtain compound (40b) (16.52 g, 86%) as a white solid.1H-NMR (CDCl3) delta 9.56 (1H, brs), 8.30 (1H, dd, J=4.6, 1.2 Hz), 7.89 (1H, dd, J=7.8, 1.5 Hz), 7.09-7.06 (2H, m), 2.33 (3H, s); LRMS (ESI) m/z 133 [M+H]+.
With dmap; In tetrahydrofuran; at 25℃; for 20.5h;Inert atmosphere;
To a solution of 3-methyl-lH-pyrrolo[2,3-b]pyridine (1 g, 8 mmol) in THF (15 mL) was added DMAP (9.2 mg, 0.08 mmol) followed by the addition of di-fer/-butyl dicarbonate (2.48 g, 11.4 mmol). The reaction was stirred at -25 C under nitrogen for 20.5 h. Water (0.1 mL) was added to the reaction and stirring was continued at -25 C for 40 min. All solvents were removed in vacuo. The crude product was azeotroped with toluene (3 x 5 mL) to give the title compound as a tan solid (quanititative yield). The product was used without further purification. LC-MS retention time = 3.11 min; m/z = 255.10 [M+Na] +. (Column: Phenomenex Luna C18 50 x 2.0 mm 3 muiotaeta. Solvent A = 90% Water : 10% MeOH : 0.1% TFA. Solvent B = 10% Water : 90% MeOH : 0.1% TFA. Flow Rate = 0.8 mL/rnin. Start % B = 0. Final % B = 100. Gradient Time = 4 minutes, then a 1 minute hold at 100% B. Oven temperature = 40 C. Wavelength = 220 nm). NMR (400 MHz, DMSO-d6) delta 8.37 (dd, J=4.6, 1.6 Hz, IH), 7.98 (dd, J=7.8, 1.8 Hz, IH), 7.55 (d, J=1.3 Hz, IH), 7.27 (dd, J=7.8, 4.8 Hz, IH), 2.23 (d, J=1.3 Hz, 3H), 1.60 (s, 9H).
With hydrogen bromide; dihydrogen peroxide In 1,2-dimethoxyethane; water at 50℃; Green chemistry;
4.2. General Procedure-1 for halide catalyzed oxidation
General procedure: To a 10 mL round-bottom flask equipped with a magnetic stir bar, indole (0.5 mmol), HBr (10 mol%, 0.05 mmol, 48%wt solution in water), and 1,2-dimethoxyethane (2.0 mL), were added. Then 30% hydrogen peroxide (77 mL, 0.75 mmol, 30% wt solution in water) was added dropwise. The reaction mixture was stirred for 30 min at 50 °C under air atmosphere. The reaction mixture was diluted by adding ethyl acetate and was quenched with a saturated aqueous solution of NaCl. Two layers were separated, and the aqueous layer extracted with ethyl acetate three times. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give oxindole product.
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