* 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.
Stage #1: With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 20 h; Inert atmosphere; Irradiation Stage #2: With hydrogenchloride In water; dimethyl sulfoxide for 20 h;
At room temperature, will be 52 mg (0.4 mmol) quinoxaline, 414 mg (2.8 mmol) 2, 2 - ethoxy acetic acid, 182 mg (0.8 mmol) of the ammonium persulfate and 260 mg (0.8 mmol) Cs2CO3Dissolved in 6 ml in dimethyl sulfoxide, mix, nitrogen 30 min after the blue LEDs arranged under the lamp illumination reaction 20 h, adding 7.2 concentration is 3 M hydrochloric acid catalytic hydrolysis 20 h, using sodium bicarbonate adjusting pH to neutral, extraction, the combined organic phase, by the rotary concentrate by the Rotavapor after turns on lathe does, then to the volume ratio of 15:1 petroleum ether: ethyl acetate mixed solution of eluant, performing silica gel column chromatography purification and separation, to obtain the corresponding formylation heterocyclic derivatives, its reaction is Product purity is 99percent, and the yield is 63percent.
53%
With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 24 h; Inert atmosphere; Irradiation; Green chemistry
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
Reference：
[1] Patent: CN108640807, 2018, A, . Location in patent: Paragraph 0044-0047
[2] Synlett, 2018, vol. 29, # 14, p. 1881 - 1886
6
[ 110-88-3 ]
[ 91-19-0 ]
[ 1593-08-4 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 4, p. 536 - 537
7
[ 91-19-0 ]
[ 17056-99-4 ]
[ 112259-29-7 ]
[ 1196-57-2 ]
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
8
[ 91-19-0 ]
[ 17056-99-4 ]
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[1] Russian Journal of General Chemistry, 2004, vol. 74, # 3, p. 428 - 437
Reference：
[1] Journal of the Chemical Society, 1957, p. 2521,2527
21
[ 91-19-0 ]
[ 89-01-0 ]
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[1] Helvetica Chimica Acta, 1994, vol. 77, # 6, p. 1549 - 1556
[2] Chemische Berichte, 1907, vol. 40, p. 4852
[3] Organic Syntheses, 1950, vol. 30, p. 88
[4] Journal of the American Chemical Society, 1941, vol. 63, p. 3153
[5] Journal of the American Chemical Society, 1953, vol. 75, p. 679
[6] Patent: US2710865, 1953, ,
[7] Patent: US2723974, 1953, ,
[8] Recueil des Travaux Chimiques des Pays-Bas, 1959, vol. 78, p. 109,110, 112
[9] Yakugaku Zasshi, 1957, vol. 77, p. 891,893, 894[10] Chem.Abstr., 1958, p. 1181
[11] Dalton Transactions, 2007, # 6, p. 633 - 645
[12] Patent: US2723974, 1953, ,
22
[ 91-19-0 ]
[ 76982-23-5 ]
[ 148231-12-3 ]
Yield
Reaction Conditions
Operation in experiment
70%
With bromine In tetrachloromethane for 45 h; Reflux; Inert atmosphere
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With bromine In acetonitrile for 2.5 h; Reflux; Inert atmosphere
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0℃; for 16h;Inert atmosphere;
Quinoxaline (295 mg, 1.71 mmol) was added in a two-necked flask (10 mL) equipped with a stirring bar. Under nitrogen atmosphere, dry and degas CH2Cl2 (3 mL) was added. At 0C, a solution of m-chloroperbenzoic acid (150 mg, 1.15 mmol in 3 mL of CH2Cl2) was added dropwise at the reaction mixture. After 16 hours, NaHCO3 solution was added and extracted with CH2Cl2 (3 x 10 mL). The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/methanol 8:1) to obtain white crystals (199 mg, 80%), m.p.: 122 - 123C, 1H NMR (300 MHz, CDCl3) delta = 8.68 (d, J = 3.5 Hz, 1H), 8.59 (dd, J = 8.5, 1.3 Hz, 1H), 8.36 (d, J = 3.5 Hz, 1H), 8.14 (dd, J = 8.3, 1.0 Hz, 1H), 7.84 (ddd, J = 8.4, 7.0, 1.6 Hz, 1H), 7.76 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) delta = 145.4, 145.3, 137.8, 132.2, 130.6, 129.7, 129.6, 119.1.
With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 40℃; for 0.25 - 6h;
Formation of Quinoline-N-oxides: The appropriate quinoline (10 mmol) may be dissolved in CH2Cl2 and treated with solid NaHCO3 (50 mmol) followed by m-CPBA (10.0 mmol). The reaction may be stirred at between 0-40C for between 15 minutes to 6 hours. In one variation, the reaction is stirred at about 23 C for 4 hours. The mixture may then be transferred to a separatory funnel and washed with water, saturated aqueous NaHCO3 and brine, and then dried (MgS04) and concentrated in vacuo. The resulting crude solid is often pure enough to carry forward to the next reaction.
With ammonia; lithium; tert-butyl alcohol; In diethyl ether; at 0 - 20℃;Inert atmosphere;
Lithium (2.64g, 380.0mmol) was added to a magnetically stirred solution of quinoxaline (1) (2.6g, 20.0mmol) in dry ether at 0C under Ar atm over 15min t-Butyl alcohol (20.16g, 272.0mmol) was added slowly to the reaction mixture and the mixture was stirred at 0C under ammonia atm for 7h and overnight at room temperature. A solution of ammonium chloride (30mL) was added to the mixture and the mixture was extracted with ether (3×50mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was purified via column chromatography on silica gel (100g) by eluting with 10% EtOAc/n-hexane and tetrahydroquinoxaline 15 was obtained as a brown solid (2.65g, 99%).
97%
General procedure: A carousel reaction tube containing a magnetic stirring bar and [Cp*IrCl2]2 (2 mg, 2.5 mumol), ligand 3d (1.6 mg, 6 mumol), quinoxaline substrate (0.5 mmol), and HCOONa (340 mg, 5 mmol) in an aqueous solution of HOAc/NaOAc (5 M, 5 mL, pH=5.5) was sealed without degassing. The reaction mixture was stirred at 80 C for the time indicated in Table 3, then cooled to room temperature and basified with an aqueous solution of KOH. The resulting mixture was extracted with diethyl ether (3×5 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the product was purified by flash column chromatography.
96%
With sodium tetrahydroborate; In water; at 60℃; under 760.051 Torr; for 4h;Inert atmosphere;Catalytic behavior;
Precatalyst (50 mg), NaBH4 (or NaBD4) (3e12 mmol), 1 mmol ofthe N-cyclic substrate and 5 ml deionized and degassed water (orD2O) were placed in a 25 ml three-necked flask equipped with areflux condenser and a pressure release valve to discharge thehydrogen gas self-generated during the reactions. The operationwas carried out under inert atmosphere. The reaction mixture wasvigorously stirred at different temperatures (25e60 C) for the timeselected. The complete conversion of substrate was determined bysubmitting small samples to spot thin layer chromatography (TLC).After completion, the slurry was centrifuged to separate the catalyst.The solid phase obtained was washed with deionized H2O andthen several times with ethyl acetate to remove all organic residue.The filtrate was collected, extracted with ethyl acetate and theextract dried over anhydrous MgSO4. After removal of the solvent invacuo, the corresponding product was obtained. In some cases, asilica-gel column chromatography was used to purify the product(isolated yield). The product analysis and identification was conductedby comparing the NMR spectral data with those of thepublished pure substances (all analyzed by 1H NMR and 13C NMRon Bruker Avance II 400 MHz spectrometer). The reaction selectivitieswere obtained from the NMR spectra by integration ofcharacteristic peaks for the product and reactant.
92%
General procedure: Under an argon atmosphere, pyridine 1 or N-heteroaromatic 3 (0.10 mmol) and HMPA (3.5 mg,0.02 mmol) were added in anhydrous DCM (0.7 mL) and stirred at room temperature for 10 min, andthen trichlorosilane (2.0 M, 0.3 mL) was added. The reaction was stirred at room temperature for 24h, quenched with H2O, and then the pH was adjusted to ~7-8 with saturated NaHCO3. The mixturewas extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, driedover anhydrous Na2SO4, concentrated under reduced pressure and purified with columnchromatography (silica gel, DCM/MeOH/TEA = 10/1/0.1) to afford a pure product.
91%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium hydroxide; zinc; In water; toluene; at 40℃;Inert atmosphere; Schlenk technique;
Under argon, add [Rh (COD) Cl] 2, Zn powder, KOH and 1.0 mL of toluene to a Schlenk tube equipped with a magnetic stir bar,A toluene solution (1.0 mL) of quinoxaline was added to the above mixture.After adding H2O, the mixture was stirred at 40 C.Monitor by TLC until quinoxaline is completely consumed. Where quinoxaline,The molar ratio of [Rh (COD) Cl] 2, Zn powder, KOH, and H2O was 1: 0.025: 3: 0.25: 30. The residue was purified by silica gel column chromatography,The desired product 1,2,3,4-tetrahydroquinoxaline was obtained. White solid, yield 91%,
90%
With C23H21MnN2O3P(1+)*Br(1-); potassium tert-butylate; hydrogen; In tetrahydrofuran; at 120℃; under 60006 Torr; for 16h;Autoclave;
General procedure: In a glove box filled with argon, potassium tert-butoxide (5.6 mg, 0.05 mmol), and a manganese catalyst (0.005 mmol) were sequentially added to a 4 mL glass bottle with a stirrer, the manganese catalysts being Formula I to Formula IV, respectively. The manganese catalysts of the structure shown are recorded as manganese catalysts [Mn] -1, [Mn] -2, [Mn] -3, [Mn] -4), tetrahydrofuran (0.5 mL) and quinoline (0.25 mmol), Cap the bottle cap, insert a needle with a vent hole (length 3cm, hole diameter 1mm) into the bottle cap, put the glass bottle into the autoclave, and then remove the autoclave from the glove box. Replace the argon gas in the autoclave with hydrogen (3 × 10bar), then fill with 80bar hydrogen, and react at 120 C for 16h. After the reaction, the ice-water bath is cooled, and the gas in the autoclave is carefully released. The resulting reaction product system is sampled for The target product was obtained by GC quantification and separation by column chromatography. According to the method of Example 2, the manganese catalyst [Mn] -4 was used for catalytic hydrogenation of other types of nitrogen-containing unsaturated heterocyclic compounds. The structural formula and yield of each target product are listed in Table 3.
80%
General procedure: In a 1.5 mL reaction vial, B(C6F5)3 (0.025 mmol, 5.0 mol %) was dissolved in chloroform (0.60 mL), towhich diethylsilane (1.75 mmol, 3.5 equiv) was added. After shaking briefly, quinolines (1a-p, 0.50 mmol, 1.0equiv) was subsequently added to the above catalyst solution under argon atmosphere. The reaction mixturewas stirred at 25-65 oC for 6-24 h for the reaction of 1a-h, and at 25-100 oC for 2-24 h for the reaction of 1i-p,then allowed to cool down to room temperature and concentrated under reduced pressure to give the crudeproduct. This reaction mixture was then treated with 0.25 N HCl ethereal solution (7 mL) and stirred at roomtemperature for 1 h to give the solid residue, which was subsequently washed with ether. The solid residue wasthen dissolved or suspended in MeOH (1.0 mL) and neutralized with Na2CO3·H2O (0.5 g) at 0 oC. After stirringfor 2 h, MeOH was removed under reduced pressure, and the neutralized reaction residue was dissolved inCH2Cl2 and washed with brine (5 mL) and water (5 mL). The crude product was then obtained from the organicphase of CH2Cl2 solution and finally purified by column chromatography on silica gel to give 2a-h(EtOAc/Hexane = 1/9) and 2i-p (EtOAc/Hexane = 3/7).
79%
With palladium diacetate; caesium carbonate; bis(pinacol)diborane; In water; at 20℃; for 10h;Inert atmosphere; Green chemistry;
A solution of 0.6 mmol of bis(pinacolato)diboron, 0.02 mmol of palladium acetate and 00.1 mmol of cesium carbonate were added to the reaction tube, after filling with nitrogen, 0.2 mmol of quinoxaline and 2 ml of water were injected into the reaction tube, the reaction was stirred at room temperature for 10 h, the reaction was followed by TLC and GC to determine the specific reaction time. After cooling to room temperature and mixing well with ethyl acetate, the mixed solution was diluted with ethyl acetate. After concentration, the organic phases were combined, using petroleum ether: ethyl acetate = 4: 1 eluent, the product was obtained by columnation, the yield was 79%.
68%
With tetrahydrofuran; sodium tetrahydroborate; trifluoroacetic acid; at 0 - 20℃; for 2.5h;
Quinoxaline (10g, 74.52mmol) was dissolved in a tetra-hydrofuran100 ml and then NaBH4 were stirred into a (10g, 26.4mmol).Then, lowering the reaction temperature to 0 C was added dropwise for 30 min slowly trifluoroacetic acid (10ml, 5.89mmol).When the addition was complete, the temperature raised slowly to room temperature and stirred for 2 hours. After confirming that the reaction was completed by TLC the input of distilled water and extracted with ethyl acetate.The organic layer is Na2SO4 dried, and evaporated under a reduced pressure and then purified by column chromatography to give the title compound (7g, 68% yield).
PtO2; In ethanol;
EXAMPLE 3 TGQB (II, n=0, R1 =C6 H5, R2 to R8 =H) Quinoxaline was hydrogenated at 60 psi, 50 C. with PtO2 catalyst in ethanol, to produce 1,2,3,4-tetrahydroquinoxaline (THQ).
PtO2; In ethanol;
EXAMPLE 5 XC (VI, n=0, R1 to R8 =H, X=Cl, Y=H) Quinoxaline was hydrogenated at 60 psi, 50 C. with PtO2 catalyst in ethanol, to produce 1,2,3,4-tetrahydroquinoxaline (THQ).
PtO2; In ethanol;
EXAMPLE 6 XCD (VI, n=0, R1 to R8 =H, X=Y=Cl) Quinoxaline was hydrogenated at 60 psi, 50 C. with PtO2 catalyst in ethanol, to produce 1,2,3,4-tetrahydroquinoxaline (THQ).
With lithium borohydride; methyl iodide; In tetrahydrofuran; methanol; hexane; at 20℃;Inert atmosphere; Cooling with ice;
Under a nitrogen atmosphere, to a solution of lithium borohydride (741 mg) in tetrahydrofuran (50 ml), methyl iodide (1.93 ml) was added dropwise under ice cooling and stirred at room temperature for 10 minutes. To this mixture, a solution of quinoxaline (1.32 g) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes and then stirred at room temperature for 5 minutes. To the reaction mixture, methanol (10 ml) was added and stirred for 5 minutes, followed by addition of additional methanol (40 ml) and stirring at room temperature for 30 minutes. After the reaction mixture was concentrated, the resulting residue was dissolved again in methanol and evaporated under reduced pressure to remove the solvent. The resulting residue was diluted with 4M aqueous sodium hydroxide (100 ml) and extracted four times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was converted into a powder form by addition of n-hexane, and then collected by filtration to give the titled compound, i.e., 1,2,3,4-tetrahydroquinoxaline (1.17 g) as a light-brown crystal. 1H NMR (300 MHz, CHLOROFORM-D) delta 3.42 (s, 4 H), 6.45-6.53 (m, 2 H), 6.55-6.62 (m, 2 H).
With ethanol; Dimethylphenylsilane; Au-TiO2; In neat (no solvent); at 70℃; for 3h;
General procedure: To a dry vial containing 8-methoxyquinoline, 1 (0.048 g, 0.3 mmol), Me2PhSiH (185 muL, 1.2mmol) and ethanol (70 muL, 1.2 mmol), Au/TiO2 (60 mg, 1.0 mol%) was added. The Au contentin catalyst was ~1 wt%. The mixture was heated to 70 oC and the progress of reaction wasmonitored by TLC and GC. After 15 min (100% conversion), ethanol (1 mL) was added and theresulting slurry was filtered under reduced pressure through a short pad of silica gel with the aidof ethanol (2-3 mL) to withhold the supported catalyst. The filtrate was evaporated undervacuum and the residue was chromatographed (n-hexane/ethyl acetate, 10:1) to afford 8-methoxy-1,2,3,4-tetrahydroquinoline (1a) (41 mg, 84% yield).
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃; for 48h;Inert atmosphere;
To a magnetically stirred solution of quinoxaline (1) (2.60g, 20.0mmol) in chloroform (150mL) was added m-CPBA (13.45g, 77%, 60.0mmol) portionwise at 0C. The reaction mixture was stirred for 48hat room temperature. The mixture was diluted with a solution of sodium hydroxide (10%, 20mL) and extracted with methylene chloride (3×50mL). The combined organic layers were washed with saturated brine (2×30mL), water, dried over Na2SO4, and filtered. The solvent was removed in vacuo. Quinoxaline-1,4-dioxide (26),20f,28 (3.20g, 99%) was obtained as a pure product (Yellow solid, mp 241-242C, lit.20f mp 241-243C). 1H NMR (400MHz, CDCl3) delta 8.60 (AA? part of AA?BB? system, 2H), 8.26 (s, 2H), 7.88 (BB? part of AA?BB? system, 2H). 13C NMR (100MHz, CDCl3) delta 138.5, 132.2, 130.5, 120.5. IR (KBr, cm-1) 3048w, 1642b, 1524m, 1373s, 1287m, 1233m, 1086w, 815m, 778s.
With cobalt(II) 5,10,15,20-tetraphenylporphyrin; oxygen; In N,N-dimethyl-formamide; for 15h;
General procedure: N-Heterocyclic amine (0.50 mmol), CoTPP (10 mg) and DMF (2 mL) were mixed in a carousel reaction tube. The reaction mixture was stirred at 120 C under oxygen atmosphere, the reaction was sampled periodically and monitored by TLC (petroleum ether/ethyl acetate (10:1 v/v)). After the reaction, the reaction mixture was then cooled to room temperature and purified using flash chromatography to give the corresponding product. All the dehydrogenation products are known, and their NMR spectra were consistent with the literature. NMR spectra were recorded at 25 C on an Bruker AVANCE III 400-NMR spectrometer at 400 MHz for 1H and 100 MHz for 13C, using CDCl3 as solvent with TMS as the internal standard. Thin-layer chromatography was performed on silica gel 60 F254 (Sinopharm) thin-layer chromatography plates using petroleum ether/ethyl acetate (10:1 v/v) as the mobile phase.
46%
With oxygen; iron(II) chloride; In para-xylene; dimethyl sulfoxide; at 110℃; for 26h;Schlenk technique;
General procedure: To a Schlenk tube equipped with a magnetic stir bar were added8-methyl-1,2,3,4-tetrohydroquinoline (0.50 mmol), FeCl2 (1.9mg, 1.5·10-2 mmol), DMSO (31.2 mg, 0.4 mmol), and p-xylene (1mL). The reaction mixture was stirred at 110 C under anoxygen atmosphere using a balloon and monitored by TLC. Afterthe reaction, the mixture was cooled to room temperature andpurified using flash chromatography (hexane-EtOAc, 10:1) togive the corresponding product 8-methylquinoline in 70% yield.8-MethylquinolineColorless oil. 1H NMR (400 MHz, CDCl3): delta = 8.93 (m, 1 H), 8.10(m, 1 H), 7.64 (d, J = 4.0 Hz, 1 H), 7.54 (m, 1 H), 7.43-7.35 (m, 2H) 2.82 (s, 3 H). 13C NMR (100 MHz, CDCl3): delta = 149.2, 147.3,137.1, 136.3, 129.6, 128.3, 126.3, 125.9, 120.8, 18.2. HRMS: m/zcalcd for [C10H9N + H+]: 144.0813; found: 144.0813.
With oxygen; In 1,3,5-trimethyl-benzene; at 80℃; under 760.051 Torr; for 9h;
General procedure: 200mg Ni2Mn-LDH type hydrotalcite catalyst, 0.5mmol tetrahydroquinoline and 2mL 1,3,5-trimethylbenzene solvent Was added to the reactor, the reaction was carried out at atmospheric pressure and at a temperature of 80 C. The reaction time was 2.5 h under an atmosphere of oxygen, and the contents of the quinoline, the starting material, in the liquid were analyzed by gas chromatography internal standard method (nitrobenzene as internal standard) Content,The conversion and selectivity of the reaction were calculated. The conversion of tetrahydroquinoline was> 99% and the selectivity of the reaction was 78.3%
With 10 wtpercent sulfated polyborate; In neat (no solvent); at 100℃; for 0.05h;Green chemistry;
General procedure: To a mixture of substituted o-phenylenediamines derivative(2.0 mmol) and 1,2-diketone / alpha-hydroxy ketone (2.0 mmol),was added sulfated polyborate (10 wt%). The reaction mixture was stirred at 100 C in an oil bath. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the mixture was cooled to room temperature and quenched by water. The resultant product was filtered/extracted with EtOAc to get the product. Crude products were either recrystallized from ethanol or purified by column chromatography using silica as the stationary phase and EtOAc: pet. ether as mobile phase. The products obtained were known compounds and were identified by melting point and 1H and 13C NMR spectroscopy. The spectral data were compared with the literature values.
82%
With potassium fluoride on basic alumina; at 20℃; for 1h;
General procedure: A mixture of 1,2-diamine (1 mmol) and alpha-dicarbonyl compound (1 mmol) was intimately mixed with pre-activated KF-alumina (1:4) (0.5 g) (Basic; Grade: Brockmann 1, and activated by heating under vacuum at 150 C until bubbling ceases and then cooled to room temperature under vacuum) and stirred solid mixture with a magnetic spin bar at room temperature for hours as indicated in refPreviewPlaceHolderTable 4. After the reaction was complete, the solid mixture washed with diethyl ether (3 × 10 mL) and the solid was filtered off. The filtrate was concentrated and passed through a short column of silica gel to afford the quinoxalines. The desired product was pure on TLC and characterized by spectral (1H and 13C NMR) data and compared to those reported.
30%
With polyvinylimidazole-based Bronsted acidic ionic liquid grafted silica; In ethanol; at 20℃; for 1h;
General procedure: To a mixture of 1,2-diketone (1 mmol) and 1,2-diamine (1 mmol) in 4 mL of ethanol was added catalyst III (0.006 g, 0.5 mol%) or catalyst IV (0.017 g, 1 mol%). The reaction mixture was stirred at room temperature for the appropriate time. The progress of the reaction was followed by TLC. Upon completion, the product and the catalyst were separated easily from each other by simple ltration. The ltrate was concentrated under reduced pressure and the crude product was puried by silica gel column chromatography with petroleum ether (bp 60 C) and ethyl acetate (in some cases recrystallization was used). The obtained quinoxalines were identied by their 1H NMR and 13C NMR spectra and comparison of their melting points with those of the authentic samples.
With graphene oxide; In neat (no solvent); at 60℃; for 2h;Sealed tube; Green chemistry;
General procedure: A mixture of 2-nitro aniline (1 mmol), hydrazine monohydrate (2.2 mmol) and GO (20 mg) was taken in a screw-capped glass tube and stirred the reaction mixture for 3-4 h at 100 C temperature. After the complete reduction (as monitored by tlc and by the colour change of the reaction mixture from yellow to total black), 1,2-dicarbonyl compound (or alpha-hydroxy ketone) (1 mmol) was added to the reaction mixture and stirred for few hours at 60 C (80 C for alpha-hydroxy ketone), as mentioned in the Table 2. After completion of the reaction (checked by tlc), the reaction mixture was cooled to room temperature. Water and ethyl acetate were added to the reaction mixture and centrifuge (5000 rpm) the whole reaction mixture to separate the GO (which is now converted to rGO). This process was repeated for three times. The combined organic-aqueous part was then taken in a separating funnel and the organic layer was separated from aqueous layer, and finally dried over anhydrous Na2SO4. Evaporation of the solvent afforded the desired quinoxaline (satisfactorily pure), which was further purified by passing through a short column of silica gel and using the light petroleum ether:ethyl acetate (97:3) as the eluent. All products were characterized by 1H, 13C NMR data and compared with the reported melting points for known solid compounds.
With sodium metabisulfite; sodium hydrogen sulfate; In water; at 70℃;
General procedure: A solution of 40% aqueous glyoxal (10 mmol, 0.58 g) and sodium hydrogen sulfite (20 mmol, 2.08 g mixture of sodium bisulfate and sodium metabisulfite) in water (16 mL) was heated to 70 oC and then pured into a suspense on of 1,2-diaminobenzene. The reaction mixture was then allowed to reach room temperature at which point it was basified to PH 7.5 with solid sodium carbonate. The organic materials were extracted with dichloromethane (3 × 20 mL) and the combined organic extracts dried and evaporated to dryness. The residue was flash chromatographed on silica gel.
With ammonium peroxydisulfate; silver nitrate; trifluoroacetic acid; In dichloromethane; water; at 40℃;
Quinoxaline (0.65g, 5 mmol), pyruvic acid (1.32g, 15 mmol), AgNO3 (0.068g, 0.4 mmol), (NH4) 2S2O8 (1.71g, 7.5 mmol), CF3CO2H (1.7g, 15 mmol) were dissolved in a 1 : 1 mixture of DCM/H2O (50ml). The reaction mixture was stirred at 40 C. After cooling to room temperature the mixture was extracted with DCM, washed with brine and dried over Mg S04, then evaporated to give 1-quinoxalin-2-yl-ethanone (0. 89g, 100%).
67%
With ferrous(II) sulfate heptahydrate; ammonium peroxydisulfate; formic acid; dimethyl sulfoxide; In dichloromethane; water; at 40℃;
General procedure: N-heteroarene (1 mmoL, 80 mg), alpha-keto acid (3 mmol), Formic acid (1 mmol, 38 muL), ammonium persulfate (3 mmoL, 685 mg), ferrous sulfate heptahydrate (0.08 mmoL, 22 mg) and 20 mL of mixed solvent (DCM: H2O = 3: 1) , 0.1 mL DMSO was added into a 25 mL round-bottomed flask. The mixture was stirred at 40 oC until TLC analysis indicating that the reaction was complete (witnessed by the disappearance of the N-heteroarene). After separation of organic phase, the residue was neutralized by 0.1 M sodium hydroxide solution, then extracted with DCM (3×20 mL), combined the organic phases, dried over Na2SO4, and concentrated in vacuo. The residue was N-heteroarene (1 mmoL, 80 mg), alpha-keto acid (3 mmol), Formic acid (1 mmol, 38 muL), ammonium persulfate (3 mmoL, 685 mg), ferrous sulfate heptahydrate (0.08 mmoL, 22 mg) and 20 mL of mixed solvent (DCM: H2O = 3: 1) , 0.1 mL DMSO was added into a 25 mL round-bottomed flask. The mixture was stirred at 40 oC until TLC analysis indicating that the reaction was complete (witnessed by the disappearance of the N-heteroarene). After separation of organic phase, the residue was neutralized by 0.1 M sodium hydroxide solution, then extracted with DCM (3×20 mL), combined the organic phases, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether/EtOAc (v : v = 20 : 1) as eluent to afford the desired pure product.
42.9%
With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In dichloromethane; water; at 40℃; for 2.5h;
Step 11 -(quinoxalin-2-yl)ethanone (JS110)Quinoxaline (1 .1864 g, 9.1 1 mmol), Pyruvic acid (1.90 ml, 27.3 mmol), AgN03 (0.124 g, 0.73 mmol), N2H8S208 (3.12 g, 13.67 mmol) and H2S04 (0.49 ml, 9.1 1 mmol) were stirred in 1 :1 CH2CI2/H20 (150 ml) at 40 C for 2 ½ h. The solution was then basified via the addition of NaOH and the organics extracted (3x) and washed brine, dried (MgS04), filtered and solvent removed. Flash chromatography (Pet Ether; 3:1 Pet Ether/EtOAc) afforded the title compound as a yellow solid (617.5 mg, 3.91 mmol, 42.9%). Mpt: 70-74 C [Lit.( J. Org. Chem., 1991 , 56, 2866-2869) 76-97 C]; Rf = 0.24 (3:1 Pet Ether/EtOAc); IR (vmax/cm"1, thin film): 1689 (CO stretch), 1357; 1H NMR (500 MHz, CDCI3): deltaEta = 2.84 (s, 3H, 12-H), 7.82-7.90 (m, 2H, 7,8-H), 8.14-8.21 (m, 2H, 6,9-H), 9.47 (s, 1 H, 3-H); 13C NMR (125 MHz, CDCI3): 5C = 25.6 (C-12), 129.5 (C-6), 130.5 (C-8), 130.8 (C-9), 132.3 (C-7), 141 .1 (C-10), 143.1 (C-3), 143.9 (C-5), 146.6 (C- 2), 199.8 (C-11 ); LRMS m/z (El+): 172 [M]+, 130 [M-Ac]+, 86; HRMS m/z (El+): Found 172.06372; Ci0H8N2O requires 172.0631 1 ; Anal. Calcd. for Ci0H8N2O: C, 69.76; H, 4.68; N, 16.27. Found C, 69.28; H, 4.56; N, 16.00%.
a) 1-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-quinoxalin-1-ium bromide A mixture of quinoxaline (1.0 g, 7.68 mmol) and 2-bromo-1-(4-methoxy-carbonyl-phenyl) ethanone (2.0 g, 8.73 mmol) was heated at 60 C. for 10 minutes and 5 mL of ethyl acetate was added, continued to stirr for another 10 minutes. The off white precipitate was filtered on a Buchner funnel. The solid was dried in vacuo to yield 228 mg (8%) of the title compound. 1H NMR (DMSO-d6): 9.86 (d, J=2.4 Hz, 1H), 9.62 (d, J=2.4 Hz, 1H), 8.60 (m, 2H), 8.32 (m 2H), 8.14 (d, J=8.7 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.10 (s, 2H) 3.92 (s, 3H).
A. 1,2,3,4-Tetrahydro-quinoxaline Pt(IV)O2 (Adams' catalyst, 200 mg) was added to a solution of quinoxaline (2.75 mg, 21 mmol) in absolute EtOH (100 mL) and the mixture was hydrogenated (1 atm) at rt for 6 hrs. The mixture was fitered through Celite and the filtrate was concentrated to give 2.74 g of Compound A as an off-white solid (97%). MS (M+H) 135.
Example 3 Preparation and Characterization of the Co-Crystal <strong>[287714-41-4]Rosuvastatin</strong> Quinoxaline (1:2) of Formula (V) [0095] Preparation [0096] To an assay tube equipped with magnetic stirrer containing 30 mg of <strong>[287714-41-4]Rosuvastatin</strong> (as acid form) (0.06 mmol) and 250 mg of quinoxaline (1.9 mmol, 30 eq) were added 0.3 mL of toluene and the crude was sonicated for 5 min before stirring for 20.5 h at room temperature. The resulting brown suspension was centrifuged at room temperature (14000 rpm, 10 min), the supernatant liquid was discarded and the resulting solid was dried under vacuum to provide 25.3 mg of the co-crystal <strong>[287714-41-4]Rosuvastatin</strong> quinoxaline (1:2) as a brown solid for a molar yield of about 55%. 1H-NMR Characterization [0097] Proton nuclear magnetic resonance analyses were recorded in deuterated chloroform (CDCl3) in a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.6 mL of deuterated solvent. [0098] 1H NMR (CDCl3, 400 MHz): delta=8.90-8.86 (m, 4H); 8.18-8.09 (m, 4H); 7.86-7.76 (m, 4H); 7.68-7.59 (m, 2H); 7.13-7.04 (m, 2H); 6.63 (d, J=16.0 Hz, 1H); 5.47 (dd, J=5.5 Hz, J=16.0 Hz, 1H); 4.53-4.43 (m, 1H); 4.31-4.20 (m, 1H); 3.56 (s, 3H); 3.51 (s, 3H); 3.34 (q, J=6.6 Hz, 1H); 2.60-2.49 (m, 1H); 1.67-1.45 (m, 3H); 1.60-1.48 (m, 1H); 1.45-1.35 (m, 1H); 1.26 (d, J=6.6 Hz, 6H). (See FIG. 8-1H-NMR). X-Ray Powder Diffraction (XRPD) Characterization [0099] XRPD analysis was performed using a Philips X'Pert diffractometer with Cu Kalpha radiation in Bragg-Brentano geometry. The system is equipped with a mono-dimensional, real time multiple strip detector. The diffractogram was recorded from 3 to 40 (20) at a scan rate of 17.6 per minute. (See FIG. 9) [0100] List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated) are shown in Table 6
With sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; palladium diacetate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 1h;Inert atmosphere;
General procedure: Pd(OAc)2-PPh3, Pd2(dba)3-tbpf, Pd2(dba)3-DavePhos Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos. Anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 mol%) and PPh3 (17.7 mg, 1.132 mmol, 20 mol%) were added and the resulting mixture stirred at room temperature for 30 min. The halogenated heterocycle (0.66 mmol), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature or heated at 65 C under argon for the proper time. The residue was taken up in brine and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was purified by flash chromatography (mixtures of petroleum ether and ethyl acetate) to give pure hydrodehalogenated heterocycles
quinoxalin-2-yl-di-p-tolylphosphine oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With dipotassium peroxodisulfate; In acetonitrile; at 20℃; for 2h;Inert atmosphere; Sealed tube;
put <strong>[2409-61-2]bis(p-methylphenyl)phosphine oxide</strong> (69.07mg, 0.3mmol) and potassium persulfate (108.13mg, 0.4mmol) into the reaction vessel, seal the tube of the reaction vessel with a rubber stopper, and then vacuum , Fill N2 gas, After replacing the gas in the reaction vessel three times in this way, quinoxaline (25.83 mg, 0.2 mmol) and acetonitrile (4 ml) were sequentially added. Then at room temperature, stirring for 2h, take it out, vacuum distillation, column chromatography, and finally The target product 2-bis(p-methylphenyl)phosphinoquinoxaline (69.53mg, yield 97%) was obtained.
With bromine; In acetonitrile; at 82℃; for 3h;Inert atmosphere;
Bromine (960mg, 0.31mL, 6.0mmol) was added dropwise to a magnetically stirred refluxing solution of 5,6-dihydroquinoxaline (24) (132mg, 1.0mmol) in acetonitrile (20mL) at room temperature. The resulting reaction mixture was heated at reflux temperature for 3h. The resulting reaction mixture was allowed to warm to room temperature and the solvent was evaporated. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with methylene chloride (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was purified via column chromatography on silica gel (50g) by eluting with 15% EtOAc/n-hexane. The first fraction was 5,8-dibromoquinoxaline (12) (64mg, 22%) data as before. The second fraction was 5-bromoquinoxaline (9) (95mg, 44%) data as before. The third fraction was quinoxaline (1) (20mg, 15%) data as before.
With bromine; In tetrachloromethane; for 45h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With N-Bromosuccinimide; dibenzoyl peroxide; In acetic acid; for 20h;Reflux; Inert atmosphere;
A solution of quinoxaline (1) (390mg, 3.0mmol), NBS (390mg, 3.0mmol), and benzoyl peroxide (catalytic amount) in glacial acetic acid (10mL) was heated at reflux temperature for 20h. The reaction was monitored by TLC or 1H NMR spectroscopy. The resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. 6-Bromoquinoxaline (10) (315mg, 50%) was obtained as a sole product. The reaction was repeated using DMF as a solvent at the same reaction condition and monobromide 10 was obtained in 51% yield.
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; for 45h;Reflux; Inert atmosphere;
General procedure: A solution of quinoxaline (1) (390mg, 3.0mmol), NBS (390mg, 3.0mmol), and benzoyl peroxide (catalytic amount) in glacial acetic acid (10mL) was heated at reflux temperature for 20h. The reaction was monitored by TLC or 1H NMR spectroscopy. The resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. 6-Bromoquinoxaline (10) (315mg, 50%) was obtained as a sole product. The reaction was repeated using DMF as a solvent at the same reaction condition and monobromide 10 was obtained in 51% yield.
With bromine; barium carbonate; In acetonitrile; for 25h;Reflux; Inert atmosphere;
Bromine (3.84g, 24mmol) was added dropwise to a magnetically stirred refluxing mixture of quinoxaline (1) (390mg, 3.0mmol) and barium carbonate (1.20g, 6.1mmol) in acetonitrile (20mL). The resulting reaction mixture was heated at reflux temperature for 25h and allowed to warm to room temperature. The solvent was evaporated and the mixture was diluted with a saturated solution of sodium carbonate (10mL). The mixture was extracted with ethyl acetate (3×25mL) and combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue was purified via column chromatography on silica gel (100g) by eluting with 15% EtOAc/n-hexane. The first fraction was 6-bromoquinoxaline (10) (195mg, 31%) data as before. The second fraction was 5,8-dibromoquinoxaline (12) (45mg, 5%) data as before. The third fraction was 6,7-dibromoquinoxaline (13) (50mg, 6%) data as before. The fourth fraction was 5,7-dibromoquinoxaline (11) (120mg, 14%) data as before. The fifth fraction was 5,6-dibromoquinoxaline (14) (240mg, 28%) data as before.
With N-Bromosuccinimide; dibenzoyl peroxide; In acetonitrile; for 20h;Reflux; Inert atmosphere;
General procedure: A solution of quinoxaline (1) (390mg, 3.0mmol), NBS (390mg, 3.0mmol), and benzoyl peroxide (catalytic amount) in glacial acetic acid (10mL) was heated at reflux temperature for 20h. The reaction was monitored by TLC or 1H NMR spectroscopy. The resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. 6-Bromoquinoxaline (10) (315mg, 50%) was obtained as a sole product. The reaction was repeated using DMF as a solvent at the same reaction condition and monobromide 10 was obtained in 51% yield.
With bromine; acetic acid; for 24h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With bromine; In acetonitrile; for 25h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With bromine; In tetrachloromethane; for 18h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or tetrahydroquinoxaline 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
6,7-dibromo-1,2,3,4-tetrahydroquinoxaline[ No CAS ]
5,7-dibromoquinoxaline[ No CAS ]
[ 89980-70-1 ]
Yield
Reaction Conditions
Operation in experiment
35%; 7%; 5%; 10%; 5%; 15%
With bromine; In acetonitrile; for 2.5h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or <strong>[3476-89-9]tetrahydroquinoxaline</strong> 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
6,7-dibromo-1,2,3,4-tetrahydroquinoxaline[ No CAS ]
[ 89980-70-1 ]
Yield
Reaction Conditions
Operation in experiment
50%; 20%; 30%
With bromine; In acetonitrile; for 2.5h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or <strong>[3476-89-9]tetrahydroquinoxaline</strong> 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With bromine; In acetonitrile; for 10h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or <strong>[3476-89-9]tetrahydroquinoxaline</strong> 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
With bromine; In acetonitrile; for 2.5h;Reflux; Inert atmosphere;
General procedure: Bromine was added dropwise to a magnetically stirred refluxing solution of quinoxaline (1) or <strong>[3476-89-9]tetrahydroquinoxaline</strong> 15 or 19 in the relevant solvent. The resulting reaction mixture was heated at reflux temperature. The reaction was monitored by TLC or 1H NMR spectroscopy. After the desired time, the resulting reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The mixture was diluted with a saturated solution of sodium carbonate (10mL) and the mixture was extracted with ethyl acetate (2×25mL). Combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude was purified appropriate method described in below.
2-(quinoxalin-2-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With copper diacetate; potassium carbonate; Selectfluor In nitromethane at 120℃; for 12h;
76%
With C10H3F6IO4 In ethyl acetate at 60℃; for 8h;
II. Synthesis procedure for compounds 3 (3a as an example).
General procedure: quinoline 1a (64.5 mg, 0.5 mmol), saccharin 2a (100.6 mg, 0.55 mmol) and PhI(OCOCF3)2 (430.0 mg, 1.0 mmol) were added to EtOAc2 (3 mL). The mixture was stirred at 60 oC for 8.0 h (monitored by TLC), quenched with water, extracted with dichloromethane (5×3 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by a shot flash silica gel column chromatography (EtOAc/petro ether = 1:6) to give compound 3a as a white solid (97.2 mg, 79%).
At room temperature, will be 52 mg (0.4 mmol) quinoxaline, 414 mg (2.8 mmol) 2, 2 - ethoxy acetic acid, 182 mg (0.8 mmol) of the ammonium persulfate and 260 mg (0.8 mmol) Cs2CO3Dissolved in 6 ml in dimethyl sulfoxide, mix, nitrogen 30 min after the blue LEDs arranged under the lamp illumination reaction 20 h, adding 7.2 concentration is 3 M hydrochloric acid catalytic hydrolysis 20 h, using sodium bicarbonate adjusting pH to neutral, extraction, the combined organic phase, by the rotary concentrate by the Rotavapor after turns on lathe does, then to the volume ratio of 15:1 petroleum ether: ethyl acetate mixed solution of eluant, performing silica gel column chromatography purification and separation, to obtain the corresponding formylation heterocyclic derivatives, its reaction is Product purity is 99%, and the yield is 63%.
53%
With ammonium peroxydisulfate; caesium carbonate; In dimethyl sulfoxide; at 20℃; for 24h;Inert atmosphere; Irradiation; Green chemistry;
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
With sodium persulfate; sulfuric acid; silver trifluoroacetate In water; butanone at 50℃; for 24h; Inert atmosphere;
9
Add compound (II) 1-heptanol (232.4, 2.0 mmol) and quinoxaline (65.1 mg, 0.5 mmol) into a two-necked flask equipped with magnetic stirring. Silver trifluoroacetate (44.2mg, 0.2mmol), sodium persulfate (238.1mg, 1.0mmol), sulfuric acid (147.1mg, 1.5mmol), The mixture was dissolved in methyl ethyl ketone/distilled water (1:1, 4mL), protected by nitrogen, Stir the reaction at 50°C for 24 hours, TLC tracked until the raw materials disappeared and the reaction was completed (using a mixture of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the developing agent), the reaction solution was quenched with sodium bicarbonate, washed with saturated brine, and then washed with ethyl acetate After extraction, the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column using n-hexane/ethyl acetate to obtain 92.4 mg of product with a yield of 75.6% and an HPLC purity of 99.1%.
With sodium selenide; caesium carbonate; zinc(II) sulfate In N,N-dimethyl-formamide at 20 - 70℃; for 8h;
2 Example 2: Preparation of product 4b
At room temperature, add 10mmol quinoxaline, 12mmol sodium selenide and 10mmol iodonaphthalene in a 50mL round-bottom flask, then add 30mL DMF, 1mmol zinc sulfate and 20mmol cesium carbonate in sequence, and stir at 70 for 8 Hour. After cooling, add 20mL saturated sodium chloride aqueous solution to the system, extract 3 times with ethyl acetate, 20mL each time, combine the organic phases, dry with anhydrous sodium sulfate, evaporate the solvent, 200-300 mesh silica gel column chromatography The pure product of 2-phenylselenosulfonyl quinoxaline compound 4b.
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