* 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.
Reference：
[1] Journal of the Chemical Society, 1945, p. 622,625
[2] Patent: US2537870, 1946, ,
3
[ 1196-57-2 ]
[ 1448-87-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
With trichlorophosphate In toluene for 1 h; Reflux
The chlorination of the 2-hydroxy quinoxaline was carried out in neat POCl3 (2.3 eqs) at reflux for an hour and produced the 2-chloro-quinoxaline (1D-008) in very good yield. This chemistry was tested on 100 g scale and afforded typically 103-105 g (98-99percent). A quick filtration through a Pad of silica of the crude reaction mixture resulted in clean material (99percent pure by LCMS). This reaction has beenscaled up to 600 g.
Reference：
[1] Patent: US2017/143706, 2017, A1, . Location in patent: Paragraph 0050; 0106; 0107
[2] Helvetica Chimica Acta, 2001, vol. 84, # 5, p. 1112 - 1118
[3] Heterocycles, 2005, vol. 65, # 1, p. 181 - 185
[4] Heterocycles, 2006, vol. 68, # 9, p. 1973 - 1979
[5] Journal of the Chemical Society, 1945, p. 622,625
[6] Journal of the Chemical Society, 1957, p. 3236,3237
[7] Bulletin de la Societe Chimique de France, 1959, p. 1793,1796
[8] Patent: US2537870, 1946, ,
[9] Heterocycles, 1985, vol. 23, # 10, p. 2603 - 2611
[10] Chemistry Letters, 1984, p. 323 - 326
[11] Heterocycles, 2012, vol. 86, # 2, p. 1583 - 1590
4
[ 1196-57-2 ]
[ 1448-87-9 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 110℃; for 12 h; Inert atmosphere
The 2.000g2-hydroxy quinoxaline in 20mL phenylphosphonic dichloride, under nitrogen conditions, 110 ° C reflux 12h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water slowly with constant stirring. product After precipitation, filtration, washing, drying, you can get 1.830g2- chloro quinoxaline (intermediate II-1), a yield of 81percent.
75%
for 2 h; Reflux
Place 2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) in 100 mLIn a three-neck flask, add 5 drops of DMF, and transfer the system to reflux for 2h.In a 500 mL beaker, add an appropriate amount of ice water. White solids precipitated,Yield 75percent.
75%
for 2 h; Reflux
2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) were placed in 100 mL of threeStir in the bottle, add 5 drops of DMF, reflux for 2 h, transfer the system to a 500 mL beaker, and add an appropriate amount of ice water. Precipitating whiteSolid, yield 75percent
35%
at 79 - 100℃; for 0.25 h;
General procedure: 0.13 mL of N,N-dimethylformamide was added dropwise to a slurry monohydroxy quinoxaline 1d-e (0.5g, 3.1 mmol) and thionyl chloride (0.73 g, 6.2 mmol) in 1-chlorobutane(5 mL). The resulting reaction mixture was refluxed for 15min., and then evaporated to dryness under reduced pressure to leave a solid. The residue was taken up in a minimum of CH2Cl2, filtered and washed with CH2Cl2. Concentration then give the halogenated derivatives.
Reference：
[1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
[2] ChemMedChem, 2015, vol. 10, # 1, p. 193 - 206
[3] Patent: CN103787992, 2016, B, . Location in patent: Paragraph 0079-0082
[4] Patent: CN107602539, 2018, A, . Location in patent: Paragraph 0043
[5] Patent: CN108530435, 2018, A, . Location in patent: Paragraph 0015; 0017
[6] Tetrahedron Letters, 1999, vol. 40, # 42, p. 7477 - 7478
[7] Synthetic Communications, 2005, vol. 35, # 15, p. 1983 - 1987
[8] Synthetic Communications, 2011, vol. 41, # 23, p. 3532 - 3540
[9] Chemistry - A European Journal, 2009, vol. 15, # 19, p. 4857 - 4864
[10] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4508 - 4522
[11] Revue Roumaine de Chimie, 2017, vol. 62, # 12, p. 903 - 906
[12] Journal of Physical Organic Chemistry, 1994, vol. 7, # 10, p. 545 - 550
[13] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 2054 - 2057
[14] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6723 - 6728
[15] Patent: US4076806, 1978, A,
[16] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1660 - 1673
5
[ 1196-57-2 ]
[ 1448-87-9 ]
[ 877078-00-7 ]
Reference：
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 2005, vol. 180, # 8, p. 1795 - 1807
6
[ 61645-34-9 ]
[ 1448-87-9 ]
[ 1196-57-2 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 217 - 220[2] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 2, p. 265 - 267
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1987, p. 1722 - 1724
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 9, p. 1065 - 1072
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 18, p. 3319 - 3324
[2] Bioorganic Chemistry, 2014, vol. 56, p. 16 - 26
26
[ 1196-57-2 ]
[ 6272-25-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1403 - 1407
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4508 - 4522
27
[ 1196-57-2 ]
[ 55686-94-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4508 - 4522
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6169 - 6186
[3] Journal of the Brazilian Chemical Society, 2017, vol. 28, # 10, p. 1874 - 1878
28
[ 1196-57-2 ]
[ 89898-96-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 2, p. 255 - 267
[2] Yakugaku Zasshi, 1959, vol. 79, p. 658[3] Chem.Abstr., 1959, p. 21979
29
[ 1196-57-2 ]
[ 25652-34-0 ]
Reference：
[1] Bioorganic Chemistry, 2014, vol. 56, p. 16 - 26
[2] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 2, p. 255 - 267
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 18, p. 3319 - 3324
[4] Patent: US2009/264426, 2009, A1, . Location in patent: Page/Page column 43
[5] Patent: WO2007/29847, 2007, A1, . Location in patent: Page/Page column 66
30
[ 1196-57-2 ]
[ 82031-32-1 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 20℃; for 12 h;
[0288] To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at rt for 12 h, then poured into ice- water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one as an off-white solid (74 g, 88percent).
88%
at 20℃; for 12 h;
To a solution of quinoxalin-2(1H)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at rt for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(1H)-one as an off-white solid (74 g, 88percent).
88%
at 20℃; for 12 h;
Example 1: Preparation of -(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea 1 -(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea [0186] To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at room temperature for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one (74 g, 88percent).
88%
With bromine In acetic acid at 20℃;
[0174] To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL)dropwise. The resulting mixture was stirred at r.t. for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one as an off-white solid (74 g, 88percent yield).
73%
at 20℃; for 48 h; Inert atmosphere
Example 69: 3-oxo-3.,4-dihvdro-2H-benzo[l,41thiazine-6-carboxylic acid {l-[2-(7- methylsulfanyl-quinoxalin-2-yloxy)-ethyll-piperidin-4-yl}-amide: Preparation of 7-bromo-iH-quinoxalin-2-one: Bromine (7.36 mL, 147 mmol, 1.05 eq) is added at room temperature to a stirred suspension of iH-quinoxalin-2-one (20 g, 137 mmol, 1.0 eq) in acetic acid (400 mL). After 48 hours stirring at room temperature, the reaction mixture is poured into ice (500 mL) and the resulting precipitate is collected by filtration, washed with water and ethyl acetate to afford7-bromo-iH-quinoxalin-2-one as a yellow solid (29.4 g, 73percent yield). 1H-NMR (400 MHz, DMSO-t/6) δ ppm: 12.44 (br, IH), 8.17 (s, IH), 7.69 (d, J = 8.8 Hz, IH), 7.44 (m, 2H).MS m/z (+ESI): 225.1 [M+H]+.
66%
With bromine In acetic acid at 20℃; for 19.5 h;
Step B: Preparation of 7-bromo-1H- uinoxalin-2-oneTo a stirred solution of 1 H-quinoxalin-2-one (50 g, 342.5 mmol) in glacial acetic acid (2500 ml.) was added bromine (54.7 g, 342.5 mmol in 120 ml_ acetic acid) over a period of 1.5 h at rt. After 18 h stirring, the mixture was slowly poured into 2000 ml_ water and stirred for 1 h at rt. The precipitate was filtered and the residue was washed with water and dried to give 7-bromo-1 H- quinoxalin-2-one as an off-white solid (51 g, 66percent): 1H-NMR (300 MHz, d6- DMSO): δ = 12.42 (1 H, s), 8.19 (1 H, s), 7.75 (1 H, d), 7.44 (2H, m) ppm.
58%
at 0℃; for 2 h;
To a cooled 0 °C solution of quinoxalin-2(1 /-/)-one (I-70) (50 g, 342.2 mmol) in acetic acid (800 ml_) was added in a dropwise manner a solution of bromine (32 ml_) in acetic acid (200 ml_) over a period of 30 min. Solids formed within the reaction upon addition of bromine, and the reaction was allowed to stir slowly for a further 90 min. The solid was filtered, washed with MeOH and ether, and dried under high vacuum to afford 7-bromoquinoxalin-2(1 /-/)-one (1-71) (45 g, 58percent) as a white solid. LCMS (APCI), m/z 224.1 [M + H]+; 1H NMR (400 MHz, DMSO-c/6J 8 ppm 12.46 (s, 1 H), 8.16 - 8.18 (m, 1 H), 7.69 - 7.72 (d, 1 H), 7.44 - 7.46 (m, 2 H).
26%
at 20℃; for 1.5 h;
Bromine (3.56 mL, 68.63 mmol) was slowly added to a solution of quinoxalin-2(lH)-one (10.03 g, 68.63 mmol) in 0.1M acetic acid (686.3 mL). The reaction mixture was stirred at ambient temperature for 1.5 hours. The resulting solids were collected by filtration and washed with hexanes to afford 7-bromoquinoxalin-2(lH)-one (4.02 g, 17.86 mmol, 26.0percent yield). 1H NMR (400 MHz, (CD3)2SO) δ = 12.466 (s, 1H), 8.191 (s, 1H), 7.724-7.700 (d, 1H), 7.470-7.444 (m, 2H).
With bromine; silver sulfate In tetrachloromethane; sulfuric acid at 20 - 50℃;
The quinoxalin-2(1H)-one (14.6 g, 0.1 mol, Aldrich, cat. no. 260517) and silver sulphate (15.6 g, 0.05 mol) were dissolved in cone. Sulfuric acid (100 ml) at 200C. Bromine (5.2 ml, 0.1 mol) was added and the reaction mixture was stirred vigorously for 24 hours. The reaction mass was then diluted with carbon tetrachloride (100 ml_), and this was heated at 5O0C. The reaction mass was then filtered and the filtrate was poured into ice cold water and stirred for 30 minutes to obtain a precipitate. The precipitate was filtered and the solid material was dried in vacuo to afford the title product (9.0 g, 40percent).
With trichlorophosphate; In toluene; for 1h;Reflux;
The chlorination of the 2-hydroxy quinoxaline was carried out in neat POCl3 (2.3 eqs) at reflux for an hour and produced the 2-chloro-quinoxaline (1D-008) in very good yield. This chemistry was tested on 100 g scale and afforded typically 103-105 g (98-99%). A quick filtration through a Pad of silica of the crude reaction mixture resulted in clean material (99% pure by LCMS). This reaction has beenscaled up to 600 g.
With ammonium peroxodisulphate In lithium hydroxide monohydrate; acetonitrile at 60℃;
1 Example 1
In a 25 mL tube, add compound 1 0.2 mmol, ammonium persulfate 0.6 mmol, add acetonitrile: water (4:1 volume ratio) 2 ml as a solvent, stirred at 60 degrees Celsius. After the TLC (Thin Layer Chromatography) detection reaction is completed, the reaction liquid is cooled to room temperature, 10 ml of water is added, filtered with a sand core funnel, and the vacuum drying box is dried to obtain the target product - Compound 2, with a yield of 91%.
91%
With ammonium peroxodisulphate; lithium hydroxide monohydrate In acetonitrile at 60℃;
21 Example 21
In a 25 mL test tube, add quinoxaline-2-one 0.2 mmol, ammonium persulfate 0.6 mmol, add acetonitrile: water (4:1 volume ratio) 2 ml as a solvent, stirred at 60 degrees Celsius. After the TLC (Thin Layer Chromatography) detection reaction is completed, the reaction liquid is cooled to room temperature, 10 ml of water is added, filtered with a sand core funnel, and the vacuum drying box is dried to obtain the target product, with a yield of 91%.
75%
With tert.-butylnitrite; lithium hydroxide monohydrate In dimethyl sulfoxide at 100℃; for 3h; Sealed tube;
52%
With sodium hydroxide; potassium permanganate In lithium hydroxide monohydrate Heating;
52%
With sodium hydroxide; potassium permanganate for 1h; Heating;
With dihydrogen peroxide; glacial acetic acid
Multi-step reaction with 2 steps
1: PCl5 / 30 h / 220 - 240 °C
2: H2O / 7 h / Heating
1.1.A
Step A: Preparation of 1 H-quinoxalin-2-oneTo a stirred suspension of o-phenylenediamine (50 g, 462.9 mmol) in ethanol(200 ml_), at rt was added a solution of ethyl glyoxalate in toluene (50 ; 113 ml_, 555.48 mmol) over a period of 45 min. After heating to 45 °C for 10 h, the mixture was left at rt under stirring. The precipitate was filtered and the residue was washed with water and dried to give 1 H-quinoxalin-2-one as an off-white powder (63 g, 93%): 1H-NMR (300 MHz, d6-DMSO): δ = 12.44 (1 H, s),8.19 (1 H, s), 7.78 (1 H, d), 7.55 (1 H, dd), 7.32 (2H, m) ppm.
92%
In ethanol; toluene at 50℃; for 12h;
15 Example 15. Synthesis of 7-bromoquinoxaline-2-carbonitrile (xlv, CAS 1609932-73-1)
Diamine xxxviii (200 g, 1.85 mol) is dissolved in ethanol (1.2 L). Ethyl glyoxalate (50% in toluene, 450 mL) is added dropwise. The reaction is heated to 50°C for 12 hours, then cooled to 5 °C for 1 hour. The mixture is filtered and the solid washed with water to give xxxix in 92% yield.
50%
In ethanol; toluene at 45℃; Schlenk technique; Inert atmosphere;
With ethanol
In ethanol at 120℃; for 18h;
26 Preparation 26; Preparation of 7-Bromo-2-chloro-quinoxaline
Heat BENZENE-1, 2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethyl ester (20 mL) in ethanol (100 mL) at 120 C for 18 h. Cool, filter the resulting precipitate, and wash with dry ether to give LH-QUINOXALIN-2-ONE (6.7 g). Dissolve LH-QUINOXALIN-2-ONE in acetic acid (300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h. Filter the resulting crystals and wash with ether to afford 7-BROMO-LH-QUINOXALIN-2-ONE (7.2 g). Reflux 7-BROMO-LH-QUINOXALIN-2-ONE in POC13 (30 mL) for 18 h. Remove POC13 in vacuo, dissolve the product in 3: 1 chloroform/isopropyl alcohol, and wash the organic phase with saturated sodium bicarbonate. Dry over sodium sulfate and purify by silica gel flash chromatography eluting with dichloromethane to 10% methanol/90% dichloromethane to afford the title compound as a yellow solid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).
In ethanol at 20℃; Reflux; Inert atmosphere;
In ethanol at 20℃; for 17h; Reflux;
137 mg
With sodium dioctyl sulfosuccinate In water monomer at 20℃; for 1h;
With potassium carbonate In ethanol at 20℃; for 24h; Reflux;
General Procedure for the Preparation of Quinoxalinone Substrates
General procedure: To a suspension of o-arylenediamine (4. 0 mmol, 1. 0 equiv) and potassium carbonate (2.0 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv). The reaction mixture was stirred and heated at reflux in an oil bath for 12 h, then at room temperature for 12 h. Upon completion, the suspension was washed with ethanol, then filtered and dried to give quinoxalinone. For alkylation, the corresponding alkyl halide (1.6 equiv) was added to a suspension of quinoxalinone (1 equiv) and potassium carbonate (1.2 equiv) in DMF (16 mL). The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was washed with saturated solution of ammonium chloride (5 mL), ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting organic residue was purified by flash chromatography column over silica gel (SiO2) to afford the alkylated quinoxalinone.
In ethanol at 20℃; for 16h; Reflux; Inert atmosphere;
In ethanol at 45℃; for 8h;
Dissolve o-phenylenediamine (10 mmol, 1 equivalent) in 40 ml of ethanol,After adding ethyl glyoxylate (11 mmol, 1.1 equivalents) to the reaction flask,The reaction was carried out at a temperature of 45 ° C for 8 hours.After the reaction is completed, the reaction stock solution is filtered,Rinse the solid 3 times with 50 ml of water,Compound II-1 was obtained as a white solid after vacuum drying.
In ethanol for 16h; Reflux;
In ethanol at 85℃; for 1h;
In ethanol at 80℃;
In ethanol for 1h; Reflux;
In ethanol at 200℃; for 0.25h; Microwave irradiation;
Microwave-assisted synthesis of quinoxaline-2(1H)-one (1)
1,2-Phenylenediamine (5.4 g, 0.05 mol) and ethyl glyoxalate(6.2 mL, 0.06 mol) were reacted in a vial (30 mL) ofmicrowave synthesis reactor (Anton-Paar Monowave 300)in ethanol. The reaction was maintained under the conditionsof 200 °C and 25 bar for 15 min. After this time, thereaction mixture was cooled and the solvent was evaporated.The residue was washed with water, dried andrecrystallized from ethanol (Yan-Yan 2010).
at 70℃; for 9h;
1.1; 2.1; 3.1 Synthesis of quinoxaline-2(1H)-one
Add 5 mmol o-phenylenediamine and 5.5 mmol ethyl glyoxylate to 8 mL of organic solvent, reflux for 1 hour at 70°C, cool to room temperature, and stir overnight (8 h); filter and wash with deionized water , 100 drying, that is, quinoxaline-2 (1H)-one.
In ethanol Reflux;
In ethanol at 80℃;
In ethanol at 20 - 90℃; for 12h;
In ethanol for 1h; Reflux;
In ethanol at 45℃; for 8h;
In ethanol at 20℃; for 17h;
General Procedure for the Preparation of Quinoxalinone Substrates
General procedure: Ethyl-2-oxoacetate (1.1 equiv.) was added to a suspension of o-arylenediamine (4mmol, 1 equiv.) in ethanol (1 mol/L). The reaction mixture was stirred and heated at reflux inan oil bath for 1 h, then at room temperature for 16 h. Upon completion (as monitored by TLC), the precipitate was filtered and washed with ethanol, then dried to give quinoxalinone.
In ethanol for 1h; Reflux;
2.1 Preparation of substrates 1
General procedure: A mixture of o-phenylenediamine (5 mmol), ethyl 2-oxoacetate (6 mmol) and ethanol (20 mL) in a dried 50 mL round-bottom flask was stirred at reflux for 1 hour. After the completion (as indicated by TLC), the reaction mixture was filtered, washed with ethanol and then dried to give quinoxalinone 1'. Subsequently, A mixture of quinoxalinone 1', K2CO3 (1.2 equiv.), corresponding halogenoalkane (1.6 equiv.) and DMF (20 ml) in a dried 50 mL round-bottom flask was stirred at room temperature overnight. After the completion (as indicated by TLC), The mixture was then extracted with ethyl acetate and the collected organic layer was washed with brine, dried with MgSO4. The solvent was removed under reduced pressure, and the crude product was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 5:1) to afford desired substrates 1.
In ethanol; toluene at 55℃; Sealed tube;
In ethanol at 80℃; for 1h;
In ethanol at 20℃; for 4h;
In ethanol Reflux;
3. Preparation of Quinoxalin-2(1H)-ones
General procedure: Quinoxalin-2(1H)-one was prepared from 1,2-phenylenediamines following the procedure of Cui and co-workers [1] on 5 mmol scale. To a solution of 1,2-phenylenediamines (5 mmol, 1.0 equiv.)in ethanol (40 mL) was added ethyl glyoxalate (6 mmol, 1.2 equiv.). The resultant reaction mixturewas stirred at reflux until the raw material disappears. Then, the mixture was filtered and washedby ethanol. The solid was dried in vacuo. For alkylation, the corresponding halogenoalkane (1.6equiv.) was added to a suspension of quinoxalinone (1.0 equiv.) and potassium carbonate (1.2 equiv.)in DMF (16 mL). The mixture was stirred at room temperature overnight. After complete reaction,brine was added, and then extracted three times with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue waspurified by column chromatography on silica gel to afford the desired product.
In ethanol at 20℃; for 17h; Reflux;
In ethanol at 55℃;
In ethanol at 20 - 90℃; for 12h;
2.2 The preparation of quinoxalin-2(1H)-ones[1]
General procedure: To a suspension of o-arylenediamine (1 equiv.) in ethanol was added ethyl glyoxalate (1.1equiv.). The mixture was stirred at reflux for 1 h, then at room temperature overnight. Theprecipitated solid was filtered and washed with ethanol, then dried to give quinoxalinone. To asuspension of quinoxalinone (1 equiv.) in DMF was added potassium carbonate (1.2 equiv.) andthe corresponding halogenoalcane (1.6 equiv.). The mixture was stirred at room temperatureovernight. Ethyl acetate and water were added. The aqueous layer was extracted twice withEtOAc. The combined organic layers were washed with a saturated solution of NaCl, dried overMgSO4, filtered, and evaporated under reduced pressure. The residue is purified by flashchromatography over silica gel to afford the desired product N-alkyl quinoxalinone (Scheme S1).
With sulfuric acid; potassium nitrate; at 0 - 20℃;
Production Example 26-2 6-Nitroquinoxalin-2(1H)-one As divided in plural portions, potassium nitrate (3.7 g) was intermittently added at 0 C. to a concentrated sulfuric acid solution (60 mL) of the compound (5.3 g) obtained in Production Example 26-1. After heated up to room temperature and stirred for 6 hours, the formed precipitate was collected by filtration, and washed with water and diisopropyl ether. This was dried under reduced pressure to obtain the entitled compound (7.1 g).
[0288] To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at rt for 12 h, then poured into ice- water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one as an off-white solid (74 g, 88%).
88%
With bromine; acetic acid; at 20℃; for 12.0h;
To a solution of quinoxalin-2(1H)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at rt for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(1H)-one as an off-white solid (74 g, 88%).
88%
With bromine; acetic acid; at 20℃; for 12.0h;
Example 1: Preparation of -(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea 1 -(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea [0186] To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL) dropwise. The resulting mixture was stirred at room temperature for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one (74 g, 88%).
88%
With bromine; In acetic acid; at 20℃;
[0174] To a solution of quinoxalin-2(lH)-one (54.64 g, 374 mmol, 1.0 eq.) in HOAc (1000 mL) was added a solution of Br2 (19.18 mL, 374 mmol, 1.0 eq.) in HOAc (200 mL)dropwise. The resulting mixture was stirred at r.t. for 12 h, then poured into ice-water. The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one as an off-white solid (74 g, 88% yield).
85%
With bromine; acetic acid; at 20 - 60℃; for 24.0h;
Quinoxalone xxxix (250 g, 1.7 mol) is dissolved in acetic acid (4500 mL). A mixture of acetic acid (988 mL) and bromine (108 mL, 2.1 mol) is added dropwise, and the mixture stirred at room temperature for 12 hours, then heated to 60 C for 12 hours. After cooling to room temperature, the reaction is filtered and the solid washed with water. The wet cake (500 g) is then dissolved in 1500 mL of methanol and heated to 60 C, then filtered and dried at 60 C to give xl in 85% yield.
73%
With bromine; acetic acid; at 20℃; for 48.0h;Inert atmosphere;
Example 69: 3-oxo-3.,4-dihvdro-2H-benzo[l,41thiazine-6-carboxylic acid {l-[2-(7- methylsulfanyl-quinoxalin-2-yloxy)-ethyll-piperidin-4-yl}-amide: Preparation of 7-bromo-iH-quinoxalin-2-one: Bromine (7.36 mL, 147 mmol, 1.05 eq) is added at room temperature to a stirred suspension of iH-quinoxalin-2-one (20 g, 137 mmol, 1.0 eq) in acetic acid (400 mL). After 48 hours stirring at room temperature, the reaction mixture is poured into ice (500 mL) and the resulting precipitate is collected by filtration, washed with water and ethyl acetate to afford7-bromo-iH-quinoxalin-2-one as a yellow solid (29.4 g, 73% yield). 1H-NMR (400 MHz, DMSO-t/6) delta ppm: 12.44 (br, IH), 8.17 (s, IH), 7.69 (d, J = 8.8 Hz, IH), 7.44 (m, 2H).MS m/z (+ESI): 225.1 [M+H]+.
66%
With bromine; In acetic acid; at 20℃; for 19.5h;
Step B: Preparation of 7-bromo-1H- uinoxalin-2-oneTo a stirred solution of 1 H-quinoxalin-2-one (50 g, 342.5 mmol) in glacial acetic acid (2500 ml.) was added bromine (54.7 g, 342.5 mmol in 120 ml_ acetic acid) over a period of 1.5 h at rt. After 18 h stirring, the mixture was slowly poured into 2000 ml_ water and stirred for 1 h at rt. The precipitate was filtered and the residue was washed with water and dried to give 7-bromo-1 H- quinoxalin-2-one as an off-white solid (51 g, 66%): 1H-NMR (300 MHz, d6- DMSO): delta = 12.42 (1 H, s), 8.19 (1 H, s), 7.75 (1 H, d), 7.44 (2H, m) ppm.
58%
With bromine; acetic acid; at 0℃; for 2.0h;
To a cooled 0 C solution of quinoxalin-2(1 /-/)-one (I-70) (50 g, 342.2 mmol) in acetic acid (800 ml_) was added in a dropwise manner a solution of bromine (32 ml_) in acetic acid (200 ml_) over a period of 30 min. Solids formed within the reaction upon addition of bromine, and the reaction was allowed to stir slowly for a further 90 min. The solid was filtered, washed with MeOH and ether, and dried under high vacuum to afford 7-bromoquinoxalin-2(1 /-/)-one (1-71) (45 g, 58%) as a white solid. LCMS (APCI), m/z 224.1 [M + H]+; 1H NMR (400 MHz, DMSO-c/6J 8 ppm 12.46 (s, 1 H), 8.16 - 8.18 (m, 1 H), 7.69 - 7.72 (d, 1 H), 7.44 - 7.46 (m, 2 H).
26%
With bromine; acetic acid; at 20℃; for 1.5h;
Bromine (3.56 mL, 68.63 mmol) was slowly added to a solution of quinoxalin-2(lH)-one (10.03 g, 68.63 mmol) in 0.1M acetic acid (686.3 mL). The reaction mixture was stirred at ambient temperature for 1.5 hours. The resulting solids were collected by filtration and washed with hexanes to afford 7-bromoquinoxalin-2(lH)-one (4.02 g, 17.86 mmol, 26.0% yield). 1H NMR (400 MHz, (CD3)2SO) delta = 12.466 (s, 1H), 8.191 (s, 1H), 7.724-7.700 (d, 1H), 7.470-7.444 (m, 2H).
With bromine; In acetic acid; for 1.0h;
Heat BENZENE-1, 2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethyl ester (20 mL) in ethanol (100 mL) at 120 C for 18 h. Cool, filter the resulting precipitate, and wash with dry ether to give LH-QUINOXALIN-2-ONE (6.7 g). Dissolve LH-QUINOXALIN-2-ONE in acetic acid (300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h. Filter the resulting crystals and wash with ether to afford 7-BROMO-LH-QUINOXALIN-2-ONE (7.2 g). Reflux 7-BROMO-LH-QUINOXALIN-2-ONE in POC13 (30 mL) for 18 h. Remove POC13 in vacuo, dissolve the product in 3: 1 chloroform/isopropyl alcohol, and wash the organic phase with saturated sodium bicarbonate. Dry over sodium sulfate and purify by silica gel flash chromatography eluting with dichloromethane to 10% methanol/90% dichloromethane to afford the title compound as a yellow solid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).
With bromine; silver sulfate; In tetrachloromethane; sulfuric acid; at 20 - 50℃;
The quinoxalin-2(1H)-one (14.6 g, 0.1 mol, Aldrich, cat. no. 260517) and silver sulphate (15.6 g, 0.05 mol) were dissolved in cone. Sulfuric acid (100 ml) at 200C. Bromine (5.2 ml, 0.1 mol) was added and the reaction mixture was stirred vigorously for 24 hours. The reaction mass was then diluted with carbon tetrachloride (100 ml_), and this was heated at 5O0C. The reaction mass was then filtered and the filtrate was poured into ice cold water and stirred for 30 minutes to obtain a precipitate. The precipitate was filtered and the solid material was dried in vacuo to afford the title product (9.0 g, 40%).
With bromine; silver sulfate; In sulfuric acid; at 20℃;Inert atmosphere;Product distribution / selectivity;
Quinoxalin-2(1H)-one (5 g, 34.2 mmol) was stirred in sulphuric acid (50 ml_) and silver sulphate was added (5.3 g, 17.1 mmol). The mixture was vigorously stirred until complete dissolution, whereupon bromine (1.76 ml_, 34.2 mmol) was added dropwise. The resulting mixture was stirred at room temperature under nitrogen overnight. Carbon tetrachloride (50 ml_) was added and the mixture was heated to 500C for 30 minutes, then filtered. The solid was washed with carbon tetrachloride and the filtrate was collected. This was poured into a beaker of crushed ice and slurried to give a thick off-white suspension. The crude material was filtered and the resulting solid was triturated in methanol and re-filtered. The solid pulled dry to give 5.44 g of the title compound as a pale brown solid.1H-NMR (400 MHz, DMSOd6): delta=12.52(1 H, bs), 8.17(1 H, s), 7.94(1 H, d), 7.68(1 H, dd), 7.22(1 H, d). LCMS (run time = 6 min): R4 = 2.29 min; m/z 225; 227 [M+H]+
With P,P-dichlorophenylphosphine oxide; at 110℃; for 12h;Inert atmosphere;
The 2.000g2-hydroxy quinoxaline in 20mL phenylphosphonic dichloride, under nitrogen conditions, 110 C reflux 12h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water slowly with constant stirring. product After precipitation, filtration, washing, drying, you can get 1.830g2- chloro quinoxaline (intermediate II-1), a yield of 81%.
75%
With N,N-dimethyl-formamide; trichlorophosphate; for 2h;Reflux;
Place 2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) in 100 mLIn a three-neck flask, add 5 drops of DMF, and transfer the system to reflux for 2h.In a 500 mL beaker, add an appropriate amount of ice water. White solids precipitated,Yield 75%.
75%
With N,N-dimethyl-formamide; trichlorophosphate; for 2h;Reflux;
2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) were placed in 100 mL of threeStir in the bottle, add 5 drops of DMF, reflux for 2 h, transfer the system to a 500 mL beaker, and add an appropriate amount of ice water. Precipitating whiteSolid, yield 75%
75%
With trichlorophosphate; In N,N-dimethyl-formamide; for 2h;Reflux;
2-Hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) were placed in a 100 ml three-necked flask and 5 drops of DMF were added.After refluxing for 2 hours, the system was transferred to a 500 ml beaker and precipitated by adding 200 ml of ice water.White solid,The yield was 75%.
75%
With trichlorophosphate; In N,N-dimethyl-formamide; for 2h;Reflux;
2-hydroxyquinoxaline (2g)Mix with phosphorus oxychloride (20 mL) in a 100 mL three-necked flask and add 5 drops of DMF.After refluxing for 2 h, the system was transferred to a 500 mL beaker and added to an appropriate amount of ice water.A white solid precipitated in a yield of 75%.
74%
With trichlorophosphate; In N,N-dimethyl-formamide; at 90℃; for 1h;
General procedure: In the water less condition, 2-hydroxyquinoxaline was dissolved in phosphorus oxychloride and DMF, stirred and refluxed at 90 C for 1 h until the completion of the reaction. Following this, it was poured into ice water, and filtered toobtain a white solid compound 2a, with yield 74%.
35%
With thionyl chloride; N,N-dimethyl-formamide; at 79 - 100℃; for 0.25h;
General procedure: 0.13 mL of N,N-dimethylformamide was added dropwise to a slurry monohydroxy quinoxaline 1d-e (0.5g, 3.1 mmol) and thionyl chloride (0.73 g, 6.2 mmol) in 1-chlorobutane(5 mL). The resulting reaction mixture was refluxed for 15min., and then evaporated to dryness under reduced pressure to leave a solid. The residue was taken up in a minimum of CH2Cl2, filtered and washed with CH2Cl2. Concentration then give the halogenated derivatives.
With 2,3-Dimethylaniline; trichlorophosphate; In Petroleum ether;
EXAMPLE 6 STR32 A mixture of 74 g (0.5 mole) of 2-hydroxy-benzopyrazine, 12 g of dimethylaniline and 250 ml of phosphorus oxychloride was heated under reflux for 10 minutes. At about 80 C, all the material had dissolved; the reaction solution was cooled and poured onto ice, and the product was filtered off. The residue was dried on clay and was then taken up in petroleum ether, and the solution was filtered through active charcoal. The reaction solution was evaporated and 78 g (87.5% of theory) of 2-chloro-benzopyrazine of melting point 48-49 C, were obtained. STR33
Iodine-Catalyzed Oxidative Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones 1 and Indoles 2; General Procedure
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
85%
With trifluorormethanesulfonic acid In N,N-dimethyl-formamide at 80℃; for 15h;
43%
With p-toluenesulfonyl chloride In tetrahydrofuran at -15 - 20℃; for 2h;
40%
With trifluoroacetic acid In dichloromethane for 2h; Heating;
201 mg
With oxygen; titanium(IV) oxide In acetic acid at 120℃; for 5h; UV-irradiation;
With KNO3; phosphorus pentachloride; In conc. H2 SO4; trichlorophosphate;
C. Preparation of 7-Nitrotetrazole Compounds. KNO3 (7.35 g, 0.0727 mmol) was added in three portions to a solution of quinoxalin-2-one (10.62 g, 72.7 mmol) in conc. H2 SO4 (120 ml) maintained in an ice bath. The ice bath was removed, and the mixture allowed to stir for 21/2 hours longer, and then poured onto 1 liter of ice-H2 O to cause precipitation of a yellow solid. The mixture stood overnight before collecting the precipitate by filtration, washing with H2 O, and air drying to yield 9.97 g of a yellow solid. This <strong>[25652-34-0]6-nitroquinoxalin-2-one</strong> (3.00 g, 15.7 mmol) was heated at reflux in POCl3 ml) and PCl5 (6.0 g) under N2 for 31/2 hours. Upon cooling, the mixture was poured onto H2 O, adding ice as necessary to cool the resultant exotherm. The resulting crystals were collected by filtration, washed with H2 O, and air-dried to yield 3.00 g of yellow needles comprising 2-chloro-6-nitroquinoxaline.
Example 1; Preparation of 2-(4-morpholinyl)-7-(1H-pyrazolo[3,4-b]pyridin-5-yl)quinoxaline; a) 7-bromo-2(1H)-quinoxalinone; Prepared according to the procedure described in Journal of Medicinal Chemistry, 1981, 24(1), 93-101.
EXAMPLE 8 2-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-quinoxaline To a solution of <strong>[18718-79-1](5-methyl-3-phenyl-isoxazol-4-yl)-methanol</strong> (100 mg, 0.53 mmol) in THF (6 mL) was added 2-hydroxyquinoxaline (77 mg, 0.53 mmol) and tributyl phosphine (206 muL, 0.79 mmol) at ambient temperature under an argon atmosphere. After cooling to 0 C., N,N,N',N'-tetramethylazodicarboxamide (137 mg, 0.79 mmol) was added. The resulting orange solution was stirred for 16 h at ambient temperature followed by 2.5 h at 50 C. Then triphenylphosphine (208 mg, 0.79 mmol), 2-hydroxyquinoxaline (77 mg, 0.53 mmol) and diethyl azodicarboxylate (127 muL, 0.79 mmol) were added and the reaction mixture was stirred for 4 h at 50 C. The reaction mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (67 mg, 40%) as a white solid. MS: m/e=318.2 [M+H]+.
With oxygen; titanium(IV) oxide In acetic acid at 120℃; for 5h; UV-irradiation;
86%
With trifluorormethanesulfonic acid In N,N-dimethyl-formamide at 80℃; for 6h;
38%
With iodine In methanol at 20℃; for 8h;
Iodine-Catalyzed Oxidative Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones 1 and Indoles 2; General Procedure
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
35%
Stage #1: quinoxalin-2(1)-one With (S)-(+)-N-tosylvaline chloride In tetrahydrofuran at -15℃; for 0.0833333h;
Stage #2: 2-methyl-1H-indole In tetrahydrofuran at -15 - 20℃; for 3h;
With trifluorormethanesulfonic acid In N,N-dimethyl-formamide at 80℃; for 6h;
69%
With iodine In methanol at 20℃; for 8h;
Iodine-Catalyzed Oxidative Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones 1 and Indoles 2; General Procedure
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
3 General procedure for the synthesis of the substrate (2b-2e)
General procedure: A general procedure: To a stirred solution of quinoxalin-2(1H)-ones (3 mmol) in DMF (10 mL) was added the corresponding halide (1.6 eq.) and potassium carbonate (1.2 eq.) at room temperature. After disappearance of quinoxalin-2(1H)-ones, the resulting mixture was added with water, and extracted with ethyl acetate for three times. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain the desired product 2b to 2e.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
2.1 Preparation of substrates 1
General procedure: A mixture of o-phenylenediamine (5 mmol), ethyl 2-oxoacetate (6 mmol) and ethanol (20 mL) in a dried 50 mL round-bottom flask was stirred at reflux for 1 hour. After the completion (as indicated by TLC), the reaction mixture was filtered, washed with ethanol and then dried to give quinoxalinone 1'. Subsequently, A mixture of quinoxalinone 1', K2CO3 (1.2 equiv.), corresponding halogenoalkane (1.6 equiv.) and DMF (20 ml) in a dried 50 mL round-bottom flask was stirred at room temperature overnight. After the completion (as indicated by TLC), The mixture was then extracted with ethyl acetate and the collected organic layer was washed with brine, dried with MgSO4. The solvent was removed under reduced pressure, and the crude product was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 5:1) to afford desired substrates 1.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With methylene chloride; potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Reflux;
General Procedure for the Preparation of Quinoxalinone Substrates
General procedure: To a suspension of o-arylenediamine (4. 0 mmol, 1. 0 equiv) and potassium carbonate (2.0 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv). The reaction mixture was stirred and heated at reflux in an oil bath for 12 h, then at room temperature for 12 h. Upon completion, the suspension was washed with ethanol, then filtered and dried to give quinoxalinone. For alkylation, the corresponding alkyl halide (1.6 equiv) was added to a suspension of quinoxalinone (1 equiv) and potassium carbonate (1.2 equiv) in DMF (16 mL). The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was washed with saturated solution of ammonium chloride (5 mL), ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting organic residue was purified by flash chromatography column over silica gel (SiO2) to afford the alkylated quinoxalinone.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate; chloroacetic acid ethyl ester In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Reflux;
General Procedure for the Preparation of Quinoxalinone Substrates
General procedure: To a suspension of o-arylenediamine (4. 0 mmol, 1. 0 equiv) and potassium carbonate (2.0 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv). The reaction mixture was stirred and heated at reflux in an oil bath for 12 h, then at room temperature for 12 h. Upon completion, the suspension was washed with ethanol, then filtered and dried to give quinoxalinone. For alkylation, the corresponding alkyl halide (1.6 equiv) was added to a suspension of quinoxalinone (1 equiv) and potassium carbonate (1.2 equiv) in DMF (16 mL). The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was washed with saturated solution of ammonium chloride (5 mL), ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting organic residue was purified by flash chromatography column over silica gel (SiO2) to afford the alkylated quinoxalinone.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
2.1 Preparation of substrates 1
General procedure: A mixture of o-phenylenediamine (5 mmol), ethyl 2-oxoacetate (6 mmol) and ethanol (20 mL) in a dried 50 mL round-bottom flask was stirred at reflux for 1 hour. After the completion (as indicated by TLC), the reaction mixture was filtered, washed with ethanol and then dried to give quinoxalinone 1'. Subsequently, A mixture of quinoxalinone 1', K2CO3 (1.2 equiv.), corresponding halogenoalkane (1.6 equiv.) and DMF (20 ml) in a dried 50 mL round-bottom flask was stirred at room temperature overnight. After the completion (as indicated by TLC), The mixture was then extracted with ethyl acetate and the collected organic layer was washed with brine, dried with MgSO4. The solvent was removed under reduced pressure, and the crude product was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 5:1) to afford desired substrates 1.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
General procedure for the synthesis of quinoxalinones substrates
General procedure: To a suspension of o-arylenediamine (1 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv.). The mixture was stirred at reflux for 1h, then at room temperature overnight. The precipitated solid was filtered and washed with ethanol, then dried to give quinoxalinone 1’. To a suspension of quinoxalinone 1’ (1 equiv.) in DMF was added potassium carbonate (1.2 equiv.) and the corresponding halogenoalcane (1.6 equiv.). The mixture was stirred at room temperature overnight. Ethyl acetate and water were added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated solution of NH4Cl then brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography over silica gel to afford the desired product 1.
3-(diphenylphosphoryl)quinoxaline-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With lithium perchlorate In acetonitrile at 40℃; Electrolysis;
97%
With tert-butylammonium hexafluorophosphate(V) In acetonitrile at 50℃; for 7h; Electrolysis; Green chemistry;
1 Example 1
Quinolinone is compound II-1 (0.5 mmol, 1 equivalent) and diphenylphosphine is compound III-1 (0.75 mmol,1.5 equivalent) in a 50mL three-necked bottle,At the same time, tetrabutylammonium hexafluorophosphate ([n-Bu4NPF6], 0.5 mmol, 1 equivalent) was added as an electrolyte,Add 15mL of anhydrous acetonitrile (CH3CN) as solvent, use platinum electrode as anode and graphite electrode as cathode,The reaction was conducted for 7 hours under the conditions of 10 mA of direct current and a temperature of 50 ° C.Cool to room temperature, spin dry the solvent, separate and purify by dry loading column (eluent: dichloromethane / methanol = 100/5)The target compound I-1 was obtained as a yellow solid in a yield of 97%.
69%
With eosin B disodium salt In acetonitrile at 20℃; for 3h; Inert atmosphere; Irradiation;
3. General procedure for the visible light mediated photoredox-catalyzed phosphorylation of quinoxalin-2(1H)-ones
General procedure: An oven-dried flask was equipped with a magnetic stir bar, quinoxalin-2(1H)-ones 1 (0.2 mmol), diphenyl phosphine oxide 2 (121.3 mg, 0.6 mmol), eosin B (3.5 mg, 0.006 mmol), and acetonitrile (2 mL) under N2 atmosphere. The reaction mixture was allowed to stir for 1-3 h under irradiation of house hold 20 W compact fluorescence light (CFL) bulb. After the reaction was finished, the mixture was added water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were dried over Na2SO4, concentrated in vacuum and purified by chromatography on silica gel (methanol:dichloromethane=1:30) to afford the 3-phosphorylated quinoxalin-2(1H)-ones 3.
61%
With dipotassium peroxodisulfate In acetonitrile at 100℃; for 8h; Green chemistry;
61%
With dipotassium peroxodisulfate In acetonitrile at 100℃; for 8h;
17 Preparation of 3- (diphenylphosphono) quinoxaline-2 (1H) -one
A mixture of quinoxaline-2 (1H) -one0.2 mmol,Diphenylphosphine oxide0.3 mmol, 0.6 mmol of potassium persulfate, 2.0 mL of acetonitrile,Was added to a 10 mL reaction tube, placed in an oil bath at 100 ° C, and reacted under air for 8 h. The reaction was stopped and allowed to cool to room temperature. anti-The product was spin-dried with a rotary evaporator and 42.2 mg of the target product was isolated by column chromatography in a yield of 61%.
Stage #1: quinoxalin-2(1)-one; benzenesulfonyl chloride With dmap In dichloromethane at 0℃; for 0.0833333h;
Stage #2: With triethylamine In dichloromethane at 20℃; for 1.08333h;
3.2.1. 2-Benzensulfonyloxyquinoxaline (1)
In a round bottom flask, quinoxalinone (5 g, 34 mmol), DMAP (0.416 g, 3.4 mmol) and benzenesulfonyl chloride (8.72 mL, 68 mmol) were dissolved in DCM (100 mL), cooled to 0 °C andstirred for 5 min. Et3N (12 mL, 88 mmol) was added drop-wise over 5 min, the solution allowed to stirat room temperature for 1 h, and the reaction quenched with aqueous NaHCO3 (80 mL). The two layerswere separated and the aqueous layer washed twice with DCM (2 x 60 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and dissolved in EtOAc (15 mL). The filtrate was concentrated to give 2-benzenesulfonyloxyquinoxaline as a brown solid (8.23 g, 85%); m.p. 90-91 °C; δH (400 MHz, CDCl3) 7.58-7.63 (2H, m), 7.69-7.77 (3H, m), 7.87-7.90 (1H, m), 8.09-8.17 (3H, m) and 8.67 ppm (1H, s); δC (100 MHz, CDCl3) 128.51, 128.80, 129.01, 129.22, 129.51, 131.20, 134.74,136.41, 139.10, 139.71, 141.32 and 150.90; HRMS (ES): MH+ calcd for [C14H10N2SO3]+: 286.04212,found: 286.0421.
With tert.-butylhydroperoxide; iodine In 1,4-dioxane; water at 20℃; for 16h;
83%
With oxygen In N,N-dimethyl acetamide at 80℃; for 16h; Green chemistry;
Experimental
General procedure: In a representative experiment, a solution of quinoxalin-2(1H)-one (0.029 g, 0.20 mmol), morpholine (0.035 g,0.40 mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an internal standard in dimethylacetamide (1 mL) was added into a 8 mL screw-capvial. Pre-calculated amount of Cu-CPO-27 catalyst was then introduced to the vial. The catalyst quantity was enumerated with reference to the copper/quinoxalin-2(1H)-one molar ratio. The reaction mixture was magnetically stirred at 80 °C for 16 h under an oxygen atmosphere. The reaction yield was determined by withdrawing samples from the reaction mixture, and quenching with brine (1 mL). The organic compounds were subsequently extracted into ethyl acetate phase (3 mL), dried utilizing anhydrous Na2SO4, and analyzed by GC regarding diphenyl ether. The product of the reaction was purified by column chromatography. 1H NMR, 13C NMR, and GC-MS analyses were conducted to validate the identity of the product.
With tert.-butylhydroperoxide; iodine In 1,4-dioxane; water at 20℃; for 16h;
69%
With lithium perchlorate; acetic acid In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;
56%
With oxygen In N,N-dimethyl acetamide at 80℃; for 16h; Green chemistry;
Experimental
General procedure: In a representative experiment, a solution of quinoxalin-2(1H)-one (0.029 g, 0.20 mmol), morpholine (0.035 g,0.40 mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an internal standard in dimethylacetamide (1 mL) was added into a 8 mL screw-capvial. Pre-calculated amount of Cu-CPO-27 catalyst was then introduced to the vial. The catalyst quantity was enumerated with reference to the copper/quinoxalin-2(1H)-one molar ratio. The reaction mixture was magnetically stirred at 80 °C for 16 h under an oxygen atmosphere. The reaction yield was determined by withdrawing samples from the reaction mixture, and quenching with brine (1 mL). The organic compounds were subsequently extracted into ethyl acetate phase (3 mL), dried utilizing anhydrous Na2SO4, and analyzed by GC regarding diphenyl ether. The product of the reaction was purified by column chromatography. 1H NMR, 13C NMR, and GC-MS analyses were conducted to validate the identity of the product.
3-[benzyl(methyl)amino]quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With lithium perchlorate; acetic acid In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;
65%
With oxygen In N,N-dimethyl acetamide at 80℃; for 24h; Green chemistry;
Experimental
General procedure: In a representative experiment, a solution of quinoxalin-2(1H)-one (0.029 g, 0.20 mmol), morpholine (0.035 g,0.40 mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an internal standard in dimethylacetamide (1 mL) was added into a 8 mL screw-capvial. Pre-calculated amount of Cu-CPO-27 catalyst was then introduced to the vial. The catalyst quantity was enumerated with reference to the copper/quinoxalin-2(1H)-one molar ratio. The reaction mixture was magnetically stirred at 80 °C for 16 h under an oxygen atmosphere. The reaction yield was determined by withdrawing samples from the reaction mixture, and quenching with brine (1 mL). The organic compounds were subsequently extracted into ethyl acetate phase (3 mL), dried utilizing anhydrous Na2SO4, and analyzed by GC regarding diphenyl ether. The product of the reaction was purified by column chromatography. 1H NMR, 13C NMR, and GC-MS analyses were conducted to validate the identity of the product.
64%
With tert.-butylhydroperoxide; iodine In 1,4-dioxane; water at 20℃; for 16h;
With oxygen In N,N-dimethyl acetamide at 80℃; for 24h; Green chemistry;
Experimental
General procedure: In a representative experiment, a solution of quinoxalin-2(1H)-one (0.029 g, 0.20 mmol), morpholine (0.035 g,0.40 mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an internal standard in dimethylacetamide (1 mL) was added into a 8 mL screw-capvial. Pre-calculated amount of Cu-CPO-27 catalyst was then introduced to the vial. The catalyst quantity was enumerated with reference to the copper/quinoxalin-2(1H)-one molar ratio. The reaction mixture was magnetically stirred at 80 °C for 16 h under an oxygen atmosphere. The reaction yield was determined by withdrawing samples from the reaction mixture, and quenching with brine (1 mL). The organic compounds were subsequently extracted into ethyl acetate phase (3 mL), dried utilizing anhydrous Na2SO4, and analyzed by GC regarding diphenyl ether. The product of the reaction was purified by column chromatography. 1H NMR, 13C NMR, and GC-MS analyses were conducted to validate the identity of the product.
56%
With tert.-butylhydroperoxide; iodine In 1,4-dioxane; water at 20℃; for 16h;
With tert.-butylhydroperoxide; iodine In 1,4-dioxane; water at 20℃; for 16h;
61%
With oxygen In N,N-dimethyl acetamide at 80℃; for 24h; Green chemistry;
Experimental
General procedure: In a representative experiment, a solution of quinoxalin-2(1H)-one (0.029 g, 0.20 mmol), morpholine (0.035 g,0.40 mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an internal standard in dimethylacetamide (1 mL) was added into a 8 mL screw-capvial. Pre-calculated amount of Cu-CPO-27 catalyst was then introduced to the vial. The catalyst quantity was enumerated with reference to the copper/quinoxalin-2(1H)-one molar ratio. The reaction mixture was magnetically stirred at 80 °C for 16 h under an oxygen atmosphere. The reaction yield was determined by withdrawing samples from the reaction mixture, and quenching with brine (1 mL). The organic compounds were subsequently extracted into ethyl acetate phase (3 mL), dried utilizing anhydrous Na2SO4, and analyzed by GC regarding diphenyl ether. The product of the reaction was purified by column chromatography. 1H NMR, 13C NMR, and GC-MS analyses were conducted to validate the identity of the product.
With tert.-butylnitrite; methanesulfonic acid In acetone at 20℃; for 1.5h;
1 Example 1. Preparation of 3- (p-Tolyl) quinoxalin-2-one Derivatives with R1 = R2 = -H and R3 = -CH3
Quinoxalin-2-one (0.2 mmol, 29.2 mg) and p-toluidine (0.2 mmol, 21.4 mg) were added to a 25 mL round bottom flask followed by methanesulfonic acid (0.2 mmol, 19.2 mg) andTert-butyl nitrite (0.24 mmol, 24.7 mg) and finally 3 mL of acetone as a solvent.At room temperature for 1.5h;After the reaction was completed, the solvent was removed under reduced pressure, 10 mL of water was added to the residue, and the mixture was extracted twice with 20 mL of ethyl acetate. The extract was washed twice with saturated sodium bicarbonate 20 mL and once with saturated saline solution. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1/1) to give 0.040 g of a colorless solid in a yield of 85.0%.
80%
With tert.-butylnitrite; methanesulfonic acid In acetone at 20℃; for 1.5h; Schlenk technique;
75%
Stage #1: <i>p</i>-toluidine With tetrafluoroboric acid; tert.-butylnitrite In ethanol; water at 0 - 20℃; for 1h;
Stage #2: quinoxalin-2(1)-one With tetrabutylammonium tetrafluoroborate; trifluoroacetic acid In dimethyl sulfoxide at 20℃; for 4.5h; Electrochemical reaction;
With tert.-butylnitrite; methanesulfonic acid In methanol at 20℃; for 2h;
2 Example 2. Preparation of 3- (4-Bromophenyl) quinoxalin-2-one Derivatives with R1 = R2 = -H and R3 = -Br
In a 25 mL round bottom flask were added quinoxalin-2-one (0.2 mmol, 29.2 mg) and p-bromoaniline (0.24 mmol, 41.0 mg) followed by methanesulfonic acid (0.24 mmol, 23.0 mg) and t-butyl nitrite (0.3 mmol, 30.9 mg) and finally Into 4mL of methanol as a solvent. The reaction at room temperature 2.0h; After the reaction was completed, the solvent was removed under reduced pressure to the residue was added 10mL of water, The mixture was extracted twice with 20 mL of ethyl acetate. The extract was washed twice with 20 mL of saturated sodium bicarbonate and once with saturated brine The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1/1) From the purification, 0.052 g of a colorless solid was obtained in a yield of 87.0%.
76%
With tert.-butylnitrite; methanesulfonic acid In acetone at 20℃; for 1.5h; Schlenk technique;
3-(4-methylpiperidin-1-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With oxygen In N,N-dimethyl acetamide at 80℃; for 16h; Green chemistry;
Experimental
General procedure: In a representative experiment, a solution of quinoxalin-2(1H)-one (0.029 g, 0.20 mmol), morpholine (0.035 g,0.40 mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an internal standard in dimethylacetamide (1 mL) was added into a 8 mL screw-capvial. Pre-calculated amount of Cu-CPO-27 catalyst was then introduced to the vial. The catalyst quantity was enumerated with reference to the copper/quinoxalin-2(1H)-one molar ratio. The reaction mixture was magnetically stirred at 80 °C for 16 h under an oxygen atmosphere. The reaction yield was determined by withdrawing samples from the reaction mixture, and quenching with brine (1 mL). The organic compounds were subsequently extracted into ethyl acetate phase (3 mL), dried utilizing anhydrous Na2SO4, and analyzed by GC regarding diphenyl ether. The product of the reaction was purified by column chromatography. 1H NMR, 13C NMR, and GC-MS analyses were conducted to validate the identity of the product.
76%
With lithium perchlorate; acetic acid In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;
3.1.2. Preparation of alkylated quinoxalinones.
General procedure: Haloalkanes (1.6 equiv) were added to a suspension of quinoxalinone (1.0 equiv) and K2CO3 (1.2 equiv) in DMF. The mixture was stirred at room temperature for 8 h, and the reaction progress was monitored by TLC. The reaction mixture was washed with saturated ammonium chloride, ethyl acetate and water, respectively. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. Filtration and rotary evaporation under reduced pressure to obtain crude product. Purified by column chromatography to obtain alkylated quinoxalinone.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
3 General procedure for the synthesis of the substrate (2b-2e)
General procedure: A general procedure: To a stirred solution of quinoxalin-2(1H)-ones (3 mmol) in DMF (10 mL) was added the corresponding halide (1.6 eq.) and potassium carbonate (1.2 eq.) at room temperature. After disappearance of quinoxalin-2(1H)-ones, the resulting mixture was added with water, and extracted with ethyl acetate for three times. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain the desired product 2b to 2e.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Reflux;
General Procedure for the Preparation of Quinoxalinone Substrates
General procedure: To a suspension of o-arylenediamine (4. 0 mmol, 1. 0 equiv) and potassium carbonate (2.0 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv). The reaction mixture was stirred and heated at reflux in an oil bath for 12 h, then at room temperature for 12 h. Upon completion, the suspension was washed with ethanol, then filtered and dried to give quinoxalinone. For alkylation, the corresponding alkyl halide (1.6 equiv) was added to a suspension of quinoxalinone (1 equiv) and potassium carbonate (1.2 equiv) in DMF (16 mL). The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was washed with saturated solution of ammonium chloride (5 mL), ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting organic residue was purified by flash chromatography column over silica gel (SiO2) to afford the alkylated quinoxalinone.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
2.1 Preparation of substrates 1
General procedure: A mixture of o-phenylenediamine (5 mmol), ethyl 2-oxoacetate (6 mmol) and ethanol (20 mL) in a dried 50 mL round-bottom flask was stirred at reflux for 1 hour. After the completion (as indicated by TLC), the reaction mixture was filtered, washed with ethanol and then dried to give quinoxalinone 1'. Subsequently, A mixture of quinoxalinone 1', K2CO3 (1.2 equiv.), corresponding halogenoalkane (1.6 equiv.) and DMF (20 ml) in a dried 50 mL round-bottom flask was stirred at room temperature overnight. After the completion (as indicated by TLC), The mixture was then extracted with ethyl acetate and the collected organic layer was washed with brine, dried with MgSO4. The solvent was removed under reduced pressure, and the crude product was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 5:1) to afford desired substrates 1.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
General procedure for the synthesis of quinoxalinones substrates
General procedure: To a suspension of o-arylenediamine (1 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv.). The mixture was stirred at reflux for 1h, then at room temperature overnight. The precipitated solid was filtered and washed with ethanol, then dried to give quinoxalinone 1’. To a suspension of quinoxalinone 1’ (1 equiv.) in DMF was added potassium carbonate (1.2 equiv.) and the corresponding halogenoalcane (1.6 equiv.). The mixture was stirred at room temperature overnight. Ethyl acetate and water were added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated solution of NH4Cl then brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography over silica gel to afford the desired product 1.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Reflux;
General Procedure for the Preparation of Quinoxalinone Substrates
General procedure: To a suspension of o-arylenediamine (4. 0 mmol, 1. 0 equiv) and potassium carbonate (2.0 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv). The reaction mixture was stirred and heated at reflux in an oil bath for 12 h, then at room temperature for 12 h. Upon completion, the suspension was washed with ethanol, then filtered and dried to give quinoxalinone. For alkylation, the corresponding alkyl halide (1.6 equiv) was added to a suspension of quinoxalinone (1 equiv) and potassium carbonate (1.2 equiv) in DMF (16 mL). The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was washed with saturated solution of ammonium chloride (5 mL), ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting organic residue was purified by flash chromatography column over silica gel (SiO2) to afford the alkylated quinoxalinone.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
2.1 Preparation of substrates 1
General procedure: A mixture of o-phenylenediamine (5 mmol), ethyl 2-oxoacetate (6 mmol) and ethanol (20 mL) in a dried 50 mL round-bottom flask was stirred at reflux for 1 hour. After the completion (as indicated by TLC), the reaction mixture was filtered, washed with ethanol and then dried to give quinoxalinone 1'. Subsequently, A mixture of quinoxalinone 1', K2CO3 (1.2 equiv.), corresponding halogenoalkane (1.6 equiv.) and DMF (20 ml) in a dried 50 mL round-bottom flask was stirred at room temperature overnight. After the completion (as indicated by TLC), The mixture was then extracted with ethyl acetate and the collected organic layer was washed with brine, dried with MgSO4. The solvent was removed under reduced pressure, and the crude product was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 5:1) to afford desired substrates 1.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate; 3-chloroprop-1-ene In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
General procedure for the synthesis of quinoxalinones substrates
General procedure: To a suspension of o-arylenediamine (1 equiv.) in ethanol (1 mol/L) was added ethyl 2-oxoacetate (1.1 equiv.). The mixture was stirred at reflux for 1h, then at room temperature overnight. The precipitated solid was filtered and washed with ethanol, then dried to give quinoxalinone 1’. To a suspension of quinoxalinone 1’ (1 equiv.) in DMF was added potassium carbonate (1.2 equiv.) and the corresponding halogenoalcane (1.6 equiv.). The mixture was stirred at room temperature overnight. Ethyl acetate and water were added. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with a saturated solution of NH4Cl then brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography over silica gel to afford the desired product 1.
3-(5-chloro-1H-indol-3-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With iodine In methanol at 20℃; for 8h;
Iodine-Catalyzed Oxidative Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones 1 and Indoles 2; General Procedure
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
3-(7-benzyloxy-1H-indol-3-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With iodine; In methanol; at 20℃; for 8h;
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
3-(6-methoxy-1H-indol-3-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With iodine In methanol at 20℃; for 8h;
Iodine-Catalyzed Oxidative Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones 1 and Indoles 2; General Procedure
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
3-(7-methoxy-1H-indol-3-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With iodine In methanol at 20℃; for 8h;
Iodine-Catalyzed Oxidative Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones 1 and Indoles 2; General Procedure
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1H-indole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With iodine; In methanol; at 60℃; for 8h;
General procedure: To a 2 dram vial (8 mL) equipped with a magnetic stir bar were added quinoxalinone 1 (0.50 mmol, 1.0 equiv), indole 2 (0.55 mmol, 1.1 equiv), molecular I2 (7.2 mg, 0.05 mmol, 0.10 equiv), and CH3OH (1.00 mL), respectively. The reaction mixture was stirred at r.t. under atmospheric air for 8 h. Upon completion, distilled deionized H2O (10 mL) and sat. aq Na2S2O3 (5 mL) were added, and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo. The crude product was purified by SiO2 column chromatography to afford the desired indolylquinoxalin-2(1H)-one product 3.
With bis-[(trifluoroacetoxy)iodo]benzene In N,N-dimethyl-formamide at 20℃; Schlenk technique; Inert atmosphere;
64%
With bis-[(trifluoroacetoxy)iodo]benzene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;
7 Implementation example 7:
Add the substrate quinoxaline-2(1H)-one to a 15 ml reaction tube (43.8 mg, 0.3 mmol, the substituent R1 on the structural formula is a hydrogen atom, and R2 is a hydrogen atom), Sodium trifluoromethylsulfinate (CF3SO2Na, 140.5 mg, 0.9 mmol), An oxidizing agent iodobenzene bis(trifluoroacetate) (387.0 mg, 0.9 mmol) was added. The oil pump was evacuated, argon-filled, and repeated 3 times, and 3 ml of N,N-dimethylformamide was added by syringe. The mixture was stirred at room temperature under an argon atmosphere for 12 hours. The reaction was carried out by TLC, and the reaction mixture was applied to a mixture of 100 ml of water and 100 ml of dichloromethane. The mixture was separated and then extracted twice with 100 ml of dichloromethane. The organic layer was combined and washed with 100 ml of saturated aqueous sodium chloride.The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated to dryness.Then, it was separated by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the product 3-trifluoromethylquinoxaline-2(1H)-one 41.2 mg, with a total yield of 64%
42%
With eosin In dimethyl sulfoxide at 20℃; for 24h; Irradiation;
With manganese(III) triacetate dihydrate In acetonitrile at 120℃; for 12h; Inert atmosphere;
General procedure
General procedure: A sealed tube was charged with quinoxalin-2(1H)-one (1, 0.625mmol) and CH3CN (5 mL) and the solution was purged with argongas for 30 min and then Mn(OAc)3*2H2O (1.873 mmol) and arylboronicacid (2, 0.745 mmol) were added. After removal of oxygenby argon gas, the reaction vessel was sealed with a Teflon screw.The reaction was stirred at 120 C for 12 h. The resulting suspensionwas cooled to room temperature and diluted with ethyl acetate.The organic layer was filtered through Whatman filter paperand evaporated under reduced pressure. The residue was purifiedby flash chromatography over silica gel to afford the desiredproduct.
63%
With dipotassium peroxodisulfate; potassium carbonate In water at 80℃; for 3h;
44%
With dipotassium peroxodisulfate; eosin Y disodium salt In water at 20℃; for 12h; Irradiation; Green chemistry;
1.2 General procedure for the synthesis of 3-arylquinoxalin-2(1H)-ones (3)
General procedure: Aryl boronic acid (2) should be portionwise added into a mixture of quinoxalinones (1) (0.2 mmol), K2S2O8 (1.5 equiv.), Eosin Y (3 mol %) and H2O (2 mL) in a 10 mL tube under blue LED for 12 hours. After completion of the reaction, as monitored by TLC, The mixture was then extracted with EtOAc and the collected organic layer was dried with MgSO4. The solvent was evaporated in vacuum, and the obtained residue was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 4:1).
cyclobutanone O-(4-(trifluoromethyl)benzoyl) oxime[ No CAS ]
[ 1501-33-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
With tetrabutylammonium tetrafluoroborate In N,N-dimethyl acetamide at 20℃; for 36h; Electrolysis; Green chemistry;
5. General Procedure for Electrolysis
General procedure: An oven-dried 20 mL undivided bottle was equipped with two graphite sheet electrodes (10 mm× 100 mm × 3 mm). The corresponding quinoxalin-2(1H)-one (48.0 mg, 0.3 mmol, 1.0 equiv.), thecyclobutanone oxime ester (154.2 mg, 0.6 mmol, 2.0 equiv.) and nBu4NBF4 (197.4 mg, 0.6 mmol,42.0 equiv.) was added into the undivided cell. And then DMA (5 mL) was added. The reactionmixture was stirred and electrolyzed at a constant-voltage of 3.0 V under room temperature for 36h. Later the brine was added, the solvent was extracted three times with EtOAc. The combinedorganic layers were firstly washed with saturated NaHCO3 then with brine, dried over anhydrousNa2SO4, filtered and then concentrated in vacuum. The pure product was obtained by flash columnchromatography on silica gel (petroleum ether/ethyl acetate = 3/1).
60%
With eosin y In dichloromethane at 20℃; Irradiation; Inert atmosphere; Green chemistry;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;
68%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In dimethyl sulfoxide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
3.2.2. Synthesis of Quinoxalin-2(1H)-ones
General procedure: Quinoxalin-2(1H)-one (5 mmol), DMF (15 mL) was added to a 100 mL round-bottomedflask with a stir bar, then potassium carbonate (828 mg, 6 mmol) was added, followedby the dropwise addition of R2-X (8 mmol, X = Cl, Br or I2). The reaction mixture wasthen stirred for 1~12 h at room temperature, poured into brine and extracted with EtOAc.The combined extracts were dried over Na2SO4, filtered, and evaporated. The residuewas purified by column chromatography (petroleum ether/EtOAc) to afford the desiredquinoxalin-2(1H)-ones. Quinoxalin-2(1H)-ones are known compounds.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;
2.2 The preparation of quinoxalin-2(1H)-ones[1]
General procedure: To a suspension of o-arylenediamine (1 equiv.) in ethanol was added ethyl glyoxalate (1.1equiv.). The mixture was stirred at reflux for 1 h, then at room temperature overnight. Theprecipitated solid was filtered and washed with ethanol, then dried to give quinoxalinone. To asuspension of quinoxalinone (1 equiv.) in DMF was added potassium carbonate (1.2 equiv.) andthe corresponding halogenoalcane (1.6 equiv.). The mixture was stirred at room temperatureovernight. Ethyl acetate and water were added. The aqueous layer was extracted twice withEtOAc. The combined organic layers were washed with a saturated solution of NaCl, dried overMgSO4, filtered, and evaporated under reduced pressure. The residue is purified by flashchromatography over silica gel to afford the desired product N-alkyl quinoxalinone (Scheme S1).
With C114H108N24O24; potassium carbonate; In dimethyl sulfoxide; for 24h;Irradiation;
in room temperature,In a 5 mL photoreaction tube, quinoxaline-2 (1H) -one (0.1 mmol), <strong>[637-04-7]3-methylphenylhydrazine hydrochloride</strong> (0.3 mmol), 2D-COF-1 (4 mg), K2CO3 (0.3 mmol) and dimethyl sulfoxide (1.5 mL). Stir in the air for 24 hours under the irradiation of a blue LED lamp with a power of 34W and a wavelength of 400-500nm. The reaction was stopped, extracted with ethyl acetate and water, and then concentrated under reduced pressure to obtain a crude product. Finally, it was washed with a mixed eluent of petroleum ether and ethyl acetate, and the corresponding quinoxalinone derivative was obtained by flash column chromatography (silica gel column) (yellow solid 16 mg, yield 69%).
With C114H108N24O24; potassium carbonate; In dimethyl sulfoxide; for 18h;Irradiation;
in room temperature,In a 5 mL photoreaction tube, quinoxaline-2 (1H) -one (0.1 mmol), <strong>[24214-72-0]cyclopentylhydrazine hydrochloride</strong> (0.2 mmol), 2D-COF-1 (4 mg), and K2CO3 (0.2 mmol) were sequentially added. And dimethyl sulfoxide (1.5 mL). Stir in the air for 18 hours under the irradiation of a blue LED lamp with a power of 34W and a wavelength of 400-500nm. The reaction was stopped, extracted with ethyl acetate and water, and then concentrated under reduced pressure to obtain a crude product. Finally, it was washed with a mixed eluent of petroleum ether and ethyl acetate, and flash column chromatography (silica gel column) was used to obtain the corresponding quinoxalinone derivative (15 mg of a light yellow solid, yield 70%).
1,3-dioxoisoindolin-2-yl 4-phenylbutanoate[ No CAS ]
3-(3-phenylpropyl)quinoxaline-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3h; Sealed tube; Inert atmosphere; Electrochemical reaction;
89%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3.5h; Sealed tube; Inert atmosphere; Electrochemical reaction;
11 Example 11: Synthesis of 3-(3-phenylpropyl)quinoxaline-2(1H)-one by electrochemical method
In a 10ml single-chamber electrolytic cell, add the raw materials 2-quinoxalinone (0.3mmol), redox active ester (0.6mmol), LiClO4 (1.0mmol), NiCl2.6H2O (0.6mmol), 4,4'- Di-tert-butyl-2,2'-bipyridine (0.6 mmol). Seal the device and inject argon into the tube (three times). Then, under an argon atmosphere, N,N-dimethylacetamide (DMA, 4.0 mL) and triethylamine (0.25 mL) were added via a syringe and stoppered with a rubber stopper, and an argon-filled balloon was inserted into the bottle. The mixture was first reacted under magnetic stirring at 60°C for 30 minutes, and then electrolyzed at a current density of 8 mA/cm2 for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (3×10 ml). The organic phase is concentrated on a rotary evaporator. The desired product was purified by column chromatography on a silica gel (petroleum ether: ethyl acetate) system and separated by column chromatography to obtain 3-(3-phenylpropyl)quinoxalin-2(1H)-one. Yield: 89%.
1,3-dioxoisoindolin-2-yl cyclopentanecarboxylate[ No CAS ]
[ 100381-62-2 ]
Yield
Reaction Conditions
Operation in experiment
91%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3h; Sealed tube; Inert atmosphere; Electrochemical reaction;
91%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3.5h; Sealed tube; Inert atmosphere; Electrochemical reaction;
5 Example 5: Synthesis of 3-cyclopentylquinoxaline-2(1H)-one by electrochemical method
In a 10ml single-chamber electrolytic cell, add the raw materials 2-quinoxalinone (0.3mmol), redox active ester (0.6mmol), LiClO4 (1.0mmol), NiCl2.6H2O (0.6mmol), 4,4'- Di-tert-butyl-2,2'-bipyridine (0.6 mmol). Seal the device and inject argon into the tube (three times). Then, under an argon atmosphere, N,N-dimethylacetamide (DMA, 4.0 mL) and triethylamine (0.25 mL) were added via a syringe and stoppered with a rubber stopper, and an argon-filled balloon was inserted into the bottle. The mixture was first reacted under magnetic stirring at 60°C for 30 minutes, and then electrolyzed at a current density of 8 mA/cm2 for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (3×10 ml). The organic phase is concentrated on a rotary evaporator. The desired product was purified by column chromatography on a silica gel (petroleum ether: ethyl acetate) system and separated by column chromatography to obtain 3-cyclopentylquinoxalin-2(1H)-one. Yield: 91%.
1,3-dioxoisoindolin-2-yl cyclobutanecarboxylate[ No CAS ]
3-cyclobutylquinoxaline-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3h; Sealed tube; Inert atmosphere; Electrochemical reaction;
90%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3.5h; Sealed tube; Inert atmosphere; Electrochemical reaction;
6 Example 6: Synthesis of 3-cyclobutylquinoxaline-2(1H)-one by electrochemical method
In a 10ml single-chamber electrolytic cell, add the raw materials 2-quinoxalinone (0.3mmol), redox active ester (0.6mmol), LiClO4 (1.0mmol), NiCl2.6H2O (0.6mmol), 4,4'- Di-tert-butyl-2,2'-bipyridine (0.6 mmol). Seal the device and inject argon into the tube (three times). Then, under an argon atmosphere, N,N-dimethylacetamide (DMA, 4.0 mL) and triethylamine (0.25 mL) were added via a syringe and stoppered with a rubber stopper, and an argon-filled balloon was inserted into the bottle. The mixture was first reacted under magnetic stirring at 60°C for 30 minutes, and then electrolyzed at a current density of 8 mA/cm2 for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (3×10 ml). The organic phase is concentrated on a rotary evaporator. The desired product was purified by column chromatography on a silica gel (petroleum ether: ethyl acetate) system and separated by column chromatography to obtain 3-cyclobutylquinoxalin-2(1H)-one. Yield: 90%.
1,3-dioxoisoindolin-2-yl (tert-butoxycarbonyl)alaninate[ No CAS ]
tert-butyl (1-(3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3h; Sealed tube; Inert atmosphere; Electrochemical reaction;
90%
With nickel(II) chloride hexahydrate; lithium perchlorate; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 60℃; for 3.5h; Sealed tube; Inert atmosphere; Electrochemical reaction;
16 Example 16: Synthesis of tert-butyl (1-(3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl) carbamate by electrochemical method
In a 10ml single-chamber electrolytic cell, add the raw materials 2-quinoxalinone (0.3mmol), redox active ester (0.6mmol), LiClO4 (1.0mmol), NiCl2.6H2O (0.6mmol), 4,4'- Di-tert-butyl-2,2'-bipyridine (0.6 mmol). Seal the device and inject argon into the tube (three times). Then, under an argon atmosphere, N,N-dimethylacetamide (DMA, 4.0 mL) and triethylamine (0.25 mL) were added via a syringe and stoppered with a rubber stopper, and an argon-filled balloon was inserted into the bottle. The mixture was first reacted under magnetic stirring at 60°C for 30 minutes, and then electrolyzed at a current density of 8 mA/cm2 for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (3×10 ml). The organic phase is concentrated on a rotary evaporator. Purify the desired product by column chromatography on a silica gel (petroleum ether: ethyl acetate) system and separate the desired product by column chromatography to obtain tert-butyl (1-(3-oxo-3,4-dihydroquinoxaline-2- Yl)ethyl)carbamate. Yield: 90%.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In dimethyl sulfoxide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
3.2.2. Synthesis of Quinoxalin-2(1H)-ones
General procedure: Quinoxalin-2(1H)-one (5 mmol), DMF (15 mL) was added to a 100 mL round-bottomedflask with a stir bar, then potassium carbonate (828 mg, 6 mmol) was added, followedby the dropwise addition of R2-X (8 mmol, X = Cl, Br or I2). The reaction mixture wasthen stirred for 1~12 h at room temperature, poured into brine and extracted with EtOAc.The combined extracts were dried over Na2SO4, filtered, and evaporated. The residuewas purified by column chromatography (petroleum ether/EtOAc) to afford the desiredquinoxalin-2(1H)-ones. Quinoxalin-2(1H)-ones are known compounds.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;
2.2 The preparation of quinoxalin-2(1H)-ones[1]
General procedure: To a suspension of o-arylenediamine (1 equiv.) in ethanol was added ethyl glyoxalate (1.1equiv.). The mixture was stirred at reflux for 1 h, then at room temperature overnight. Theprecipitated solid was filtered and washed with ethanol, then dried to give quinoxalinone. To asuspension of quinoxalinone (1 equiv.) in DMF was added potassium carbonate (1.2 equiv.) andthe corresponding halogenoalcane (1.6 equiv.). The mixture was stirred at room temperatureovernight. Ethyl acetate and water were added. The aqueous layer was extracted twice withEtOAc. The combined organic layers were washed with a saturated solution of NaCl, dried overMgSO4, filtered, and evaporated under reduced pressure. The residue is purified by flashchromatography over silica gel to afford the desired product N-alkyl quinoxalinone (Scheme S1).
With dipotassium peroxodisulfate; In dimethyl sulfoxide; at 90℃; for 12h;
General procedure: To a 10 mL Schlenk tube, coumarin 1a (0.3 mmol, 1 equiv),difluoromethane-sulfinate (0.6 mmol, 2 equiv), K2S2O8 (3 equiv.)were dissolved in DMSO (2.0 mL). Then the mixture was stirred at90 C for 12 h. To the residue was added water (10 mL) andextracted with ethyl acetate (5 mL 3). The combined organicfractions were dried over Na2SO4, and concentrated under vacuumto yield the crude product, which was purified by column chromatographyto give the target product. The same procedure was applied for to produce other compounds, after purification by silicagel column chromatography (EA: PE 1/10 to 1/2).
ethyl 2-((3-oxo-3,4-dihydroquinoxalin-2-yl)thio)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.2%
With acetic acid In dimethyl sulfoxide at 20℃; for 10h; Electrolysis;
14 Example 14 2-((3-oxo-3,4-dihydroquinoxalin-2-yl)thio)ethyl acetate (III-n)
In a 50 mL open round bottom flask equipped with magnetic stirring was added compound (I) quinoxalinone (73.1 mg, 0.5 mmol), ethyl 2-mercaptoacetate (480.1 mg, 4 mmol), acetic acid (48 mg, 0.8 mmol) DMSO (5mL) was added to the mixture, and the reaction was stirred at 20°C for 10 hours. TLC tracked until the end of the reaction (using a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1 as the developing solvent), and the reaction mixture was saturated with Wash with salt water. The mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using n-hexane/ethyl acetate to obtain 112.5 mg of the product with a yield of 85.2% and an HPLC purity of 98.5%.
82%
With tetrabutylammonium tetrafluoroborate; acetic acid In N,N-dimethyl-formamide at 20℃; for 8h; Electrochemical reaction;
3,4-diallyl-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With tin In tetrahydrofuran at 75℃; for 18h;
4.1. General experimental procedure for the synthesis of compounds 3
General procedure: A mixture of quinoxalin-2(1H)-ones 1 (0.2 mmol, 1 equiv), tin powder (0.3 mmol, 1.5 equiv) and allyl bromides 2 (0.7 mmol, 3.5equiv) in THF (3 mL) was stirred at 75 C in the metal bath for 18 h.The mixture was cooled to room temperature and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (3 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using ethyl acetate/petroleum ether (1/31/2) as the eluent furnished the pure products 3.4.1.1. 3,4-Diallyl-3,4-dihydroquinoxalin-2(1H)-one (3a)Yellow oil (95%, 43.3 mg); Rf 0.6 (EA/PE 1/2); 1H NMR(600 MHz, CDCl3) d 9.61 (s, 1H), 6.96 (t, J 8.4 Hz, 1H), 6.81 (d,J 7.8 Hz, 1H), 6.76 (t, J 7.2 Hz, 1H), 6.70 (d, J 8.4 Hz, 1H),5.89e5.82 (m, 1H), 5.79e5.72 (m, 1H), 5.31 (dd, J 16.8, 1.2 Hz, 1H),5.23 (dd, J 10.2, 1.2 Hz, 1H), 5.03 (dd, J 16.8, 1.2 Hz, 1H), 4.99 (dd,J 10.2, 1.2 Hz, 1H), 4.10e4.05 (m, 2H), 3.78 (dd, J 15.6, 6.0 Hz,1H), 2.44e2.39 (m, 1H), 2.37e2.32 (m, 1H); 13C NMR (100 MHz,CDCl3) d 168.5, 134.1, 133.9, 133.5, 126.4, 124.3, 119.1, 118.6, 118.4,115.8, 113.4, 62.0, 52.3, 34.6; HRMS (ESI): calcd for C14H16N2ONa[MNa] 251.1155; found 251.1166.
4.2. General experimental procedure for the synthesis ofcompounds 4
General procedure: A mixture of quinoxalin-2(1H)-ones 1 (0.2 mmol, 1 equiv), tin powder (0.7 mmol, 3.5 equiv) and allyl bromides 2 (0.6 mmol, 3.0 equiv) in THF (3 mL) was stirred at 75 C in the metal bath for 18 h.The mixture was cooled to room temperature and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (3 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using ethyl acetate/petroleum ether (1/31/1) as the eluent furnished the pure products 4.4.2.1. 3-Allyl-3,4-dihydroquinoxalin-2(1H)-one (4a)Yellow oil (89%, 33.5 mg); Rf 0.6 (EA/PE 1/2); 1H NMR(400 MHz, CDCl3): d 9.26 (br, 1H), 6.89 (t, J 7.2 Hz, 1H), 6.80e6.73(m, 2H), 6.66 (d, J 7.6 Hz, 1H), 5.86e5.76 (m, 1H), 5.23 (d,J 10.0 Hz, 1H), 5.17 (d, J 17.2 Hz, 1H), 4.09 (br, 1H), 3.90 (dd,J 10.0, 3.2 Hz, 1H), 2.73 (d, J 14.4 Hz, 1H), 2.45e2.37 (m, 1H); 13CNMR (150 MHz, CDCl3) d 168.8, 133.4, 132.8, 125.4, 123.9, 119.6,119.5, 115.5, 114.3, 55.1, 36.0; HRMS (ESI): calcd for C11H12N2ONa[MNa] 211.0842; found 211.0846.
diethyl 2,2’-((3-oxo-3,4-dihydroquinoxaline-2(1H)-diyl)bis(methylene))diacrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With tin In tetrahydrofuran at 75℃; for 18h;
4.1. General experimental procedure for the synthesis of compounds 3
General procedure: A mixture of quinoxalin-2(1H)-ones 1 (0.2 mmol, 1 equiv), tin powder (0.3 mmol, 1.5 equiv) and allyl bromides 2 (0.7 mmol, 3.5equiv) in THF (3 mL) was stirred at 75 C in the metal bath for 18 h.The mixture was cooled to room temperature and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (3 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using ethyl acetate/petroleum ether (1/31/2) as the eluent furnished the pure products.
3,4-bis(2-(4-bromophenyl)allyl)-3,4-dihydroquinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With tin In tetrahydrofuran at 75℃; for 18h;
4.1. General experimental procedure for the synthesis of compounds 3
General procedure: A mixture of quinoxalin-2(1H)-ones 1 (0.2 mmol, 1 equiv), tin powder (0.3 mmol, 1.5 equiv) and allyl bromides 2 (0.7 mmol, 3.5equiv) in THF (3 mL) was stirred at 75 C in the metal bath for 18 h.The mixture was cooled to room temperature and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (3 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using ethyl acetate/petroleum ether (1/31/2) as the eluent furnished the pure products.
3-(4,4,4-trifluoro-1-phenylbutan-2-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With dipotassium peroxodisulfate In water; acetonitrile at 80℃; for 24h; Sealed tube;
63%
With dipotassium peroxodisulfate In water; acetonitrile at 80℃; for 24h;
20 Example 20
At room temperature, add quinoxalinone 1t (0.2mmol), allylbenzene (0.4mmol), sodium trifluoromethylsulfinate (0.4mmol), potassium peroxodisulfate (0.6mmol) in a 15mL reaction tube Acetonitrile: 2.5mL of water (4:1), mixed evenly, then stirred at 80°C in the air for 24h. After detecting the completion of the reaction by TLC, the reaction solution was concentrated under vacuum (0.08Mpa) under reduced pressure to no solvent to obtain a crude product, which was then washed with a mixed eluent of petroleum ether and ethyl acetate in a volume ratio of 5:1, silica gel Column flash column chromatography to obtain 4t of this example as a white solid 41.8mg, yield 63%.
61%
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In 1,4-dioxane; water at 20℃; for 12h; Irradiation;
27
Add the photocatalyst 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.002 mmol), quinoxalinone 1i (0.2 mmol), and allylbenzene 2a ( 0.4 mmol), sodium trifluoromethanesulfinate 3a (0.4 mmol), 1,4-dioxane/water (volume ratio 6:1) 4 mL, mix well, and then under the 3W blue LED light , React at room temperature in the air for 12 hours. After the reaction was detected by TLC until the reaction was completed, ethyl acetate was added to extract 3 times, and the extract was concentrated under vacuum (0.08 Mpa) until there was no solvent to obtain the crude product. Then, the volume ratio of petroleum ether and ethyl acetate was 5:1 The mixed eluent was washed with silica gel column flash column chromatography to obtain 4i of this example, which was 40.5 mg of yellow solid, and the yield was 61%.
61%
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In 1,4-dioxane; water at 20℃; for 12h; Irradiation;
3. General procedure for visible-light-induced three-component reaction of quinoxalin-2(1H)-ones, alkenes and CF3SO2Na
General procedure: To a solution of quinoxalin-2(H)-one 1 (0.1 mmol), CF3SO2Na 3 (0.2 mmol), 4CziPN (0.001 mmol, 1 mol %), 1,4-dioxane/H 2 O (6/1, 2.5 mL) was added alkene 2 (0.2 mmol). The reaction mixture was open to the air and stirred under the irradiation of 3 W blue LEDs at room temperature for 12 h. After completion of the reaction, the solution was concentrated in vacuum. The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to give the desired product 4.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;
3.1.2. Preparation of alkylated quinoxalinones.
General procedure: Haloalkanes (1.6 equiv) were added to a suspension of quinoxalinone (1.0 equiv) and K2CO3 (1.2 equiv) in DMF. The mixture was stirred at room temperature for 8 h, and the reaction progress was monitored by TLC. The reaction mixture was washed with saturated ammonium chloride, ethyl acetate and water, respectively. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. Filtration and rotary evaporation under reduced pressure to obtain crude product. Purified by column chromatography to obtain alkylated quinoxalinone.
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
3.2.2. Synthesis of Quinoxalin-2(1H)-ones
General procedure: Quinoxalin-2(1H)-one (5 mmol), DMF (15 mL) was added to a 100 mL round-bottomedflask with a stir bar, then potassium carbonate (828 mg, 6 mmol) was added, followedby the dropwise addition of R2-X (8 mmol, X = Cl, Br or I2). The reaction mixture wasthen stirred for 1~12 h at room temperature, poured into brine and extracted with EtOAc.The combined extracts were dried over Na2SO4, filtered, and evaporated. The residuewas purified by column chromatography (petroleum ether/EtOAc) to afford the desiredquinoxalin-2(1H)-ones. Quinoxalin-2(1H)-ones are known compounds.
With potassium carbonate In dimethyl sulfoxide at 20℃;
3-(isoquinolin-1-yl)quinoxalin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With 1,1,1,3',3',3'-hexafluoro-propanol; tetrabutylammonium tetrafluoroborate In dichloromethane at 20℃; for 4h; Inert atmosphere; Electrochemical reaction;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
