* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate In ethanol at 50℃; for 4.5 h;
In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer4mmol5-bromofuran-2-carbaldehyde (1-18), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, and then the reaction flask was placed in an oil bath preheated to 50 ° C and opened with a magnetic stirrer for 4.5 h. reaction The solution was stirred by adding sodium thiosulfate solution and then extracted with ether. The organic layer was separated and the solvent was evaporated under reduced pressure. The elution was carried out with a mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as an eluent, and the eluate containing the target compound was collected And the solvent was evaporated to give 5-bromofuran-2-carbonitrile with an isolated yield of 85percent.
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium perchlorate; acetic acid; lithium hexamethyldisilazane In acetonitrile for 15 h; Electrochemical reaction
General procedure: Preparative electrolysis experiments were performed using 263 APotentiostat/Galvanostat (Princeton Applied Research, USA). 0.1 MNaClO4–CH3CN solution (10 mL) containing aldehydes (1 mmol),TEMPO (0.1 mmol), HMDS (2.5mmol) and AcOH (2.5mmol) was electrolyzedwith stirring in an undivided cell (30 mL) equipped with twoplatinum sheets as anode (1.5 cm2) and cathode (3.0 cm2) respectivelyat a constant potential of 1.5 V vs Ag/Ag+ (0.1MAgNO3 in acetonitrile).The electrode separation was 1 cm. When the reaction was finished,10mL of saturatedNa2SO3 solution was added into the reactionmixtureand stirred for 15 min. Then the mixture was extracted with CH2Cl2(20 mL × 3). The organic layer was dried with anhydrous Na2SO4 andconcentrated in a rotary evaporator. The productswere obtained via purificationof column chromatography and their structures were confirmedby 1H NMR, 13C NMR and MS. NMR was performed on a BrukerAvance III spectrometer. GC-MS was performed on the Thermo TraceISQ instrument with TG 5MS capillary column.
Reference：
[1] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 5, p. 524 - 529
[2] Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163
[3] RSC Advances, 2017, vol. 7, # 3, p. 1484 - 1489
[4] Electrochimica Acta, 2017, vol. 226, p. 53 - 59
[5] Patent: CN106748881, 2017, A, . Location in patent: Paragraph 0050
[6] Electrochemistry Communications, 2016, vol. 64, p. 51 - 55
[7] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 2, p. 140 - 145[8] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 2, p. 181 - 186
[9] Patent: EP1792613, 2007, A2, . Location in patent: Page/Page column 46
[10] Angewandte Chemie - International Edition, 2015, vol. 54, # 14, p. 4241 - 4245
3
[ 4465-70-7 ]
[ 4915-06-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
With [RhCl2(p-cymene)]2 In acetonitrile for 3 h; Reflux
To a solution of aldoxime 4 (2.90 g, 15.26mmol) in CH3CN(30 mL) were added [RuCl2(p-cymene)]2 (0.28g, 0.46mmol).The reaction mixture was refluxed for 3 h. After removal of solvent under reducedpressure, the residue was purified by silica gelchromatography with petroleum ether/EtOAc (5:1) to afford 5 as a colorless oil (1.84 g, 70percent).1H NMR (300 MHz, CDCl3) δ 7.06 (1H, d, J = 3 Hz), 6.48 (1H, d, J= 3 Hz).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 2, p. 216 - 220
[2] Patent: WO2005/82899, 2005, A1, . Location in patent: Page/Page column 28-29
With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate; In ethanol; at 50℃; for 4.5h;
In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer4mmol5-bromofuran-2-carbaldehyde (1-18), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, and then the reaction flask was placed in an oil bath preheated to 50 C and opened with a magnetic stirrer for 4.5 h. reaction The solution was stirred by adding sodium thiosulfate solution and then extracted with ether. The organic layer was separated and the solvent was evaporated under reduced pressure. The elution was carried out with a mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as an eluent, and the eluate containing the target compound was collected And the solvent was evaporated to give 5-bromofuran-2-carbonitrile with an isolated yield of 85%.
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium perchlorate; acetic acid; lithium hexamethyldisilazane; In acetonitrile; for 15.0h;Electrochemical reaction;
General procedure: Preparative electrolysis experiments were performed using 263 APotentiostat/Galvanostat (Princeton Applied Research, USA). 0.1 MNaClO4-CH3CN solution (10 mL) containing aldehydes (1 mmol),TEMPO (0.1 mmol), HMDS (2.5mmol) and AcOH (2.5mmol) was electrolyzedwith stirring in an undivided cell (30 mL) equipped with twoplatinum sheets as anode (1.5 cm2) and cathode (3.0 cm2) respectivelyat a constant potential of 1.5 V vs Ag/Ag+ (0.1MAgNO3 in acetonitrile).The electrode separation was 1 cm. When the reaction was finished,10mL of saturatedNa2SO3 solution was added into the reactionmixtureand stirred for 15 min. Then the mixture was extracted with CH2Cl2(20 mL × 3). The organic layer was dried with anhydrous Na2SO4 andconcentrated in a rotary evaporator. The productswere obtained via purificationof column chromatography and their structures were confirmedby 1H NMR, 13C NMR and MS. NMR was performed on a BrukerAvance III spectrometer. GC-MS was performed on the Thermo TraceISQ instrument with TG 5MS capillary column.
N-[(5S)-3-(3-fluoro-4-piperazin-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide trifluoroacetate[ No CAS ]
[ 4915-06-4 ]
(S)-N-[(3-{3-fluoro-4-[4-(5-cyano-furan-2-yl)-piperazin-1-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In DMF (N,N-dimethyl-formamide); at 95℃; for 10.0h;
Step c: Preparation of (S)-N- [ (3-13-Fluoro-4- [4- (5-cyano-furan-2-yl)-piperazin-l- yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide; To (S)-N- ( {3- [3-Fluoro-4- (piperazin-1-yl) phenyl]-2-oxo-oxazolidin-5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.5 g, 1.48 mmol) in dry dimethylformamide, <strong>[4915-06-4]2-bromo-5-cyanofuran</strong> (0.26g, 1.48 mmol), cesium carbonate (0.58g, 1. 78mmol), rac-2,2'bis (diphenylphosphino)-1, 1'-binaphthyl (0.074g, 0. 12mmol), tris (dibenzylideneacetone) dipalladium (0) (0.054 g, 0.06 mmol), were added and heated to 95 C for about 10 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography using 1-3 % methanol/dichloromethane to yield 0.052 g of the title compound. 'H NMR (CDCl3) 8ppm : 7.46 (dd, 1H), 7.09 (dd. 1H), 7.03 (d, 1H), 6.95 (t, 1H), 5.99 (t, 1H), 5.18 (d, 1H), 4.76 (m, 1H), 3.99 (t, 1H), 3.6-3. 8 (m, 3H), 3.46 (m, 4H), 3.15 (m, 4H), 2.0 (s, 3H) M+H = 428 IR (cm-1) : 2205,1748, 1646 m. p. =164-171 Oc
With [RhCl2(p-cymene)]2; In acetonitrile; for 3.0h;Reflux;
To a solution of aldoxime 4 (2.90 g, 15.26mmol) in CH3CN(30 mL) were added [RuCl2(p-cymene)]2 (0.28g, 0.46mmol).The reaction mixture was refluxed for 3 h. After removal of solvent under reducedpressure, the residue was purified by silica gelchromatography with petroleum ether/EtOAc (5:1) to afford 5 as a colorless oil (1.84 g, 70%).1H NMR (300 MHz, CDCl3) delta 7.06 (1H, d, J = 3 Hz), 6.48 (1H, d, J= 3 Hz).
With acetic anhydride; at 100℃; for 17.0h;
Step b: Preparation of 2-bromo-5-cyanofuran; 5-bromo-2-furyloxime (2 g) in acetic anhydride (20 mL) was heated to 100 C for about 17 hours. The reaction mixture was cooled, saturated sodium bicarbonate solution was added and stirred for about 30 minutes. The reaction mixture was extracted with dichloromethane and washed with sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography 0-1% ethyl acetate in hexane to yield 0.3 g of product.
EXAMPLE 119 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [1,3]oxazin-6-yl)-furan-2-carbonitrile The title compound was prepared according to the procedure B from <strong>[4915-06-4]2-bromo-5-cyanofuran</strong> (1.0 g, 5.6 mmol) (J. Med. Chem. (1997), 40(23), 3804-3819) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8 g, 8.18 mmol) as a white solid (0.39 g, 1.45 mmol, 17%): mp. 257-260 C.; 1H-NMR (DMSO-d6) 10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H, J=3.8 Hz), 6.98 (d, 1H, J=8.9 Hz), 1.66 (s, 6H); MS ((+)-APCI) m/z=269 (M+H)+.
EXAMPLE 119 5-(4,4Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile The title compound was prepared according to the procedure B from <strong>[4915-06-4]2-bromo-5-cyanofuran</strong> (1.0 g, 5.6 mmol) (J. Med. Chem. (1997), 40(23), 3804-3819) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8 g, 8.18 mmol) as a white solid (0.39 g, 1.45 mmol, 17%): mp. 257-260 C.; 1H-NMR (DMSO-d6) 10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1 H, J=3.8 Hz), 6.98 (d, 1 H, J=8.9 Hz), 1.66 (s, 6H); MS ((+)-APCI) m/z=269 (M+H)+.
With sodium azide; triethylamine hydrochloride; at 100 - 110℃;
To a solution of <strong>[4915-06-4]5-bromo-2-furonitrile</strong> (2.5 g) in toluene was added sodium azide (1.33 g) and triethylamine hydrochloride (2.89 g). The reaction mixture was stirred at 100- 110 0C overnight. The reaction mixture was filtered and the solid was washed with methanol. The filtrate was concentrated under vacuum to yield the title compound (2.4 g).
With diisobutylaluminium hydride; In methanol; toluene;
PREPARATION 7 5-Bromo-2-furaldehyde <strong>[4915-06-4]5-Bromo-2-furylcarbonitrile</strong> (2.3 g., 13 mmoles) was dissolved in 50 ml. of ether and cooled, under nitrogen, to -10 C. Diisobutylaluminum hydride (1.9 g., 13 mmoles) as a 25% solution in toluene was added dropwise, maintaining the temperature near -10 C. The reaction was allowed to warm to room temperature and allowed to stir about 6 hours. The reaction mixture was cooled to 0 to 5 C., diluted with 1 ml. of methanol, acidified with 3 N hydrochloric acid, washed with water, and evaporated to yield 5-bromo-2-furaldehyde (1.2 g., m.p. 74-76 C.).
PREPARATION 6 5-Bromo-2-furylcarbonitrile 5-Bromo-2-furylcarboxamide (10 g.) was combined with 50 ml. of phosphorus oxychloride and refluxed for 24 hours. The mixture was poured onto ice, the product extracted into ether, which on evaporation gave 5-bromo-2-furylcaronitrile as an oil (6.4 g.).
Neat POCI3 (0.69 mL, 7.4 mmol) was added to a pyridine solution (13 mL) of 5-bromo- furan-2-carboxylic acid amide (1.0 g, 5.3 mmol). After 2 h the mixture was cooled to 0 0C and taken to pH 4.5 with concentrated aqueous HCl. The aqueous mixture was extracted with Et2O and the combined extracts were washed with brine, dried (Na2SO4), concentrated and used without further purification to give 900 mg of the title compound.
With triethylamine; trifluoroacetic anhydride; In dichloromethane; at 0℃; for 1.0h;Inert atmosphere;
A mixture of 5-bromofuran-2-carboxamide (3.17 g, 16.66 mmol) and Et3N (4.89 mL, 35.25 mmol) in DCM (30 mL) was stirred at 0 oC for 30 minutes. Then TFAA (5.13 g, 24.43 mmol) was added dropwise under N2 and the mixture was stirred at 0 oC for 1 hour. The solution was diluted with DCM (100 mL) and neutralized to pH = 6~7 with saturated NaHCO3. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford crude 5-bromofuran-2-carbonitrile (917 mg, 32%) as a black solid.1H NMR (500 MHz, CDCl3) delta 7.08 (d, J = 4.5 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H). tR = 1.72 min.
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90 - 100℃; for 24.0h;Inert atmosphere;
General procedure: Tetrakistriphenylphosphine palladium (0.288 g, 0.25 mmol) was added to a stirred mixture of the indole stannane 3 (2.29 g, 5 mmol) and the halo arylnitriles (5-bromothiophene-2-carbonitrile and 4-bromobenzonitrile) (5 mmol) in deaireated dioxane (20 mL) under a nitrogen atmosphere. The mixture was warmed to 90-100 C and stirred for 24 h. The solvent was evaporated under reduced pressure. The resultant solid was partitioned between ethyl acetate (200 mL) containing 5 mL of concentrated ammonia to destroy the palladium complex, washed with water, passed through celite, dried over sodium sulfate and evaporated. Purification was by column chromatography on silica gel, using hexanes/ethyl acetate (80:20, v/v) as the eluent.
With hydroxylamine hydrochloride; potassium carbonate; In ethanol; for 2.0h;Reflux;
To a solution of nitrile 5 (1.80 g, 8.78mmol) in EtOH (20 mL)were added K2CO3 (2.42 g, 17.56 mmol)and hydroxylammonium chloride (1.21 g, 17.56mmol).The reaction mixture was refluxed for 2 h, then filtered and concentrated. Ethyl acetate (50 mL) was added to theresulting residue, followed by washing a saturated aqueous NaHCO3 solution (30mL) and then brine (3×30 mL). The resulting organic layer was concentrated, and the residue was subjectedto silica gel chromatography with petroleum ether/acetone (2:1) to afford 6 as a white solid (1.53, 85%). 1H NMR (300 MHz, CD3OD) delta 6.75 (1H, d, J = 3 Hz), 6.48 (1H, d, J= 3 Hz). ESI-MS m/z: 204.7, 206.7 [M+H]+.
1-(tert-butoxycarbonyl)-2-(5-cyanofuran-2yl)-1H-indole-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90 - 100℃; for 24.0h;Inert atmosphere;
General procedure: Tetrakistriphenylphosphine palladium (0.288 gm, 0.25 mmol)was added to a stirred mixture of the indole stannane (3a or 3b)(5 mmol) and the aryl halide (5 mmol) in de-aireated dioxane(15 mL) under a nitrogen atmosphere. The vigorously stirred mixture was heated at 90-100C for 24 h. The solvent was evaporatedunder reduced pressure, the resulting solid was partitioned between ethyl acetate (200 mL) and 5mL of concentrated ammonia to remove the palladium complex, washed with water, passed through celite to remove the catalyst, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel, using hexanes/ethyl acetate (75/25, v/v).
tert-butyl 6-cyano-2-(trimethylstannyl)-1H-indole-1-carboxylate[ No CAS ]
1-(tert-butoxycarbonyl)-2-(5-cyanofuran-2yl)-1H-indole-6-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90 - 100℃; for 24.0h;Inert atmosphere;
General procedure: Tetrakistriphenylphosphine palladium (0.288 gm, 0.25 mmol)was added to a stirred mixture of the indole stannane (3a or 3b)(5 mmol) and the aryl halide (5 mmol) in de-aireated dioxane(15 mL) under a nitrogen atmosphere. The vigorously stirred mixture was heated at 90-100C for 24 h. The solvent was evaporatedunder reduced pressure, the resulting solid was partitioned between ethyl acetate (200 mL) and 5mL of concentrated ammonia to remove the palladium complex, washed with water, passed through celite to remove the catalyst, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel, using hexanes/ethyl acetate (75/25, v/v).
With n-butyllithium; In tetrahydrofuran; at -78 - 20℃;
To a solution of <strong>[4915-06-4]5-bromofuran-2-carbonitrile</strong> (1 g, 10.8 mmol) in 40 mL of anhydrous THF was added n-BuLi (5.6 mL, 14 mmol) at -78 C, followed 30 minutes later by the addition of SnBu3C1 (2.90 mL, 10.8 mmol). After stirring at RT overnight, the reaction mixture was quenched with saturated NH4C1 (15 mL), and extracted with EA (50 mL x 3). Theorganic phases were washed with H20 (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC (MeCN/NH4HCO3) to afford 5-(tributylstannyl)furan-2-carbonitrile (1 g, 24 %) as a yellow oil. LC-MS m/z: 383.1 [M+H]+ tR= 2.87 min
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