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CAS No. : | 4923-87-9 | MDL No. : | MFCD03069318 |
Formula : | C8H5BrS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RDSIMGKJEYNNLF-UHFFFAOYSA-N |
M.W : | 213.09 | Pubchem ID : | 2776578 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 49.53 |
TPSA : | 28.24 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.92 cm/s |
Log Po/w (iLOGP) : | 2.42 |
Log Po/w (XLOGP3) : | 3.78 |
Log Po/w (WLOGP) : | 3.66 |
Log Po/w (MLOGP) : | 3.38 |
Log Po/w (SILICOS-IT) : | 4.37 |
Consensus Log Po/w : | 3.52 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.21 |
Solubility : | 0.0132 mg/ml ; 0.0000619 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.07 |
Solubility : | 0.0183 mg/ml ; 0.0000858 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.2 |
Solubility : | 0.0134 mg/ml ; 0.000063 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 1.89 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium acetate In dimethyl sulfoxide at 20 - 80℃; for 3 h; | Dissolve 5-bromo-benzo [b] thiophene (J. Mater. Chem., 10: 2069-2081,2000 ; 49 g, 7.0 mmol) in DMSO (40 mL). Add bis (pinacolato) diboron (7 mmol), PdCl2 (dppf)-CH2Cl2 (0.33 mmol), and KOAc (20 mmol). Flush the flask with N2, and then heat the reaction mixture to 80°C with stirring. Continue to heat the reaction mixture for 3 hours, and then cool to room temperature. Add water (66 mL) and extract the aqueous layer with EtOAc (3 x 66 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-5percent Et20/pentane) to give 1.56 g of the title compound (86percent). |
64% | With potassium acetate In dimethyl sulfoxide at 85℃; for 1.5 h; | Step E: Bis(pinacolato)diboron (1.3 g, 5.12 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.1 g, 0.14 mmol) and potassium acetate (1.4 g, 14.26 mmol) were charged in a 100 ml 3 neck round-bottomed flask which had been dried with a heat gun under vacuum and cooled under nitrogen prior to use. The mixture was degassed with nitrogen three times. A solution of 5-bromothiophene (1.0 g, 4.69 mmol) in dimethyl sulfoxide (20 ml) was added, the mixture was degassed again three times and was stirred at 85° C. for 1.5 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and rinsed with water and ethyl acetate. Additional water was added to the filtrate which was extracted with ethyl acetate three times. The combined organic extracts were washed with brine once and dried over sodium sulfate to give the desired material (0.8 g, 64percent, 100percent AUC GC) after chromatography (9:1 to 5:1 heptane/ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.1, 0.6 Hz, 1H), 7.34 (d, J=5.4 Hz, 1H), 7.28 (dd, J=5.4, 0.6 Hz, 1H), 1.30 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.9% | With formic acid; dihydrogen peroxide; In dichloromethane; at 20℃; | To a 50 mL two-neck flask were added <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (231.1 mg, 1.08 mmol), dichloromethane (8 mL) and formic acid (0.25 mL), then H2O2 (0.15 mL, 30%) was added dropwise. The mixture was stirred at rt overnight. After the reaction was completed, to the mixture was added saturated brine (20 mL). The resulting mixture was extracted with DCM (20 mL*3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica-gel column chromatography (PE:EtOAc=10:1, V/V) to give a white solid (240 mg, 90.9%). MS(ESI, pos.ion)m/z:244.9 (M+1); |
29% | With Oxone; oxone; In water; acetone; at 70℃; | In a 100 mL screwcapped vessel <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (2.30 g, 10.8 mmol) was dissolved in acetone (46 ml). Oxone, monopersulfate (potassium peroxymonosulfate) (27.0 g, 43.2 mmol) and water were added and stirred at 70 C overnight. To the reaction mixture water and ethyl acetate were added. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The yellow residue was purified by flash-chromatography (n-heptane/DCM) to give 769 mg (29 %) of the title compound as a white solid. Rt = 2.393 min (HPLC method A). |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 15 - 25℃; for 16h; | Step A: 5-Bromo- 1 -benzothiophene 1 J -dioxide5-Bromo- 1 -benzothiophene (1.50 g, 7.04 mmol) was dissolved in chloroform (47 mL) and allowed to stir vigorously at ambient temperature. m-CPBA (4.34 g, 17.6 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 16 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHC03, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CDC13): delta 7.65 (dd, J= 7.9, 1.8 Hz, 1H), 7.55 (d, J= 7.9 Hz, 1H), 7.50 (d, J= 1.8 Hz, 1H), 7.15 (d, J= 6.9 Hz, 1H), 6.74 (d, J= 6.9 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With PPA; In chlorobenzene;Reflux; | This compound was prepared according to the method described by T. Tsuri et al. (2003 J. Med. Chem. 46:2446-2455) with modification. Chlorobenzene (38 mL) and polyphosphoric acid (11.4 g) were combined and heated at reflux with stirring under a nitrogen atmosphere. To the reaction mixture was added, dropwise, a solution of 1- [2,2-bis(methyloxy)ethyl]thio}-4-bromobenzene (6.1 g, 22 mmol,) in chlorobenzene (12 mL). The reaction mixture was heated at reflux overnight. The oil bath was removed and the reaction mixture was allowed to cool at room temperature. The supernatant was decanted and the remaining residue was washed twice with toluene. The decanted solutions were combined and concentrated to give a dark brown-orange liquid. The crude product was purified by flash chromatography over silica with a hexanes:ethyl acetate gradient (100:0 to 98:2) to give 2.54 g of 5-bromo-l- benzothiophene. 1H NMR indicates that a small impurity was present. An additional 0.50 g of 5-bromo-l-benzothiophene which lacked the aforementioned impurity was also obtained to give a total yield of 3.0 g (64%) of 5-bromo-l-benzothiophene. The two batches of 5-bromo-l-benzothiophene were combined and used without further purification. 1H NMR (400 MHz, CDCl3): delta 7.96 (s, IH), 7.73 (d, J = 9 Hz, IH), 7.47 (d, J = 5 Hz, IH), 7.43 (d, J = 9 Hz, IH), 7.27 (d, J = 5 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With PPA; In chlorobenzene; at 135℃; for 1h; | Step B: A solution of the product from Step A (35 g, 92 mmol) in chlorobenzene (50 ml) was added dropwise to a solution of polyphosphoric acid (100 g) in chlorobenzene (250 ml) at 135 C. After stirring at 135 C. for 1 hour, the mixture was cooled below 50 C. The chlorobenzene layer was poured out of the reaction flask and was concentrated under vacuum. Meanwhile, water was added to the reaction vessel at 0 C. to decompose polyphosphoric acid. The resulting aqueous phase was added to the residue from the chlorobenzene layer. Additional water and dichloromethane were added and the two phases were separated. The aqueous layer was extracted with dichloromethane twice. The combined organic extracts were dried with anhydrous sodium sulfate and concentrated under vacuum to give the cyclized product (18 g, 72%) after chromatography (100% heptane): 1H NMR (300 MHz, CDCl3) delta 7.98dJ=1.8 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.44-7.50 (m, 2H), 7.29 (d, J=5.8 Hz, 1H). |
51% | With Poly phosphoric acid; In chlorobenzene; at 125℃;Inert atmosphere; | Poly phosphoric acid (28 g) was dissolved in chlorobenzene (25 mL) at 125C and a solution of 1 -bromo-4-[(2,2-diethoxyethyl)sulfanyl]benzene (14 g, 55.288 mmol) in chlorobenzene (28 mL) was added under nitrogen. The reaction mixture was refluxed at 125C overnight. Progress of the reaction was monitored by TLC and, after completion of the reaction, the mixture was diluted with water and extracted using toluene. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and solvent was evaporated under reduced pressure to give residue which was purified by column chromatography using hexane as eluent on silica gel to afford 5-bromo-1-benzothiophene (5 g, 45.867 mmol, 51%) as white solid. The ?H NMR and mass was confirmed by reported literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.2% | Aluminum trichloride (3.75 g, 28.1 mmol) and dichloromethane (30 mL) were added to a 250 mL single-neck round bottom flask at 0 C. Slowly add acetyl chloride (2.21 g, 28.2 mmol) and stir for half an hour. Then 5-bromobenzothiophene (4.0 g, 18.8 mmol, dissolved in 20 mL of dichloromethane) was added dropwise. The reaction was stirred for half an hour; then transferred to 25 C for 2 hours. Quench slowly by adding water (50 mL), and separate the liquid. The organic phase was washed again with saturated sodium bicarbonate solution (50 mL×3). The organic phase was collected, dried over anhydrous sodium sulfate (2 g), filtered. The filtrate was depressurized and dried. The title compound was obtained as a yellow solid (4.41 g, 92.2%). | |
With tin(IV) chloride; In n-heptane; 1,2-dichloro-ethane; at 0 - 20℃; | Step 1 To a solution of 6-bromobenzothiophene (10.0 g, 0.047 mol) and AcCl (4.43 g, 4.0 ml, 0.056 mol) in 1,2-dichloroethane (200 mL) was added SnCl4 (1.0 M/heptane, 56 mL) at 0 C. The mixture was allowed to reach RT and then stirred for 20 h. The mixture was poured onto ice/H2O and extracted with DCM. The organic layer was washed with sat. aqueous NaHCO3, dried and concentrated. Flash chromatography (EtOAc/hexanes, 1:9 then 1:4) afforded 6A (5.6 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 20℃; for 6h;Heating / reflux; | To toluene 1.6mL solution of tert-butyl 2-(4-fluoroanilino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 79mg were added ethanol 0.60mL, water 0.30mL, 5-bromobenzothiophene 61mg, sodium hydrogen carbonate 48mg and tetrakis(triphenylphosphine)palladium(0) 11mg at room temperature, and it was heated and refluxed for 6 hours. After the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=5:1] to give tert-butyl 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoate. Trifluoroacetic acid 5.0mL was added to the obtained tert-butyl 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(benzothiophen-5-yl)-2-(4-fluoroanilino)benzoic acid 16mg of a yellow solid. 1H-NMR(DMSO-d6) delta value: 7.13(1H,dd,J=8.3,1.7Hz),7.19-7.27(2H,m),7.34-7.43(3H,m),7.52(1H,d,J=5.6Hz),7.56(1H,dd,J=8.5,1.6Hz),7 .81(1H,d,J=5.6Hz),8.00(1H,d,J=8.3Hz),8.07(1H,d,J=8.5Hz) ,8.10(1H,d,J=1.6Hz),9.66(1H,s),13.10(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 90 percent / SnCl4 / 1,2-dichloro-ethane / 20 h / 0 - 20 °C 2: 77 percent / aq. NaOH; Br2 / dioxane / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 20 - 80℃; for 3h; | Dissolve 5-bromo-benzo [b] thiophene (J. Mater. Chem., 10: 2069-2081,2000 ; 49 g, 7.0 mmol) in DMSO (40 mL). Add bis (pinacolato) diboron (7 mmol), PdCl2 (dppf)-CH2Cl2 (0.33 mmol), and KOAc (20 mmol). Flush the flask with N2, and then heat the reaction mixture to 80C with stirring. Continue to heat the reaction mixture for 3 hours, and then cool to room temperature. Add water (66 mL) and extract the aqueous layer with EtOAc (3 x 66 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-5% Et20/pentane) to give 1.56 g of the title compound (86%). |
64% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 85℃; for 1.5h; | Step E: Bis(pinacolato)diboron (1.3 g, 5.12 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.1 g, 0.14 mmol) and potassium acetate (1.4 g, 14.26 mmol) were charged in a 100 ml 3 neck round-bottomed flask which had been dried with a heat gun under vacuum and cooled under nitrogen prior to use. The mixture was degassed with nitrogen three times. A solution of 5-bromothiophene (1.0 g, 4.69 mmol) in dimethyl sulfoxide (20 ml) was added, the mixture was degassed again three times and was stirred at 85 C. for 1.5 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and rinsed with water and ethyl acetate. Additional water was added to the filtrate which was extracted with ethyl acetate three times. The combined organic extracts were washed with brine once and dried over sodium sulfate to give the desired material (0.8 g, 64%, 100% AUC GC) after chromatography (9:1 to 5:1 heptane/ethyl acetate): 1H NMR (300 MHz, CDCl3) delta 8.24 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.1, 0.6 Hz, 1H), 7.34 (d, J=5.4 Hz, 1H), 7.28 (dd, J=5.4, 0.6 Hz, 1H), 1.30 (s, 12H). |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dioxane 1-4; at 100℃; for 20h; | EXAMPLE 10A 2-Benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[3.2.1]dioxaborolane A mixture of 5-bromo-benzo[b]thiophene (Maybridge, 4.26 g, 0.0200 mol), bis(pinacolato)diboron (Aldrich, 6.09 g, 0.0240 mol) and potassium acetate (Aldrich, 2.94 g, 0.0300 mol) in 1,4-dioxane (Aldrich, 50 mL) was degassed and purged with N2 three times. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dppf).CH2Cl2 (300 mg, 0.4 mmol, Aldrich) was and the solution was heated to 100 C. for 20 hours. The mixture was then cooled to room temperature, diluted with 300 mL of EtOAc and washed with brine (2*20 mL). The organic solution was concentrated under reduced pressure and the residue was chromatographed to provide the title product. 1H NMR (300 MHz, CDCl3) delta 1.36-1.41 (S, 12H), 7.35 (d, J=5.50 Hz, 1H), 7.42 (d, J=5.70 Hz, 1H), 7.75 (d, J=8.14 Hz, 1H), 7.89 (d, J=8.14 Hz, 1H), 8.31 (s, 1H) ppm. MS (DCI/NH3) m/z 278 (M+H)+. |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 130℃; for 12h;Inert atmosphere; | Instead of 6-bromo -1H- indole, 5-bromobenzo [b] but using thiophene, as in Preparation Example 1 above 2- (benzo [b] thiophen-5-yl ) 4,4,5,5 to obtain a tetra-methyl-1,3,2-dioxaborolane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Step A: A mixture of CuCN (86 g, 960 mmol), <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (157 g, 723 mmol), pyridine (80 mL) and DMF (1400 mL) was heated at reflux for 14 h. After cooled to 80 C., the reaction mixture was poured into a cold aqueous solution of ethylenediamine (400 mL in 2 L water) cooled by an icebath. The product was extracted with ether (2×1.5 L). The ether layer was washed with brine (1 L), dried (Na2SO4), and concentrated. The residue was recrystallized from CHCl3/Hexanes (50 mL/2000 mL) to give benzo[b]thiophene-5-carbonitrile (106 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.15 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.61 (d, J=5.4 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.41 (d, J=5.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | EXAMPLE 9 N-[(5-bromobenzor[b]thien-3-yl)methyl]-sulfamide (Compound #15) 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2*100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). | |
In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid. 1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). | |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). | |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). | |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). | |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). | |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid.1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). | |
titanium tetrachloride; In 1,2-dichloro-ethane; at 20℃; for 1h; | 5-Bromobenzothiophene (1.60 g, 7.51 mmol) and dichloromethyl methyl ether (1.29 g, 11.3 mmol) were dissolved in anhydrous 1,2-dichloroethane (75 mL). Titanium tetrachloride (2.14 g, 11.3 mmol) was added, turning the solution dark. After one hour at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×100 mL). The extracts were concentrated and chromatographed (0 to 5% ethyl acetate in hexane) to yield <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong>-3-carbaldehyde (1.32 g). The 5-bromobenzothiophene-3-carboxaldehyde (1.20 g, 4.98 mmol) and sulfamide (4.0 g, 42 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.207 g, 5.47 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to provide the title compound as a yellow solid. 1H NMR (DMSO-d6): delta 8.12 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=8.6), 7.71 (1H, s), 7.52 (1H, dd, J=8.6, 1.9 Hz), 7.12 (1H, t, J=6.3 Hz), 6.72 (2H, s), 4.28 (2H, d, J=6.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a stirred mixture of 5-bromobenzthiophene (22.5 g, 105.6 mmol) and the acid chloride (17.4 ml, 141.3 mmol) in 135 ml benzene at 0 C., SnCl4 (43.1 ml, 368 mmol) was added in 2 h. Stirring was continued for 4 hours at the same temperature. The reaction mixture was poured into a mixture of 95 ml concentrated HCl (36-38%) in ice. The reaction mixture was extracted with EtOAc and the organic layer was washed with H2O (3*), 1N NaOH (1*), 5% NaHCO3 and H2O (2*). The EtOAc fraction was dried (MgSO4). The drying agent was removed by filtration and the solvent by evaporation under reduced pressure. The residue was recrystallized from 950 ml MeOH and chromatographed with Et2O/petroleum ether 1/1 as eluent to give 23.3 g (68%) of the acylated benzthiophene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium carbonate;palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 85℃; for 3.5h;Product distribution / selectivity; | Step C: Isoquinolin-4-ylboronic acid (2.4 g, 14.0 mmol) was added to a solution of the product from Step B (2.0 g, 9.4 mmol) and triphenylphosphine (0.5 g, 1.9 mmol) in 1,2-dimethoxyethane (50 ml). The suspension was degassed with nitrogen. Palladium acetate (0.2 g, 0.9 mmol) was added and the batch was stirred at room temperature for 20 minutes. Aqueous sodium carbonate (11.3 ml, 2 M solution) was added and the suspension was degassed again with nitrogen. The mixture was stirred at 85 C. for 3.5 hours, cooled, diluted with water and extracted with ethyl acetate twice. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated under vacuum and purified by chromatography (5:1 heptane/ethyl acetate) to give the desired isoquinoline (1.8 g, 74%, 98% AUC HPLC): 1H NMR (300 MHz, CDCl3) delta 9.30s, 1H), 8.59s, 1H), 7.95-8.07 m, 4H), 7.43-7.72 (mu, 5H). |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In dichloromethane; water; at 90℃; for 12h;Product distribution / selectivity; | Step A: To a solution of <strong>[192182-56-2]isoquinoline-4-boronic acid</strong> (378 mg, 2.013 mmol) and 5-bromobenzothiophene (286 mg, 1.342 mmol) in dichloroethane (8 mL), sodium carbonate (2 M aqueous, 2 mL, 4 mmol) was added and the solution degassed by alternately evacuating and releasing to argon three times. To this heterogenic mixture was added palladium tetrakistriphenylphosphine (76 mg, 0.6711 mmol), the reaction mixture was degassed 3 times and heated to 90 C. with agitation for 12 hours. To this mixture was added EtOAc (100 mL), the mixture washed with water (3×100 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography (SiO2, 30 g, 50% ethyl acetate/hexane) provided the product as a white solid (316 mg): 1H NMR (CDCl3, 300 MHz) delta 9.29 (s, 1H), 8.55 (s, 1H), 8.06-7.97 (m, 4H), 7.68-7.65 (m, 2H), 7.56-7.42 (m, 3H). ESI-MS calc. for C17H11NS [M+H]+ 262. Found 262. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium carbonate; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 15h;Heating / reflux; | Step A: A mixture of 5-bromo-benzo[b]thiophene (1.28 g, 6.0 mmol), isoquinolin-4-boronic acid (1.04 g, 6 mmol) and cesium carbonate (1.95 g, 6.0 mmol) in 1,2-dimethoxyethane (50 mL) and 2 M sodium carbonate (6 mL) was degassed with argon. Pd(PPh3)4 (416 mg, 0.36 mmol) was added and the reaction mixture was heated at reflux for 15 hours. The cooled reaction mixture was diluted with water and extracted with ethyl acetate twice. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 10% to 30% ethyl acetate/hexanes) gave the desired product (510 mg, 32%): 1H NMR (CDCl3, 500 MHz) delta 9.28 (s, 1H), 8.55 (s, 1H), 8.07-8.02 (m, 2H), 7.96-7.93 (m, 2H), 7.69-7.62 (m, 2H), 7.55 (d, J=5.4 Hz, 1H), 7.49 (dd, J=8.2, 1.6 Hz, 1H), 7.42 (dd, J=5.4, 0.4 Hz, 1H); ESI-MS m/z=262 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; magnesium In tetrahydrofuran; ethyl acetate; Petroleum ether | 31 Example 31 Example 31 A few drops of a solution of 5-bromobenzo[b]thiophene (0.93 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (10 ml) was added under nitrogen to a mixture of magnesium turnings (0.1 g), tetrahydrofuran (2 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 10 minutes. When the addition was complete, the mixture was heated under reflux for 45 minutes, then a solution of N-methoxy-N-methylbutyramide (0.6 g) in tetrahydrofuran (10 ml) was added. The mixture was heated under reflux for 1 hour, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (15 ml). Ethyl acetate (25 ml) was added, the mixture was stirred at ambient temperature for 45 minutes, the organic layer was separated, then further product was isolated from the aqueous layer by extraction into ethyl acetate (20 ml). The combined ethyl acetate solutions were washed with water (2*10 ml) and saturated aqueous sodium chloride solution (10 ml), then they were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl)butan-1-one (0.1 g) as a yellow oil which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexanes; at -78 - 0℃; for 1.5h; | Step E: To a solution of diisopropylamine (15.5 mL, 110 mmol) in THF (100 mL) at 0 C. was added n-butyllithium (40 mL of 2.5M in hexanes, 100 mmol). The resultant reaction solution was stirred at 0 C. for 30 minutes and then cooled to -40 C., before it was cannulated to a solution of 5-bromobenzothiophene (10.5 g, 50.0 mmol) and chlorotrimethylsilane (12.7 mL, 100 mmol) in THF (150 mL) at -78 C. The reaction solution was stirred at -78 C. for 1 hour, and then it was quenched with aqueous ammonium chloride at -78 C. and warmed to room temperature. The resultant mixture was extracted with ethyl acetate and the organic extract obtained was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes to 98:2 hexanes/ethyl acetate) to give the desired 5-bromo-2-trimethylsilylbenzothiophene (14.1 g, 98%) as a clear colorless oil: 1H NMR (500 MHz, CDCl3) delta 7.93 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 2.0 Hz, 1H), 7.37 (s, 1H), 0.38 (s, 9H). |
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78℃;Inert atmosphere; | (A) To a cooled (-10 qC to 5 C) solution of diisopropylamine (422 g, 4.17 mol) in anhydrous THF (4.0 L) was added n-butyllithium (1517 mL of 2.5 M in hexane, 3.79 mol) in drop-wise fashion over a period of 1.5 h under an inert atmosphere of nitrogen. Upon completion of the addition, the reaction solution was stirred at -10 C to 0 C for an additional 30 min, and then cooled to -78 C. A solution of <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (670 g, 3.16 mol) and TMSCl (512 g, 4.74 mol) in THF (3.4 L) was added in drop-wise fashion and the resulting reaction mixture was stirred at -78 C. After completion of the reaction, as judged by HPLC analysis, aq. NH4Cl solution (5% w/w, 2 L) was added in drop-wise fashion into the reaction mixture while still under a nitrogen atmosphere and maintaining a temperature between -78 qC and -65 C. The mixture was then allowed to warm to rt and the aqueous phase was removed. Water (2 L) was added to the organic phase and after stirring at room temperature for 15 min, the aqueous phase was removed. The combined aqueous layers were back-extracted with EtOAc (2 L), and the combined organic extracts were washed with sat.d aq. NaCl (2 L), dried (Na2SO4) and concentrated under reduced pressure to provide (5-bromobenzo[b]thiophen-2-yl)trimethylsilane (867 g, purity: 90.0 LCAP) as a light yellow liquid. 1H NMR (CDCl3) 7.93 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 0.37 (s, 9H); LC/MS (APCI+) m/z 283.9 [M]+. | |
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78 - 5℃;Inert atmosphere; | (A) To a cooled (-10 C. to 5 C.) solution of diisopropylamine (422 g, 4.17 mol) in anhydrous THF (4.0 L) was added n-butyllithium (1517 mL of 2.5 M in hexane, 3.79 mol) in drop-wise fashion over a period of 1.5 h under an inert atmosphere of nitrogen. Upon completion of the addition, the reaction solution was stirred at -10 C. to 0 C. for an additional 30 min, and then cooled to -78 C. A solution of <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (670 g, 3.16 mol) and TMSCl (512 g, 4.74 mol) in THF (3.4 L) was added in drop-wise fashion and the resulting reaction mixture was stirred at -78 C. After completion of the reaction, as judged by HPLC analysis, aq. NH4Cl solution (5% w/w, 2 L) was added in drop-wise fashion into the reaction mixture while still under a nitrogen atmosphere and maintaining a temperature between -78 C. and -65 C. The mixture was then allowed to warm to rt and the aqueous phase was removed. Water (2 L) was added to the organic phase and after stirring at room temperature for 15 min, the aqueous phase was removed. The combined aqueous layers were back-extracted with EtOAc (2 L), and the combined organic extracts were washed with sat.d aq. NaCl (2 L), dried (Na2SO4) and concentrated under reduced pressure to provide (5-bromobenzo[b]thiophen-2-yl)trimethylsilane (867 g, purity: 90.0 LCAP) as a light yellow liquid. 1H NMR (CDCl3) delta 7.93 (d, J=1.5 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 0.37 (s, 9H); LC/MS (APCI+) m/z 283.9 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine;tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 100℃; | Example 52 Preparation of (+)-5-benzo[b]thiophen-5-yl-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine, maleate salt and (-)-5-benzo[b]thiophen-5-yl-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine, maleate salt Step A: To a solution of <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (5.0 g, 23.5 mmol) in N,N-dimethylformamide (50 mL) at room temperature were added tri-o-tolylphosphine (0.64 g, 2.1 mmol) and triethylamine (9.9 mL, 70.4 mmol). The reaction mixture was degreased with argon and then ethyl acrylate (7.7 mL, 70.4 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.65 g, 0.7 mmol) were added to it. The resultant solution was degreased with argon and then heated at 100 C. overnight. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with water (2×), saturated ammonium chloride and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (95:5 to 93:7 hexanes/ethyl acetate) to give the desired product (2.5 g, 46%) as a light yellow oil: 1H NMR (CDCl3, 500 MHz) delta 7.94 (d, J=1.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.81 (d, J=16.0 Hz, 1H), 7.54 (dd, J=8.4 and 1.6 Hz, 1H), 7.49 (d, J=5.4 Hz, 1H), 7.36 (d, J=5.4 Hz, 1H), 6.50 (d, J=15.9 Hz, 1H), 4.28 (q, J==7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;bromotris(triphenylphosphine)copper(I); In acetonitrile; at 160℃; for 15h; | 3-Hydroxy-5-[(l>S)-2-methoxy-(l-methylethyl)oxy]-N-(l-methyl-lH-pyrazol-3- yl)benzamide (610 mg, 2.0 mmol), 5-bromobenzothiophene (639 mg, 3.0 mmol), copper bis(triphenylphosphine) bromide (372 mg, 0.40 mmol) and caesium carbonate (1.95g, 6.0 mmol) in acetonitrile (7.5 mL) were heated at 160C for 15 hours. The mixture was concentrated in vacuo and re-dissolved in DCM (50 mL). The organics were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was twice chromatographed on silica, eluting with 0-3% methanol in DCM, to give the desired material as a grey gum (178 mg). m/z 438 (M+Eta)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;bromotris(triphenylphosphine)copper(I); In ISOPROPYLAMIDE; at 200℃; for 4h;Microwave; | Cesium carbonate (163 mg, .05 mmol) was added to a solution of 3-hydroxy-N-(l-methyl- lH-pyrazol-3-yl)-5-{(l)S)-l-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (225 mg, 0.5 mmol), bromotris (triphenylphosphine) copper1 (93 mg, 0.1 mmol) and 5- bromobenzothiophene (107 mg, 0.5 mmol) in dimethylacetamide (2.5 mL) and the stirred mixture heated at 2000C in a "Biotage Initiator" microwave for 4 hours. The mixture was cooled to ambient temperature and pressure, poured onto water (40 mL) and extracted with ethyl acetate (3 x 15 mL), the combined organic layers washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give the desired compound (100 mg). m/z 580 (M+Eta)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 3h;Heating / reflux; | [0114] A mixture of <strong>[14394-70-8]2-chloro-5-methyl-pyrimidin-4-ylamine</strong> (0.30 g, 2.1 mraol), 5- bromo-benzo[]thiophene (0.6 g, 2.8 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL) . The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% EtOAc/hexane) to afford the title intermediate 13 (0.23 g, 40%) as a white solid. MS (ESI+): m/z 276 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;copper(l) iodide; ethyl 2-oxocyclohexane carboxylate; In dimethyl sulfoxide; at 20 - 95℃; for 19.5h; | Example 40(3R)-N-[(2Z)-3-(1-benzothien-5-yl)-5-(hydroxymethyl)-1,3-thiazol-2(3H)-ylidene]-3-fluoropyrrolidine-1-carboxamide; Example 36B (74 mg, 0.30 mmol), <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (77 mg, 0.36 mmol), copper (I) iodide (12 mg, 0.06 mmol), and cesium carbonate (147 mg, 0.45 mmol) were added to a reaction vial with a septum-containing cap, and flushed with nitrogen three times. Then ethyl 2-oxocyclohexanecarboxylate (19.5 muL, 0.12 mmol) and anhydrous dimethyl sulfoxide (0.30 mL) were added through the septum, the mixture was stirred 30 minutes at room temperature, and then heated at 95 C. in the dark for 19 hours. Then the mixture was quenched with concentrated aqueous ammonium hydroxide (0.60 mL), passed through diatomaceous earth with an ethyl acetate rinse, concentrated, and purified by reverse phase HPLC using an acetonitrile/water 10 mM ammonium acetate method to give the title compound.1H NMR (300 MHz, d4-MeOH) delta ppm 1.85-2.25 (2H), 3.3-3.8 (4H), 4.61 (2H), 5.0-5.35 (1H), 7.26 (1H), 7.46 (1H), 7.51-7.56 (1H), 7.71 (1H), 7.99-8.06 (2H); MS (ESI) m/z 378 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | To 5-bromo-l-benzothiophene (3.0 g, 14.1 mmol) was added methanol (32 mL) followed by sodium methoxide (25% wt/wt in methanol) (32 mL, 140 mmol), and copper(I) bromide (0.201 g, 1.4 mmol). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool at room temperature and copper powder (0.087 g, 1.37 mmol) was added. The <n="250"/>reaction mixture was heated at reflux for 18 h and stirred at room temperature for 6 h. Approximately 1 mL of the reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between water and diethyl ether. The organic phase was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an oil. 1H NMR analysis of the oil indicated that the reaction was approximately 15% complete. The reaction mixture was heated at reflux for 5 days. The reaction mixture was allowed to cool at room temperature and concentrated. To the crude product was added ice-water, followed by diethyl ether. The organic phase was separated, washed with water, followed by saturated sodium chloride, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give an orange liquid which quickly solidified to give a tan solid. The crude product was purified by flash chromatography over silica with a hexanes: ethyl acetate gradient (100:0 to 96:4) to give an oil which solidified upon standing. The oil was dissolved in dichloromethane and the solution was concentrated to give 1.48 (64%) of 5-(methyloxy)-l-benzothiophene as an oil which solidified to a white solid. 1H NMR (400 MHz, CDCl3): delta 7.73 (d, J = 9 Hz, IH), 7.44 (d, J = 5 Hz, IH), 7.27 (m, 2H), 7.00 (dd, J = 9, 2 Hz, IH), 3.87 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 62% | To a pre-dried flask equipped with a condenser is added magnesium (568 mg, 23.4 mmol) and Et20 (5 mL). To this is ADDED-1/10 OF a solution of iodomethane (1.66 g, 11.7 mmol) and 5-bromo-benzo [b] thiophene (500 mg, 2.34 mmol) in Et20 (8 mL). After adding 2-3 crystals of iodine, the reaction mixture is heated to reflux using a hot water bath. After a few minutes the iodine coloration fades and another portion (-0. 5 mL) of the IODOMETHANE/5-BROMO-BENZO [b] thiophene solution is added. The water bath is removed and further additions (-0. 5 mL) are added such that reflux is sustained. After complete addition, reflux is maintained for 30 min using a hot water bath. The Grignard solution is then cooled TO 0 C and 3-pentanone (1.20 g, 14.0 mmol) is added dropwise. After 30 min, the ice is removed and the reaction mixture is stirred for 2 h. After cooling to 0 C9 the reaction is quenched with H20 (10 mL) and saturated aqueous NH4C1 (15 mL) and is diluted with Et2O (100 mL). The organic layer is washed with brine (35 ML) dried (MGS04), FILTERED and concentrated. The reaction residue is subjected to flash chromatography (silica gel, 90: 10 petroleum ETHER/ET2O) to afford impure sub-title compound (-500 mg). Most of the impurity is removed under high vacuum (-2 d) to yield slightly impure sub-title compound (323 MG, 62#x0025;). RF 0. 43 (4: 1 Hex/EtOAc). 1H NMR (300 MHZ, CDCL3) # 0.77 (T, J = 7.4 HZ, 6H), 1.70 (S, 1H), 1.80-1.98 (SYM M, 4H), 7.32 (d, J= 5.4 Hz, 1H), 7.34 (dd, J= 1. 6,8. 5 Hz, 1H), 7.42 (d, J= 5.4 Hz, 1H), 7.82 (d, J=8. 5HZ, LH), 7.87 (d, J=1. 6 HZ, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With palladium diacetate; sodium t-butanolate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In toluene; at 70℃; for 0.5h;Inert atmosphere; | To a solution of 5-bromobenzothiophene (12, 11.5 g, 45.1 mmol) in toluene (150 mL) under argon was added palladium acetate (0.84 g, 3.75 mmol), P(iBuNCH2CH2)3N (2.6 g, 7.6 mmol), and sodium tert-butoxide (5.4 g, 56.3 mmol). The reaction mixture was stirred for 2 min at room temperature, and then 7-bromodihydroisoquinolinone (11, 9.0 g, 37.5 mmol) was added. The resultant solution was heated at 70 C for 30 min, and then it was cooled to room temperature. The reaction was quenched with aqueous ammonium chloride and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue obtained was purified by flash column chromatography (eluent: 80/20 dichloromethane/EtOAc) to give the desired 4-(5-benzothiophen-yl)dihydroisoquinolinone (13, 8.84 g, 63%) as a light yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate; In ethanol; at 85℃; for 16h;Inert atmosphere; | General procedure: A 10-mL Schlenk tube was charged with Pd(OAc)2 (1.7 mg, 0.0075 mmol, 3.0 mol %), SPhos (6.2 mg, 0.015 mmol, 6.0 mol %), Na2CO3 (53.0 mg, 0.50 mmol, 2.0 equiv), potassium 6-fluoropyridine-2-trifluoroborate (101.5 mg, 0.50 mmol, 2.0 equiv) and heteroaryl halides (0.25 mmol, 1.0 equiv), followed by the addition of ethanol (2.0 ml). The reaction was carried out at 85 C for 16 h under the protection of nitrogen gas. Then, the reaction mixture was allowed to cool down to room temperature and the reaction solution was filtered through a thin pad of silica gel (eluting with ethyl acetate) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate/hexane=1:2-1:80). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | j00348j To a solution of 5-bromobenzo[bjthiophene (2.0 g, 9.4 mmol) in tetrahydrofuran (20 mL)at -70C under nitrogen was added dropwise lithium diisopropylamide (2 M in tetrahydrofuran, 5.6mL, 11 mmol). The solution was stirred at -70C for 1 hour, and then iodomethane (2.0 g, 14mmol) was added. The resulting solution was stirred at -70C for 2 hours and at room temperature foranother 13 hours, then poured into 5% hydrochloric acid (100 mL) and extracted with ethyl acetate (2x 100 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2 x 30 mL)and concentrated in vacuo. The residue was purified by flash column chramotagraphy [100%petroleum etherj to give compound B-38 (1.9 g, 89% yield) as a white solid. 1H-NMR (CDC13, 400MHz): 7.80 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.36 (dd, J18.4 Hz, J21.6 Hz, 1H), 6.93 (s,1H), 2.61 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In a four-necked 300 mL round bottomed flask, <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (10.8 g, 50.7 mmol) was dissolved in anhydrous THF (120 mL). The reaction solution was cooled at -78 C. A 1.08M lithium diisopropylamide/hexane solution (56.0 mL, 60.5 mmol, 1.2 eq.) was added thereto, and the mixture solution was allowed to warm to 0 C. and stirred for an hour. After the reaction solution was cooled to -78 C. again, 1-iodo octane (18.0 mL, 99.7 mmol, 2.0 eq.) was added. Then, the mixture was allowed to warm to room temperature, and stirred at room temperature for a day. After completion of the reaction, water and ethyl acetate were added. An organic phase was extracted with ethyl acetate, and dried over magnesium sulfate. The resulting crude product was purified by column chromatography, whereby intermediate B1 was obtained (16.5 g, yield 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.9% | With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In diethyl ether; at 20℃; for 12h;Inert atmosphere; | The air in the flask was replaced with nitrogen. 5-bromobenzo [b] thiophene (10.44 g, 49.0 mmol) and Ni (dppp) Cl 2 (1.27 g, 2.33 mmol) were placed in the flask and 200 mL of diethyl ether was added.Thereafter, a 2.0 M solution of octyl magnesium bromide in diethyl ether (35.25 mL, 70.5 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours.Water was added to the obtained solution, and the mixture was extracted with hexane. The organic phase was dried by adding sodium sulfate.The hydrate of sodium sulfate was filtered, the filtrate was collected, and the solvent was distilled off from the filtrate using an evaporator.The obtained material was purified by column chromatography (silica gel, developing solvent: hexane) to obtain Compound 1 as a black liquid (yield = 10.0 g, 82.9%). |
62% | dichloro(diphenylphosphinopropyne)nickel; In tetrahydrofuran; at 20℃; for 24h; | In a 300 mL round bottomed flask, <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (5.6 g, 26 mmol) and dichloro(diphenylphosphinopropyne)nickel (0.54 g, 1.0 mol, 4 mol %) were dissolved in anhydrous THF (50 mL). A 1.0M octylmagnesium bromide solution (31 mL, 31 mmol, 1.2 eq.) was added thereto, and the mixture solution was stirred at room temperature for one day. After the completion of the reaction, hydrochloric acid and toluene were added, and an organic phase was extracted with toluene, and dried over sodium sulfate. The resulting crude product was purified by column chromatography, whereby intermediate C1 was obtained (4.1 g, yield 62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | n-Butyl lithium (0.64ml, 1.2 mmol) was added drop wise to a solution of diisopropyl amine (0.25 mL, 1.5 mmol) in dry THF at -78C under nitrogen atmosphere over a period of 5 minutes. The reaction mixture was stirred at -20C for 30 minutes. To this was added <strong>[4923-87-9]5-bromo-benzo[b]thiophene</strong> (200mg, 0.938 mmol) in dry THF at -78C, continued stirring for a further 30 minutes at -78C, followed by the addition of N-chlorosuccinamide (225mg, 1.68mmol) in dry THF at -78C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was dried over sodium sulfate and concentrated to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 70mg of the product (30%> yield).1H NMR (CDC13, 300 MHz): 87.815-7.811 (d, IH), 7.57-7.55 (d, IH), 7.44- 7.41 (dd, IH), 7.12 (s, IH). | |
[000887] To a mixture of LDA (2 N, 8.3 mL, 16.5 mmol) in tetrahydrofuran (10 mL) under nitrogen was added Compound 225A (3.2 g, 15.0 mmol) in tetrahydrofuran (5 mL) slowly at -78 C. It was stirred at -78 C for 1 h, and the mixture was added to a solution of carbon tetrachloride (5.5 mL, 56.6 mmol) in tetrahydrofuran (15 mL) at -78 C. The resultant mixture was stirred at -78 C for 1.5 h, quenched with ammonium chloride solution (50 mL), warmed to room temperature, and extracted with DCM (100 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to furnish Compound 225B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With [1,1?-biphenyl]-2-yldiphenylphosphane; ammonium acetate; ammonium formate; palladium diacetate; caesium carbonate; In tert-Amyl alcohol; at 90℃; for 4h;Inert atmosphere; Schlenk technique; | General procedure: Under an argon atmosphere, Pd(OAc)2 (3.3 mg, 0.015 mmol, 5 mol%),ligand [1,1?-biphenyl]-2-yldiphenylphosphane (15 mg, 0.045 mmol,15 mol%), HCO2NH4 (23 mg, 0.36 mmol), MeCO2NH4 (35 mg, 0.45mmol), benzopheneone N-tosylhydrazone 5a (126 mg, 0.36 mmol),and Cs2CO3 (195 mg, 0.6 mmol) were successively added to a flamedried flamedried25 mL Schlenk flask. The reaction flask was degassed threetimes with argon and anhyd tert-pentyl alcohol (3.0 mL) was addedusing a syringe. Then 1-bromo-4-(tert-butyl)benzene (2b; 64 mg, 0.3mmol) was added with a syringe. Note that the aryl bromide in a solidform was added to the reaction flask prior to Cs2CO3. The reactionwas heated at 90 C with stirring for about 4 h, then it was cooled tor.t., and filtered through a short pad of neutral alumina with EtOAc(25 mL) as eluent. Solvent was then removed in vacuo to leave a crudemixture, which was purified by silica gel column chromatography(eluent: PE); yellow solid (82 mg, 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 24h; | <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (3.0 g, 14.08 mmol) and 4-hydroxyphenylboronic acid (2.91 g, 21.11 mmol) were dissolved in DME 40 mL. Water 10 mL was added thereto. Pd(dbpf)Cl2 (459 mg, 0.70 mmol) and Cs2CO3 (13.68 g, 42.24 mmol) were added thereto, and refluxed with heating at 90 C for a day. The reaction mixture was filtered through Celite. The obtained filtrate was extracted with EtOAc three times, dried over MgSO4, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (15-20 % EtOAc/hexane) to yield the title compound as white solid (2.30 g, 72%). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 24h; | <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (3.0 g, 14.08 mmol) and 4-hydroxyphenylboronic acid (2.91 g, 21.11 mmol) were dissolved in DME 40 mL. Water 10 mL was added thereto. Pd(dbpf)Cl2 (459 mg, 0.70 mmol) and Cs2CO3 (13.68 g, 42.24 mmol) were added thereto, and refluxed with heating at 90 C. for a day. The reaction mixture was filtered through Celite. The obtained filtrate was extracted with EtOAc three times, dried over MgSO4, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (15-20% EtOAchexane) to yield the title compound as white solid (2.30 g, 72%) |
With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere; | General procedure: A mixture of compound 2a,b (1.17 mmol), 4-hydroxyphenylboronicacid (3, 1.45 mmol, 200 mg), cesium carbonate (2.34 mmol, 0.763 g),and dichloro-[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium (0.059 mmol, 0.038 g) in a mixture of dimethoxyethane(15 mL) and distilled water (10 mL) was flushed with nitrogen andheated at 90 C under nitrogen overnight. Once the reaction completionwas confirmed using TLC, the reaction mixture was evaporated invacuo, and the residue was partitioned between water (20 mL) andethyl acetate (3×20 mL). The combined organic layer extracts weredried over anhydrous sodium sulfate and evaporated in vacuo to dryness.They were used as such in the next steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In tetrahydrofuran; at 60℃; | To a solution of<strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (10.0 g, 47 mmol) and 1-octyne (6.20 g, 56 mmol) in dryTHF (80 mL) were added Pd(PPh3)4 (2.7 g, 2.3 mmol), copper(I) iodide (0.45 g, 2.4mmol), and triethylamine (15 mL). The mixture was stirred overnight at 60 C.After cooling to room temperature, the reaction mixture was poured into a large amountof water, and then extracted with hexane. The combined organic layers were washedwith water, and dried over anhydrous MgSO4. After filtration and evaporation, theproduct was purified by silica gel column chromatography (eluent: hexane), and driedunder vacuum to give 6 as a yellow oil (yield = 6.60 g, 58%). 1H NMR (500 MHz,CDCl3): 7.87 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H),7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.28 (d, J = 5.0 Hz, 1H), 2.43 (t, J = 7.0 Hz, 2 H),1.66-1.53 (m, 2H) , 1.51-1.44 (m, 2H), 1.37-1.31 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H).13C{1H} NMR (125 MHz, CDCl3): 139.64, 138.96, 127.59, 127.12, 126.79, 123.66,122.29, 120.20, 90.02, 80.89, 31.52, 28.93, 28.77, 22.71, 19.60, 14.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 1 h / 120 °C / Inert atmosphere 2: lithium hydroxide; water / 2 h / 120 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 0 °C / Inert atmosphere 4: manganese(IV) oxide / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide;Reflux; | Add <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (0601-38) (2.13 g, 10 mmol, 1.0 eq.) to the reaction flask.Zinc cyanide (2.34 g, 20 mmol, 2.0 eq.),Tetrakistriphenylphosphine palladium (1.16 g, 1 mmol, 0.1 eq.) and dimethylformamide (16 ml),The reaction was stirred at reflux overnight.The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1)The white solid product benzo[b]thiophene-5-carbonitrile (1.57 g, yield: 99%) was obtained. |
82% | With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 7h;Inert atmosphere; Sealed tube; | Nitrogen gas was bubbled through a mixture of <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (510 mg, 2.34 mmol) and zinc cyanide (299 mg, 2.49 mmol) in dry DMF (3 mL) for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (153 mg, 0.13 mmol) was added, the tube sealed and the mixture stirred at 90C for 7h. The reaction mixture was filtered over Celite, and the filtrate was extracted using AcOEt and NaHCO3. |
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere; | A solution of <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (LXVII) (1.2 g, 6 mmol), zinc cyanide (0.66 g, 6 mmol) and tetrakis(triphenylphosphorus)palladium (0) (0.65 g, 0.6 mmol) in dry DMF (10 mL) was stirred at reflux under nitrogen atmosphere for 1 h. The mixture was poured into cold water and extracted with EtOAc (3×). The combined organic layers were concentrated in vacuum to give the crude benzo[b]thiophene-5-carbonitrile (LXVIII) as a white solid. (0.90 g, 6 mmol, 100%) ESIMS found C9H5NS m/z 160.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 100℃;Reflux; | A solution of <strong>[4923-87-9]5-bromo-1-benzothiophene</strong> (2 g, 9.385 mmol), phenylboronic acid (1.2 g, 9.841 mmol), Pd(PPh3)4, (544 g, 0.471 mmol), potassium carbonate (1.9 g, 13.747 mmol) in toluene and water (20+20 mL) mixture was refluxed at 100C for overnight. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, filtered through a Celite bed, and washed with ethyl acetate. The combined filtrate was washed with water and brine. The organic layer was dried over sodium sulfate and concentrate under reduced pressure to give residue which was purified by column chromatography using hexane as eluent on silica gel to afford 5-phenyl-1-benzothiophene (1.7 g, 8.084 mmol, 86%) as white solid. ?H-NMR (400 MHz, CDC13): oe 7.95 (d, J=l.5 Hz, 1H), 7.86 (dd, J?=8.5 Hz, J?0.7 Hz, 1H), 7.60-7.58 (m, 2H), 7.52 (dd, J?=8.3 Hz, J?=1.7 Hz, 1H), 7.41-7.37 (m, 3H), 7.32-7.27 (m, 2H). |
67% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 70℃; for 6h;Inert atmosphere; | In DMF (500 parts), <strong>[4923-87-9]5-bromobenzo[b]thiophene</strong> (20 parts), phenylboronic acid (13.7 parts),Tripotassium phosphate (113 parts) and hydrazine (triphenylphosphine) palladium (3.0 parts) were mixed, and stirred at 70 C for 6 hours under a nitrogen atmosphere.After cooling the obtained reaction liquid to room temperature, water (500 parts) was added, and the solid fraction was separated by filtration.The obtained solid fraction was dried by washing with water and acetone to obtain 5-phenylbenzo[b]thiophene (13.3 parts, yield 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; XPhos; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; | General procedure: A solution of 4-methoxybromobenzene (2.67 mmol)and cyclopent-2-en-1-one (3.2 mmol) in DMSO was stirred at ambient temperaturefor 10 min under nitrogen, and treated with Na2CO3 (8.01mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.53 mmol).The reaction mixture was degassed with nitrogen for 10 min and treated withPd(PPh3)2Cl2 (0.13 mmol) and X-Phos (0.26mol), and stirred at 100 0C for 12 h. The reaction mixture was cooledto ambient temperature, diluted with water, and extracted with AcOEt (3 x 50ml). The combined organic layers were washed with brine, dried over anhydrousNa2SO4, and evaporated. Flash chromatograph on silica gel(AcOEt:cyclohexane 1:3) provided the Heck coupling product as brown solid (340mg, 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-pyrrolidin-2-one; 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; sodium carbonate at 120℃; for 12h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With trifluorormethanesulfonic acid; C24H36N2O2Pd*2C2H4O2; cesium trifluoroacetate; trifluoroacetic acid; p-benzoquinone; silver(l) oxide; In water; at 50℃; for 20h; | General procedure: To a 10 mL round-bottom flask were added Cat.III (3.2 mg, 0.005 mmol, 2 mol %), Ag2O (116 mg, 0.5 mmol, 2 equiv), benzoquinone (14 mg, 0.125 mmol, 0.5 equiv), Cs(tfa) (64 mg, 0.25 mmol, 1 equiv.), benzothiophene/benzofurans (0.25 mmol, 1 equiv), aryl MIDA boronate ( 0.375 mmol, 1.5 equiv), and 15% H2O and 2% CF3SO3H of TFA (1 mL). The reaction mixture was stirred at 30-50 C for 20 h. The suspension was cooled to room temperature and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with 20% aqueous NaHCO3 solution (40 mL). After evaporation of the solvent the crude product was purified by chromatography on silica gel to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With pyridine; In N,N-dimethyl-formamide; at 170℃; for 10h;Sealed tube; | To a stirred solution of compound A (500 mg, 2.35 mmol, 1 eq) in DMF (7 mL) in a sealed tube were added CuCN (273 mg, 3.05 mmol, 1.3 eq) and pyridine (0.25 mL) respectively. The resulting mixture was degassed with argon for 30 minutes and stirred for 10 h at 170 C. The reaction mixture was cooled to RT and quenched with a solution of ethylene diamine (0.25 mL) in water (6 mL) and the organic components were extracted with ethyl acetate (60 ml). The organic layer was concentrated in vacuo and the crude material was purified by flash chromatography (Combiflash) using 100-200 mesh silica gel eluting with 10% ethyl acetate/ hexane to obtain the compound B (200 mg, 54%) as off white solid. [0341] FontWeight="Bold" FontSize="10" H NMR (400 MHz, OMSO-d6) delta 8.43 (s, 1 H), 8.26 (d, / = 8 Hz, 1 H), 7.99 (2, / (0350) = 8 Hz, 1 H), 7.73-7.71 (m, 1 H), 7.58 (d, / = 6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | (C) To a solution of <strong>[4923-87-9]5-bromo-1-benzothiophene</strong> (12 g, 56.31 mmol) in dry THF (300 mL) under an inert atmosphere was added isopropyl magnesium chloride- lithium chloride complex (1.3 M in THF; 150 mL, 195 mmol) in drop-wise fashion, and the resultant solution was stirred at rt, overnight. DMF (30 mL) was then added in drop-wise fashion and the resultant solution was stirred at rt for 30 min. Water (500 mL) was added and the resulting solution was extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were concentrated under reduced pressure and the resultant residue was purified by silica gel chromatography (0-2% EtOAC/ petroleum ether) to provide benzo[b]thiophene-5-carbaldehyde (6.9 g, 68 %) as a yellow solid. 1H NMR (DMSO-d6) G 10.12 (s, 1H), 8.32 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.86 - 7.89 (m, 1H), 7.57 - 7.61 (m, 1H), 7.47 - 7.50 (m, 1H). | |
68% | With TurboGrignard; In tetrahydrofuran; at 20℃;Inert atmosphere; | (C) To a solution of <strong>[4923-87-9]5-bromo-1-benzothiophene</strong> (12 g, 56.31 mmol) in dry THF (300 mL) under an inert atmosphere was added isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF; 150 mL, 195 mmol) in drop-wise fashion, and the resultant solution was stirred at rt, overnight. DMF (30 mL) was then added in drop-wise fashion and the resultant solution was stirred at rt for 30 min. Water (500 mL) was added and the resulting solution was extracted with ethyl acetate (3*500 mL). The combined organic extracts were concentrated under reduced pressure and the resultant residue was purified by silica gel chromatography (0-2% EtOAC/petroleum ether) to provide benzo[b]thiophene-5-carbaldehyde (6.9 g, 68%) as a yellow solid. 1H NMR (DMSO-d6) delta 10.12 (s, 1H), 8.32 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.86-7.89 (m, 1H), 7.57-7.61 (m, 1H), 7.47-7.50 (m, 1H). |
68% | To the stirring solution of compoundS2(12.0 g, 56.3 mmol) in THF (300 mL) was added isopropylmagnesium chloride (150 mL, 1.3 M in THF) drop wise at 0oC under nitrogen. The resulting mixture was stirred at rt overnight. To the reaction mixture was addedN,N-dimethylformamide (30.0 mL) drop wise. The resulting solution was stirred for 30 min at rt. The reaction was then quenched by the addition of H2O (500 mL). The mixture was extracted with ethyl acetate (3 x 500 mL), and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column, eluting with ethyl acetate/petroleum ether (1:50 v/v). CompoundS2was obtained as a yellow solid (6.90 g, 68 % yield).1H NMR (400 MHz, Chloroform-d) delta 10.07 (s, 1H), 8.25 (s, 1H), 7.95 (d,J= 8.6 Hz, 1H), 7.83 (d,J= 8.6 Hz, 1H), 7.53 (d,J= 5.1 Hz, 1H), 7.43 (d,J= 6.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyridine In N,N-dimethyl-formamide at 165℃; for 22h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); lithium carbonate; In N,N-dimethyl acetamide; at 160℃; for 24h;Molecular sieve; Inert atmosphere; | General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added <strong>[2164-61-6]pyridazine-3-carboxylic acid</strong> (0.6 mmol, 1.0 eq), aryl- and heteroaryl-bromides (1.2 mmol, 2.0 eq), Pd(PPh3)4 (35 mg, 0.03 mmol, 5.0 mol %), Cu2O (84 mg, 0.6 mmol, 1.0 eq), Li2CO3 (107 mg, 1.8 mmol, 3.0 eq), 3A MS (200 mg) and DMA (4.0 mL). The mixture was stirred at 160 C for 24 h under N2. After the reaction was complete, the mixture was washed with brine and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/1), the eluent need bubbled NH3 five seconds. The eluent of TLC (ethyl acetate / petroleum ether 1:1) need bubbled NH3 two seconds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With palladium diacetate; caesium carbonate; tricyclohexylphosphine tetrafluoroborate; In isopropyl alcohol; toluene; at 80℃; for 12h;Inert atmosphere; Schlenk technique; | General procedure: Under an argon atmosphere, Pd(OAc)2 (3.3 mg, 0.015 mmol, 5 mol%),PCy3·HBF4 (22.1 mg, 0.06 mmol, 20 mol%), benzaldehyde N-tosylhydrazone1a (99 mg, 0.36 mmol), 4-bromo-1,1?-biphenyl (2a; 70 mg,0.3 mmol), and Cs2CO3 (195 mg, 0.6 mmol) were successively addedto a flame-dried 25 mL Schlenk flask. The reaction flask was degassedthree times with argon. Then anhyd toluene (2.7 mL) and i-PrOH (0.3mL) were added with a syringe. Note that the aryl bromide in oil formwas added to the reaction flask prior to i-PrOH. The reaction washeated at 80 C with stirring for about 12 h, then it was cooled to r.t.,and filtered through a short pad of neutral alumina with EtOAc (25mL) as eluent. Solvent was then removed in vacuo to leave a crudemixture, which was purified by silica gel column chromatography(eluent: PE) to give 3a3d as a white solid (59 mg, 80%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Stage #1: 5-bromobenzo[b]thiophene; 4-(piperazin-1-yl)benzoic acid With caesium carbonate; ruphos In tetrahydrofuran for 0.5h; Inert atmosphere; Sonication; Sealed tube; Stage #2: With chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butyl ether adduct In tetrahydrofuran at 70℃; for 40h; | 83 4-[4-(1-benzothiophen-5-yl)piperazin-1-yl]benzoic acid A sealed tube was charged with 5-bromo-1-benzothiophene (147.55 μL, 1.03 mmol), 4-(piperazin-1-yJ)benzoic acid (255.51 mg, 1.24 mmol), RuPhos (24.09 mg, 0.05 mmol), CS2CO3 (198.26 μL, 2.48 mmol) and anhydrous THF (7 ml). The reaction mixture was degassed by bubbling nitrogen with sonication for 30 min, prior to adding RuPhos Precatalyst (42.17 mg, 0.05 mmol) and the reaction mixture stirred at 70°C for 40 h. The mixture was allowed to cool to rt and the precipitate filtered and washes with water. The solid was triturated with heptane and DCM, and then filtered to give the title compound 0.07 g (17%) as a white solid. METCR1673 (Generic 2 minute, low pH), m/z (ES+) 250, Retention time 1.41 min. 1H NMR (500 MHz, DMSO-d6) δ 7.10 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 5.4 Hz, 1 H), 6.65 (d, J = 2.2 Hz, 1H), 6.49 (d, J = 5.4 Hz, 1H), 6.40 (dd, J = 8.8, 2.3 Hz, 1H), 6.20 (d, J = 8.8 Hz, 2H), 2.70 - 2.63 (m, 4H), 2.58 - 2.55 (m, 4H), 2.43 - 2.40 (m, 1H), 2.19 - 2.16 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: ruphos; caesium carbonate / tetrahydrofuran / 0.5 h / Inert atmosphere; Sonication; Sealed tube 1.2: 40 h / 70 °C 2.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,4-dioxane; for 5h;Heating; | 5-bromobenzo-thiophene (1 eq.) was dissolved in 1,4-dioxane, (4,4,5,5-tetramethyl-2- (2-nitrophenyl) -1,3,2-dioxaborolane, 2eq.)Followed by the addition of CsF (2eq.), Pd(PPh3)4 (0.05eq.), and the mixture was heated for 5 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane and H2O.The extract was separated and purified by column chromatography to obtain Compound 1-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2 mg | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 140℃; for 24h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,70.1 mg (0.2 mmol) of 2-dicyclohexylphosphine biphenyl (<strong>[247940-06-3]CyJohnPhos</strong>)(1,5-cyclooctadiene) chlorineRhodium (I) dimer 5 mg (5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.5-bromobenzothiophene (102.3 mg, 0.48 mmol).After stirring at 140 C for 24 hours, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The solvent was separated on a 200-300 mesh silica gel column. The petroleum ether: ethyl acetate = 100: 1The product was eluted and dried in vacuo to give 49.2 mg of product as a white solid with a gas chromatographic purity of 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With palladium diacetate; copper(II) trifluoroacetate; In N,N-dimethyl-formamide; at 120℃; for 24h;Sealed tube; | General procedure: Aryl halide (0.5 mmol), alpha-Iminonitrile (0.6 mmol), Cu(TFA)2 (1.0 mmol), Pd(OAc)2(0.1 mmol) and 2ml DMF were added into a 15 ml sealed tube with a magneticstirring bar. Stirred under air at 120C for 24 h. Monitor the reaction by TLC. Themixture was poured into water (10 ml) and extracted by ethyl acetate (3×10 ml).Dried by Na2SO4 and evaporated. Finally, pure the mixture by silica gel column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With copper(I) oxide; 2,6-bis(2-methylhydrazine-1-carbonyl)pyridine 1-oxide; tetrabutylammomium bromide; sodium hydroxide; In water; at 130℃; for 24h;Schlenk technique; | General procedure: A 25mL Schlenk tube was charged with Cu2O(0.05mmol),ArX (0.5mmol), NHR1R2(0.75mmol), NaOH (1mmol),TBAB (0.1mmol), L1 (0.1mmol) and water (1mL). Themixture was stirred at 130C for 24h. The reaction mixturewas extracted with ethyl acetate (3 × 10mL), washed withwater and brine, dried over anhydrous Na2SO4,and concentratedin vacuo. The residue was purified by flash columnchromatograph on silica gel (ethyl acetate/petroleum etheras the eluent) to provide the target products 3a-3w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -72 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: HATU; triethylamine / 4 h / 20 °C | ||
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 7 h / 90 °C / Inert atmosphere; Sealed tube 2: water; potassium hydroxide / methanol / 36 h / 80 °C 3: hydrogenchloride / 24 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Under nitrogen protection,In a round bottom flask,5-bromobenzothiophene (0301-7) (1.0 g, 4.69 mmol, 1.0 equiv) was added and35 ml of anhydrous tetrahydrofuran,Cool in a dry ice-ethanol bath to -72C,A 2.5 M solution of n-butyllithium tetrahydrofuran (2.8 mL, 7.04 mmol, 1.5 equivalents) was added dropwise.Stir for one hour and add carbon dioxide.The reaction was stirred for 1 hour.Aqueous 2M hydrochloric acid was added dropwise until the pH of the aqueous phase was 1, ethyl acetate was added for extraction, and the organic phase was dried over anhydrous sodium sulfate.concentrate,The yellow solid benzo[b]thiophene-5-carboxylic acid (924 mg, crude) was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; for 2h; | To a solution of 5-bromobenzo [b] thiophene (8.5 g, 40 mmoL) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (10.6 g, 40 mmol), Pd (dppf) Cl2 (4.4 g, 6 mmol) and Cs2CO3 (19.5 g, 60 mmol) and the mixture was heated at 80 for 2 hours. Then filter off the solid, the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (PE: EA=25: 1) to give product as yellow solid (6.6 g in 61% yield). 1HNMR (400 MHz, DMSO-d6) deltaH 7.92 (d, J= 8.8 Hz, 1H), 7.89 (s, 1H), 7.74 (d, J= 5.2 Hz, 1H), 7.46 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 6.09 (t, J = 3.6 Hz 1H), 3.93 (s, 4H), 2.63 (t, J= 5.6 Hz, 2H), 2.40 (s, 2H), and 1.85 (t, J= 6.4 Hz, 2H). [M+H] += 273.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: The appropriate Grignard reagent (1.3 equiv) generated according to GP 1 was added to ketone 15 (1.0 equiv) suspended in THF (2mL/mmol) and heated to 60C for 2h. At 25C the mixture was quenched with saturated aqueous NH4Cl solution and extracted with Et2O. The organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by recrystallization or by column chromatography over silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | To a 50 mL three-necked flask were added 5.17 mL (32 mmol) of 2-ethylhexan-1-amine, 4.50 mg (21 mmol) of 5-bromobenzo [b] thiophene, 31.17 g (8.5 mmol) of K 2 CO 3, 0.730 g mmol), 10 mL of DMSO was added, and the oil bath was set at 40 C. After N2 bubbling was carried out for 60 minutes, 0.807 g (4.3 mmol) of CuI,And then the oil bath was heated at 130 C. and stirred. The color change of the solution during that time was blue ? purple ? navy blue. After 68 hours,The mixture was poured into a separatory funnel with 100 mL of ethyl acetate,Wash the solution five times with saturated brine (100 mL), extract the origin with 100 mL of silica gel, dry the organic layer with magnesium sulfate,The solvent was removed under reduced pressure to obtain a yellow viscous substance.Thereafter, using 350 mL of silica gel, using hexane: toluene = 1: 1 as a developing solvent,Purification by column chromatography (Rf = 2.8) gave 3.0 g of the desired product. Yield 3.0 g(Yield 55%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | General procedure: To a solution in THF (4 mL) of DIPAB (863 mg, 7.5 mmol) and Mg (182 mg, 7.5 mmol) were added a PhMgBr 1M THF solution (375 muL, 375mumol) at room temperature. After 10 min, 30 mL of anhydrous THF were added followed by the arylbromide (5 mmol). The reaction mixture was cooled down to 0 C and quenched slowly with 7 mL of MeOH. After 1h, volatile were removed under reduced pressure and the resulting solid was dissolved in 1N HCl/MeOH (7/3). After 1h at room temperature, 100 mL of AcOEt were added, the organic phase was washed with 1N HCl (30 mL) and brine (3×30 mL). Organic phases were concentrated under reduced pressure yielding a solid which was recrystallized from H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.84% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene; for 3h;Inert atmosphere; Reflux; | Compound 13 in the reaction vessel(4,4,5,5-tetramethyl-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3,2-dioxaborolane , 20.0 g, 65.75 mmol) and Compound 32 (5-bromobenzo[b]thiophene, 15.41 g, 72.32 mmol) were added toluene (200 mL)In a mixed solution with methanol (20 ml),Additional CsCO3 (42.85 g, 231.5 mmol) was added.Pd(PPh3)4 (3.80 g, 3.288 mmol) was added to the reaction solution.Stir at reflux for 3 hours. The reaction was terminated by the addition of a saturated ammonium chloride solution.The reaction was cooled to room temperature and filtered through Celite using ethyl acetate.After the filtered solution is washed with salt water,It was dried over anhydrous sodium sulfate and filtered and evaporated.The concentrate was subjected to silica gel column chromatography (hexane:EtOAc = 10:1)Purification to give a white solid compound 33(14.05 g, yield 68.84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With 1,10-Phenanthroline; hexakis(acetonitrile)nickel(II) tetrafluoroborate; 2,3,5,6-tetramethyl-1,4-bis(trimethylsilyl)-1,4-diaza-2,5-cyclo-hexadiene at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With nickel(II) iodide; N,N,N,N,-tetramethylethylenediamine; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; under 12929.0 Torr; for 24h;Schlenk technique; Sealed tube; Irradiation; | General procedure: Aryl-halide (0.2 mmol, 1 equiv.), Ir(dtbbpy)(ppy)2PF6 (1.8 mg, 0.002 mmol, 1 mol %), NiI2 (3.1 mg, 0.01mmol, 5 mol %), DMSO (2.0 mL) was added to a 10 mL schlenk flask equipped with a magnetic stirrerbar. This resulting mixture was sealed and degassed via vacuum evacuation and subsequent backfill with ethylene for three times. Then, N,N,N?,N?-tetramethylethylenediamine, TMEDA (60 muL, 2 equiv.)and N,N-diisopropylethylamine, DIPEA (70 muL, 2 equiv.) were subsequently added in this order. The solution was gently bubbled with ethylene balloon for approximately 30 seconds. The solution was then taken up into a 8 mL stainless steel syringe pre-purged with argon, and quickly assembled onto thestop-flow micro tubing, SFMT setup. Solution was pumped into the SFMT at 400 muL/min while maintaining approximately 1:1 gas-liquid slug flow at 250 PSI. Filled SFMT was then irradiated with blueLED (2 meter strip, 18 W) in a 100oC oil bath for 24 hours. The SFMT was wash with DCM (8 mL) and subjected to GC analysis (Figure S5). Then water (30 mL) was added to reaction mixture and extracted with DCM (10 mL) three times. Combined organic layer was successively wash with brine three timesand dried over Na2SO4 and concentrated under reduced pressure. The residue was then subjected to flash column chromatography to yield the product as a mixture of meso/dl isomers (which could not be separated by column chromatography). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 5-bromobenzo[b]thiophene; carbon dioxide With 18-crown-6 ether; cesium fluoride; lithium tert-butoxide at 160℃; for 3h; Inert atmosphere; Sealed tube; Stage #2: methyl iodide at 60℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With [2,2]bipyridinyl; aluminum (III) chloride; nickel(II) acetylacetonate; zinc(II) oxide In 1,2-dimethoxyethane at 145℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: A mixture of magnesium (288 mg, 12 mmol) and aryl bromide (15.6 mmol) was reacted in dry tetrahydrofuran under reflux for 30 minutes. Then, a solution of 2-aminobenzonitrile (708 mg, 6.0 mmol) in dry tetrahydrofuran (8 mL) was added slowly. After a refluxed period (2 h), methyl chloroformate (977 mg, 9.0 mol) was added dropwise at 0 C, and the resulting mixture was refluxed for 14 h. The mixture was cooled to ambient temperature and poured into a hydrochloric acid solution (2 M). The mixture was neutralized with 10% sodium bicarbonate aqueous solution and extracted with dichloromethane (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo. The residue obtained was purified by flash column chromatography using dichloromethane/methanol as eluent to achieve the product. 4-(benzo[b]thiophen-5-yl)quinazolin-2(1H)-one (1m): white solid, mp: 312-313 C, 70% yield, the new compound, Rf = 0.25 (dichloromethane/methanol = 25/1); 1H NMR (400 MHz, DMSO-d6) delta 11.97 (s, 1H), 8.22 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 5.4 Hz, 1H), 7.75 (t, J = 7.8 Hz, 2H), 7.67 (dd, J = 8.4, 1.1 Hz, 1H), 7.62 (d, J = 5.4 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) delta 175.6, 155.4, 143.9, 141.5, 139.7, 135.6, 133.2, 129.4, 129.1, 125.5, 125.2, 125.0, 123.2, 122.9, 116.0, 114.8. HRMS (ESI) m/z Calculated for C16H10N2OS [M+H]+ 279.0587, found 279.0584. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 48h;Inert atmosphere; | To the reaction flask was added 1,1,2,2-tetraborate ethylene (107 mg, 0.2 mmol), 5-bromobenzothiophene (205 mg, 0.96 mmol), [1,1'-bis (under nitrogen). Diphenylphosphino)ferrocene]palladium dichloride (7.5 mg, 0.01 mmol), cesium carbonate (391 mg, 1.2 mmol), solvent dioxane (3 ml), water (40 uL). The mixed system was reacted at 70 C for 48 h. After the completion of the reaction, the reaction mixture was cooled to room temperature, and extracted with diethyl ether and water. The organic layer was combined, dried, and evaporated to dryness to give the desired product (68 mg, yield 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine; In acetonitrile; at 40℃; for 24h;Inert atmosphere; Sealed tube; | General procedure: To a solution of compound 6r (401.3 mg, 1 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), P(O-Tolyl)3 (60.9 mg, 0.2 mmol), Et3N (303.6 mg, 417 muL, 3 mmol) in ACN (10 mL) was added a solution of R2X (heteroaryl or aryl halides, X=Br, I; 1.5 mmol) in ACN (5 mL) dropwise under an argon atmosphere in a sealed tube. The mixture was stirred under an argon atmosphere at 40 C for 16-48 h. The reaction mixture was then cooled, concentrated under vacuum and re-dissolved in CH2Cl2. After filtering, the filtrate was washed with saturated NaCl aqueous solution, dried with MgSO4 and concentrated under vacuum. The crude material was purified by column chromatography (PE/EA) on silica gel to afford compound 6ra-rt.This reaction showed high stereo- and regioselectivity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With C10H8Br2N2Ni*(x)H2O; zinc In N,N-dimethyl acetamide at 80℃; for 16h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With [2,2]bipyridinyl; nickel dichloride; zinc In N,N-dimethyl acetamide at 90℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-Bromosuccinimide; acetic acid / chloroform / 6 h / 50 °C 2: palladium diacetate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate monohydrate / 1,4-dioxane / 100 °C / Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With palladium diacetate; triphenylphosphine; lithium tert-butoxide In 1,4-dioxane at 100℃; for 24h; Inert atmosphere; | 4.2. General procedure for the synthesis of 3 General procedure: To a 25 mL reaction tube equipped with a magnetic stirrer was charged with Pd(OAc)2 (1.1 mg, 2.5 mol%), PPh3 (5.2 mg,10 mol%), t-BuOLi (40 mg, 0.5 mmol), 4-bromobenzonitrile 1a (36.4 mg, 0.2 mmol), bis(phenylsulfonyl)methane 2a (59.3 mg, 0.2 mmol), and 1,4-dioxane (2 mL). The mixture was stirred at 100 οC under N2 atmosphere for 24 h. The mixture was diluted with water (5 mL) and the pH value was adjusted to about 7 with dilute hydrochloric acid solution (2 M). The mixture was extracted with CH2Cl2 (10 mL x 3). The combined organic layer was filtered through a layer of celite and concentrated under reduced pressure. The crude product was purified by flash column chromatography using petroleum ether/ethyl acetate (3:1) as eluent to afford 3a (68.3 mg, 86 %) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 5-bromobenzo[b]thiophene With sec.-butyllithium In tetrahydrofuran; cyclohexane; toluene at 25℃; for 0.0111111h; Inert atmosphere; Flow reactor; Stage #2: methoxy acetic acid dimethylamide In tetrahydrofuran; cyclohexane; toluene at -20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; ethylene glycol; triethylamine Inert atmosphere; Heating; | 1.6.1 Step 1: A round-bottom flask is charged with 6-1, palladium(II) acetate, and 1,3-bis(diphenylphosphino)propane. The flask is then evacuated and refilled with anhydrous nitrogen three times before adding ethylene glycol, triethylamine, and 6-2 via syringe. The reaction solution is then stirred with heating under nitrogen until the reaction is judged complete by TLC, HPLC, or other analytical method. Following the reaction, the mixture is cooled to room temperature, diluted with ethyl acetate, and washed three times with water. The organic layer is then dried over anhydrous Na2SO4, filtered, and concentrated to collect crude 6-3. This crude material can be taken to the next step without further purification or purified by standard techniques of the art to obtain the pure compound. |
Tags: 4923-87-9 synthesis path| 4923-87-9 SDS| 4923-87-9 COA| 4923-87-9 purity| 4923-87-9 application| 4923-87-9 NMR| 4923-87-9 COA| 4923-87-9 structure
[ 118621-30-0 ]
2-(4-Bromophenyl)-5-phenylthiophene
Similarity: 0.84
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P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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