* 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.
SeO2 (0.167 g, 1.5 mmol), p-nitroacetophenone (0.165 g, 1 mmol) in a 25 mL round bottom flask under nitrogen.Add 10 mL of anhydrous pyridine, heat the oil bath to 110 ° C and stir to reflux.After 1 hour, the progress of the reaction was detected by TLC thin layer chromatography, and after cooling for 4 hours, it was cooled to room temperature.Filtration through a Buchner funnel, filtering off the solution containing SeO2 precipitate, washing the residue with 50 mL of ethyl acetate;The filtrate was combined and treated with 1 mmol/L hydrochloric acid (20 mL).The aqueous layer was extracted three times with ethyl acetate (50 mL) to give aqueous layer 2 and organic layer 2;After the organic layer 1 and the organic layer 2 are combined, extracted three times with 25 ml of water to obtain an organic layer 3 and an aqueous layer 3;The aqueous layer 3 was treated with 1 mmol/L NaOH (50 mL), and the reaction solution was diluted to obtainTo the filtrate 4.After the filtrate 4 was combined with the aqueous layer 2, the pH was adjusted to 1.5 with hydrochloric acid (1 mmol/L).The mixture was extracted with EtOAc (3~50 mL).Drying in a vacuum desiccator overnight gave the product 4-nitrophenylglyoxylic acid.Yield: 0.154 g. The yield was 79.2percent.
Reference：
[1] Synthetic Communications, 2008, vol. 38, # 24, p. 4434 - 4444
[2] Patent: CN108623611, 2018, A, . Location in patent: Paragraph 0041; 0043; 0044; 0045; 0046
[3] Journal of Organic Chemistry, 2018, vol. 83, # 3, p. 1422 - 1430
[4] Journal of the American Chemical Society, 2010, vol. 132, # 34, p. 11898 - 11899
[5] Chemical Communications, 2013, vol. 49, # 35, p. 3640 - 3642
[6] Organic and Biomolecular Chemistry, 2017, vol. 15, # 20, p. 4320 - 4327
[7] Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2390 - 2395
[8] Organic Letters, 2017, vol. 19, # 17, p. 4556 - 4559
[9] Advanced Synthesis and Catalysis, 2018, vol. 360, # 17, p. 3345 - 3355
2
[ 122-04-3 ]
[ 14922-36-2 ]
Reference：
[1] Synthesis, 1990, # 9, p. 755 - 756
3
[ 10098-39-2 ]
[ 14922-36-2 ]
Reference：
[1] Journal of the Indian Chemical Society, 1982, vol. 59, # 5, p. 654 - 656
[2] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2000, vol. 39, # 7, p. 728 - 733
[3] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2000, vol. 39, # 7, p. 734 - 739
[4] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2001, vol. 40, # 3, p. 311 - 315
[5] International Journal of Chemical Kinetics, 2002, vol. 34, # 4, p. 248 - 254
[6] Journal of the Indian Chemical Society, 2002, vol. 79, # 11, p. 871 - 875
[7] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 12, p. 2335 - 2340
[8] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2007, vol. 46, # 3, p. 445 - 448
[9] International Journal of Chemical Kinetics, 2010, vol. 42, # 1, p. 50 - 55
4
[ 57699-27-1 ]
[ 14922-36-2 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8175 - 8185
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 45℃; for 1.03333h;Inert atmosphere;
<strong>[14922-36-2]4-nitrophenylglyoxylic acid</strong> (5) was obtained as a pale yellowishbrown solid by the previously reported methods [27]. (Scheme 1) Then,<strong>[14922-36-2]4-nitrophenylglyoxylic acid</strong> (39 mg, 0.2 mmol), oxaloyl chloride (53 muL,0.6 mmol) and 3 mL dichloromethane were mixed and stirred for 2 min,and two drops of N, N-dimethylformamide (DMF) were added. Underthe protection of nitrogen, the temperature rose to 45 C. After 1 h, the mixture was cooled to room temperature. Then, the solvent and excessoxaloyl chloride were evaporated, affording the product (40.4 mg,95%) as a light yellow transparent oil liquid.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 40℃; for 1h;
(5) 4-nitrophenylglycolic acid (39 mg) was dissolved in ultra-dry methylene chloride (2 mL), and 2 drops of DMF were added dropwise,Oxalyl chloride (53 muL) was added and refluxed at 40 C for 1 h, spin-dried to give 4-nitrophenylglyoxalyl chloride as a pale yellow solid.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 45℃;Inert atmosphere;
<strong>[14922-36-2]4-nitrophenylglyoxylic acid</strong> (39 mg, 0.2 mmol), oxalyl chloride (53 muL, 0.6 mmol) in a 25 mL round bottom flask.Add 3 mL of dichloromethane, stir with a magnetic stirrer, and add two drops of N,N-dimethylformamide. Under a nitrogen atmosphere, the oil bath was heated to 45 C and stirred under reflux.TLC thin layer chromatography was used to detect the progress of the reaction. After 1 hour, the reaction was completed and the reaction solution was cooled to room temperature.The remaining oxalyl chloride was distilled off under reduced pressure to give a crude yellow-white powder, yield: 40.4 mg, yield 95%.
With pyridine; selenium(IV) oxide; at 110℃; for 1h;Inert atmosphere;
SeO2 (0.167 g, 1.5 mmol), p-nitroacetophenone (0.165 g, 1 mmol) in a 25 mL round bottom flask under nitrogen.Add 10 mL of anhydrous pyridine, heat the oil bath to 110 C and stir to reflux.After 1 hour, the progress of the reaction was detected by TLC thin layer chromatography, and after cooling for 4 hours, it was cooled to room temperature.Filtration through a Buchner funnel, filtering off the solution containing SeO2 precipitate, washing the residue with 50 mL of ethyl acetate;The filtrate was combined and treated with 1 mmol/L hydrochloric acid (20 mL).The aqueous layer was extracted three times with ethyl acetate (50 mL) to give aqueous layer 2 and organic layer 2;After the organic layer 1 and the organic layer 2 are combined, extracted three times with 25 ml of water to obtain an organic layer 3 and an aqueous layer 3;The aqueous layer 3 was treated with 1 mmol/L NaOH (50 mL), and the reaction solution was diluted to obtainTo the filtrate 4.After the filtrate 4 was combined with the aqueous layer 2, the pH was adjusted to 1.5 with hydrochloric acid (1 mmol/L).The mixture was extracted with EtOAc (3~50 mL).Drying in a vacuum desiccator overnight gave the product 4-nitrophenylglyoxylic acid.Yield: 0.154 g. The yield was 79.2%.
With pyridine; selenium(IV) oxide; at 90℃; for 4h;Inert atmosphere;
Specific operation: p-nitroacetophenone (1g) was dissolved in pyridine (10mL), and SeO2 (1g) was added.The mixture was purged with nitrogen and stirred at 90 C for 4 h, wherein the molar ratio of p-nitroacetophenone to SeO 2 was 1:1.5.After the reaction was completed, the mixture was cooled and filtered, and the filter cake was washed three times with ethyl acetate. The organic layer was collected, washed with 2M HCl, and then the organic layer was combined.Dry with anhydrous sodium sulfate,The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography.
2-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine[ No CAS ]
[ 1036242-06-4 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; at 90℃;
As shown in Scheme 7, compound 1002 (66 mg), <strong>[14922-36-2]4-nitrophenylglyoxylic acid</strong> (135 mg), 4M HCl-dioxane (0.4 mL), and methanol (4 mL) were mixed together and heated at 90 C. overnight. After cooling, addition of ether, and filtration, compound 98 was obtained as a solid (106 mg). To compound 98 (64 mg) in 3 mL of methanol was added SnCl2.2H2O (0.3 g). After heating at 80 C. for 1 hour, followed by cooling, the reaction mixture was filtered through Celite and concentrated to give compound 102 after purification via silica gel chromatography.
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide[ No CAS ]
[ 1428848-34-3 ]
Yield
Reaction Conditions
Operation in experiment
5%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (300 mg, 0.71 mmol), <strong>[14922-36-2]2-(4-nitrophenyl)-2-oxoacetic acid</strong> (300 mg, 1.54 mmol), DMAP (150 mg, 1.23 mmol) and EDC (200 mg, 1.04 mmol) were dissolved in DCM (15 ml), and the mixture was stirred at RT for 3 hours. The reaction was diluted with HCl 1M and extracted with EtOAc. The organic phase was washed with HCl 1M, K2CO3 sat. sol. and brine, dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 50 mg of the final product. (Yield: 5%).[0935]MS/ESI+ 615.4 [MH]+[0936]1H NMR (400 MHz, acetone) delta ppm 8.25 (s, 2H), 8.16 (m, 2H), 7.94 (m, 2H), 7.10-7.15 (m, 1H), 6.97-7.01 (m, 1H), 6.85-6.92 (m, 2H), 6.33 and 6.42 (2s, 20H), 6.04-6.13 (m, 1H), 3.74-3.90 (m, 2H), 3.42-3.52 (m, 1H), 3.16-3.32 (m, 1H), 1.12-1.32 (m, 1H), 0.51-0.72 (m, 2H), 0.25-0.45 (m, 2H)
5%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)- 2-hydroxyethyl)pyridine 1-oxide (300 mg, 0.71 mmol), 2-(4-nitrophenyl)-2- oxoacetic acid (300 mg, 1.54 mmol), DMAP (150 mg, 1.23 mmol) and EDC (200 mg, 1.04 mmol) were dissolved in DCM (15 ml), and the mixture was stirred at RT for 3h. The reaction was diluted with HC1 1M and extracted with EtOAc. The organic phase was washed with HC1 1M, K2CO3 sat. sol. and brine, dried over Na2S04 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 50 mg of the final product. (Yield: 5%). MS/ESI+ 615.4 [MH]+ 1H NMR (400 MHz, acetone) delta ppm 8.25 (s, 2 H), 8.16 (m, 2 H), 7.94 (m, 2 H), 7.10 - 7.15 (m, 1 H), 6.97 - 7.01 (m, 1 H), 6.85 - 6.92 (m, 2 H), 6.33 and 6.42 (2s, 2 OH), 6.04 - 6.13 (m, 1 H), 3.74 - 3.90 (m, 2 H), 3.42 - 3.52 (m, 1 H), 3.16 - 3.32 (m, 1 H), 1.12 - 1.32 (m, 1 H), 0.51 - 0.72 (m, 2 H), 0.25 - 0.45 (m, 2 H).
With iodine; oxygen; palladium diacetate; caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 45℃; for 12h;Schlenk technique; Sealed tube;
General procedure: A 10 mL oven-dried Schlenk tube was charged with phenylglyoxylic acid 1a (49.5mg, 0.33mmol), indole 2a (35.1mg, 0.3mmol), I2 (164.5mg, 0.65mmol), Pd(OAc)2 (10mol%, 6.7mg, 0.03mmol), Cs2CO3 (292mg, 0.9mmol). The tube was evacuated and filled with O2 (this procedure was repeated three times). Then NMP (1.5mL) were added with a syringe under a counter flow of O2. The tube was sealed with a screw cap. The reaction was stirred at 45C for 12h, and was then allowed to cool to ambient temperature. The mixture was added 20mL EtOAc, and filtered, washed with water. The organic layers were dried over Na2SO4 and filtered. Solvents were evaporated under reduced pressure. The residue was purified by flash column chromatography with hexane/ethyl acetate to give the corresponding product 3.
[0269] Synthesis of Compound Tap-18H is shown below in the scheme. Synthesis of intermediate Compounds M and O are also shown in the schemes below. [0270] Referring to the scheme of synthesis of Compound Tap-18H, commercially available <strong>[14922-36-2]4-nitrophenylglyoxylic acid</strong> was condensed with N-methylpiperazine using either P15, or EDCI and NiPr2Et in DMF, or 2-chloro-4,6-dimethoxy-l,3,5-triazine in CH2C12 and N- methylmorpholine as coupling agent to produce the desired ketoamide. In a typical procedure, a solution of 2-chloro-4,6-dimethoxy-l,3,5-triazine (5 mmol) in CH2C12(20 ml), N- methylmorpholine (15 mmol) was added at 0-5 C under continuous stirring. A white suspension was formed after 30-40 minutes and to this mixture <strong>[14922-36-2]4-nitrophenylglyoxylic acid</strong> in CH2CI2 (10 ml) was added, resulting in the formation of a clear solution. After stirring the mixture for 1 hour, N-methylpiperazine (5 mmol) was added at room temperature. After completion of the reaction (TLC, 10 minutes), the mixture was washed with 10% aqueous NaHCC>3 solution (2x10 ml) followed by H20 (3x10 ml). The organic layer was dried over anhydrous sodium sulfate and removal of the solvent under reduced pressure furnished a crude product which was further purified by recrystallization or column chromatography (pet. ethenethyl acetate=8:2).
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide; In decane; benzene; at 20 - 90℃; for 12h;Schlenk technique;
General procedure: An over-dried Schlenk tube was charged with tetrabutylammonium iodide (TBAI) (0.1 mmol),phenylglyoxylic acid (1a) (0.5 mmol) and cyclohexene (2a) (1.5 mmol) in benzene (2 mL) wasadded, Then tert-butyl hydroperoxide (1.25 mmol, 5~6 M in decane) was added dropwise into themixture at room temperature. The resulting mixture was stirred at 90 C for 12 h. Then, the cooledreaction mixture was dissolved in water (5 mL) and extracted with CH2Cl2 (3×5 mL). Thecombined organic layer was dried with anhydrous MgSO4, and the product was further purified bysilica gel column chromatography and eluted with ethyl acetate and petroleum ether mixture toafford the product.
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide; In decane; benzene; at 20 - 90℃; for 12h;Schlenk technique;
General procedure: An over-dried Schlenk tube was charged with tetrabutylammonium iodide (TBAI) (0.1 mmol),phenylglyoxylic acid (1a) (0.5 mmol) and cyclohexene (2a) (1.5 mmol) in benzene (2 mL) wasadded, Then tert-butyl hydroperoxide (1.25 mmol, 5~6 M in decane) was added dropwise into themixture at room temperature. The resulting mixture was stirred at 90 C for 12 h. Then, the cooledreaction mixture was dissolved in water (5 mL) and extracted with CH2Cl2 (3×5 mL). Thecombined organic layer was dried with anhydrous MgSO4, and the product was further purified bysilica gel column chromatography and eluted with ethyl acetate and petroleum ether mixture toafford the product.
N-(4-bis(2-hydroxyethyl)amino)phenyl-2-(4-nitrophenyl)-2-oxoacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Specific procedure: Intermediate 1 (0.78g) was dissolved in DMF (5mL), intermediate 5 (0.78g), EDCI (1.145g),DIPEA (0.99 mL) was added in sequence and stirred at room temperature for 1-2 h.After the reaction is completed, the mixture is washed with water and brine, and the organic layer is combined and dried over anhydrous sodium sulfate.Distilling off the solvent under reduced pressure,Column chromatography elutionA dark brown intermediate 9 was obtained.
(N-(4-hydroxymethyl)phenyl)-2-(4-nitrophenyl)-2-oxoacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Specific procedure: Intermediate 1 (1 g) was dissolved in THF (10 mL), p-aminobenzyl alcohol (0.64 mg),EDCI (1.475g) and DIPEA (1.28mL) were added in sequence and stirred at room temperature for 1-2 hours.After the reaction is completed, the mixture is washed with water and brine, and the organic layer is combined and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to give a dark brown intermediate 2, which was directly reacted.
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