* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl acetamide at 200℃; for 1.16667 h; Microwave irradiation
[00854] Part C. Preparation of 6-bromobenzo[Z>]thiophene.; [00855] The product from Part B (0.7Og, 2.73mmol) and DBU (1.35mL, 8.94mmol) were combined inDMA (6mL) in a sealed tube and heated at 2000C in a microwave reactor for 70min. The resulting dark solution was diluted with 1 M HCl (2OmL) and extracted with CH2Cl2 (2 x 2OmL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using CH2Cl2 as the eluent to give the title compound as an oil (0.484g 83percent).
78%
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In ISOPROPYLAMIDE at 20 - 200℃; for 1 h; Microwave irradiation Stage #2: With hydrogenchloride In ISOPROPYLAMIDE; water
DBU (1.21g, 8.00mmol) was added to a stirred solution of 6-bromo- benzo[b]thiophene-2-carboxylic acid (I-25b: 2.4g, 8.85mmol) in DMA (4mL) at room temperature and the resulting mixture was heated in microwave at 200°C for 1 hour. The reaction was monitored by TLC (50percent ethyl acetate in hexane). The reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography on silica gel (100percent hexane) to afford 320mg of the product (78percent yield).1H NMR (CDC13, 300 MHZ): δ 8.18-8.0 (d, 1H), 7.7-7.6 (d, 1H), 7.5-7.59 (d, 1H), 7.59-7.42 (d, 1H), 7.3-7.29 (d, 1H).
78%
With acetic acid; silver carbonate In dimethyl sulfoxide at 120℃; for 16 h;
A mixture 3a or 4b (0.5 mmol), Ag2CO3 (0.05 mmol), AcOH(0.025 mmol) in DMSO (1.0 mL)was stirred at 120 °C. After 16 h, thereactionwas cooled down to room temperature and quenched with1 M hydrochloric acid solution (2 mL) and the aqueous phaseextracted with ethyl acetate. The combined organic layers werewashed with brine and dried sodium sulfate, filtered, and the solventswere removed under reduced pressure to give analyticallypure 4a or 4b.
73%
at 185℃; for 2 h;
Compound 23 (3.67 g, 14.3 mmol) and copper powder (0.45 g, 7.1 mmol) were suspended in quinoline (18 mL) and heated at 185 °C for 2 h. After cooling down to rt, EtOAc (25 mL) was added and the suspension filtered. The solid was washed with further EtOAc and the combined organic solutions washed with 2 N HCl (2 × 50 mL). After drying (MgSO4), filtration and evaporation in vacuo, the residue was purified by chromatography on silica with pentane to afford the desired material (2.21 g) as a crystalline white solid. Yield: 73percent. 1H NMR (CDCl3), δ: 7.31 (dd, J = 5.4, 0.9, 1H, ArH), 7.43 (d, J = 5.4, 1H, ArH), 7.48 (dd, J = 8.4, 1.6, 1H, ArH), 7.69 (d, J = 8.6, 1H, ArH), 8.03 (d, J = 1.8, 1H, ArH).
62%
Stage #1: at 20 - 195℃; for 10 h; Stage #2: at 0 - 20℃; for 1 h;
Preparation 46 <n="38"/>6-Bromo-benzorbithiopheneCopper powder (100 g, 1.57 mol) is added to a solution of 6-bromo-benzo[b]-tbdopherie-2- earboxylie acid (1.04 Kg, 4.04 mol) in quinoline (2.5 L) at room temperature. The reaction mixture is heated to reflux (195 °C) for 1O h. The reaction mixture is cooled to room temperature and poured onto ice (2.5 Kg). Concentrated HCl (2.5 L) is added while stirring the resulting mass for Ih. The reaction mixture is extracted with hexane (4 x 3 L) and washed with dilute HCl (1 x 2 L), aqueous bicarbonate (1 x 5 L), and brine solution (1 x 5 L). The layers are separated and the organic layer is dried over sodium sulfate and concentrated to give the title compound (0.54 Kg, 62percent ) as a light yellow solid.
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 264 - 281
[2] Tetrahedron Letters, 2004, vol. 45, # 52, p. 9645 - 9647
[3] Patent: WO2009/39134, 2009, A1, . Location in patent: Page/Page column 159
[4] Patent: WO2012/149413, 2012, A1, . Location in patent: Page/Page column 59
[5] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 538 - 550
[6] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 5, p. 1284 - 1304
[7] Patent: WO2007/92751, 2007, A2, . Location in patent: Page/Page column 36-37
2
[ 737802-11-8 ]
[ 17347-32-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With boron trifluoride diethyl etherate In acetic acid at 20 - 120℃; for 0.0833333 h;
To a room temperature solution OF 6-BROMO-2, 3-dihydro-benzo [b] thiophen-3-ol (785 mg, 3.39 mmol) in HOAC (7 mL) is added boron trifluoride diethyl etherate (1. 44 G, 10.2 mmol) and the reaction mixture is placed into a 120 C oil bath. After 5 min, the reaction is cooled to room temperature and basified to-pH 11 using 2 M NaOH. The aqueous suspension is extracted with ET2O (2 X 200 mL) and the combined organic layer is dried (MGS04), filtered and concentrated to afford the sub-title compound (689 mg, 95percent) as an off-white solid. RF 0. 70 (4: 1 HEX/ETOAC). mp 48-50 C. 'H NMR (300 MHz, CDCl3) 8 7.29 (d, J= 5.4 Hz, 1H), 7.41 (d, J= 5. 4 Hz, 1H), 7.46 (dd, J= = 1. 8,8. 5 Hz, 1H), 7.66 (d, J= 8.5 Hz, 1H), 8.01 (M, 1H).
With polyphosphoric acid In 1,2-dichloro-ethane for 3 h; Reflux
A solution of compound B-197 (50 g, 0.16 mol) in 1 ,2-dichloroethane (500 mL) was added dropwise to a mixture of polyphosphoric acid (100 g) in 1 ,2-dichloroethane (500 mL) at reflux. The mixture was stirred at reflux for 3 hours. On completion, the reaction mixture was cooled to room temperature and quenched with water (200 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-198 (25 g, 72percent yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ = 215.1 , tR= 0.945.
27%
With PPA In chlorobenzene for 3.5 h; Heating / reflux
Into a mixture of polyphosphoric acid (160 g) in chlorobenzene (1 L) at reflux is added a solution of the crude 3-bromobenzenethioacetaldehyde diethyl acetal (60.06 g, 196.76 mmol) in chlorobenzene (500 mL) via an addition funnel over a 1.5 h period. Upon complete addition, the mixture is heated at reflux for an additional 2 h and is then allowed to cool to room temperature. The chlorobenzene layer is decanted from the mixture and washed with saturated aqueous NaCl (500 mL). The aqueous layer is used to dilute the PPA, which is then extracted with Et2O (3 x 500 mL). The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue is then purified by silica gel chromatography (100percent hexanes). The purified fractions are combined and concentrated under reduced pressure to give 6- bromobenzo[b]thiophene as a white crystal (11.59 g, 27percent). mp 54.8-58.3 °C. IR (KBr) 3017, 1586, 1448, 1067, 814 cm4. Ion Spray MS 211.9, 213.9 (M)+.
25%
With PPA; Polyphosphoric acid (PPA) In benzene for 6 h; Heating / reflux
Step B: Synthesis of 6-bromobenzo[δ]thiophene as an intermediate; [0183] A mixture of (3-bromophenyl)(2,2-diethoxyethyl)sulfane (3.42 g, 11.2 mmol), PPA (1.0 g), and benzene (30 mL) was refluxed for 6 h. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and filtered. Evaporation of the solvents and purification by chromatography (silica, hexanes) gave 6- bromobenzo[6]thiophene (0.607 g, 25percent) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J= 8.1 Hz, IH), 7.54-7.47 (m, 3H), 7.19 (t, J= 7.8 Hz, IH).
Stage #1: With magnesium In tetrahydrofuran for 2 h; Reflux Stage #2: at 0 - 20℃;
In a 25 mL three-necked flask, magnesium (257 mg, 10.6 mmol) was suspended in THF,(1.7 mL) and heated to reflux. A solution of 6-bromobenzo[b]thiophene (1.5 g, 7.04 mmol) in THF (8.3 mL) was added dropwise. The reaction mixture was stuffed at reflux for 2 h, thencooled to 0°C. N,N-Dimethylformamide (1.03 g, 1.09 ml, 14.1 mmol) was added dropwise and the reaction allowed to warm up to room temperature. The resulting green suspension was stirred overnight then concentrated. The residue was purified by chromatography over silica gel. One fraction was isolated and dried in vacuo, affording 821 mg (72percent) of benzo[b]thiophene-6- carbaldehyde as a yellow oil.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl acetamide; at 200℃; for 1.16667h;Microwave irradiation;
[00854] Part C. Preparation of 6-bromobenzo[Z>]thiophene.; [00855] The product from Part B (0.7Og, 2.73mmol) and DBU (1.35mL, 8.94mmol) were combined inDMA (6mL) in a sealed tube and heated at 2000C in a microwave reactor for 70min. The resulting dark solution was diluted with 1 M HCl (2OmL) and extracted with CH2Cl2 (2 x 2OmL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using CH2Cl2 as the eluent to give the title compound as an oil (0.484g 83%).
78%
DBU (1.21g, 8.00mmol) was added to a stirred solution of 6-bromo- benzo[b]thiophene-2-carboxylic acid (I-25b: 2.4g, 8.85mmol) in DMA (4mL) at room temperature and the resulting mixture was heated in microwave at 200C for 1 hour. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography on silica gel (100% hexane) to afford 320mg of the product (78% yield).1H NMR (CDC13, 300 MHZ): delta 8.18-8.0 (d, 1H), 7.7-7.6 (d, 1H), 7.5-7.59 (d, 1H), 7.59-7.42 (d, 1H), 7.3-7.29 (d, 1H).
78%
With acetic acid; silver carbonate; In dimethyl sulfoxide; at 120℃; for 16h;
A mixture 3a or 4b (0.5 mmol), Ag2CO3 (0.05 mmol), AcOH(0.025 mmol) in DMSO (1.0 mL)was stirred at 120 C. After 16 h, thereactionwas cooled down to room temperature and quenched with1 M hydrochloric acid solution (2 mL) and the aqueous phaseextracted with ethyl acetate. The combined organic layers werewashed with brine and dried sodium sulfate, filtered, and the solventswere removed under reduced pressure to give analyticallypure 4a or 4b.
73%
With quinoline; copper; at 185℃; for 2h;
Compound 23 (3.67 g, 14.3 mmol) and copper powder (0.45 g, 7.1 mmol) were suspended in quinoline (18 mL) and heated at 185 C for 2 h. After cooling down to rt, EtOAc (25 mL) was added and the suspension filtered. The solid was washed with further EtOAc and the combined organic solutions washed with 2 N HCl (2 × 50 mL). After drying (MgSO4), filtration and evaporation in vacuo, the residue was purified by chromatography on silica with pentane to afford the desired material (2.21 g) as a crystalline white solid. Yield: 73%. 1H NMR (CDCl3), delta: 7.31 (dd, J = 5.4, 0.9, 1H, ArH), 7.43 (d, J = 5.4, 1H, ArH), 7.48 (dd, J = 8.4, 1.6, 1H, ArH), 7.69 (d, J = 8.6, 1H, ArH), 8.03 (d, J = 1.8, 1H, ArH).
62%
Preparation 46 <n="38"/>6-Bromo-benzorbithiopheneCopper powder (100 g, 1.57 mol) is added to a solution of 6-bromo-benzo[b]-tbdopherie-2- earboxylie acid (1.04 Kg, 4.04 mol) in quinoline (2.5 L) at room temperature. The reaction mixture is heated to reflux (195 C) for 1O h. The reaction mixture is cooled to room temperature and poured onto ice (2.5 Kg). Concentrated HCl (2.5 L) is added while stirring the resulting mass for Ih. The reaction mixture is extracted with hexane (4 x 3 L) and washed with dilute HCl (1 x 2 L), aqueous bicarbonate (1 x 5 L), and brine solution (1 x 5 L). The layers are separated and the organic layer is dried over sodium sulfate and concentrated to give the title compound (0.54 Kg, 62% ) as a light yellow solid.
With tin(IV) chloride; In dichloromethane; 1,2-dichloro-ethane; at 20℃;
Preparation 16; 2- and S-acetyl--bromobenzothiophene; To a solution of <strong>[17347-32-9]6-bromobenzothiophene</strong> (20 g, 93.8 mmol) and acetyl chloride (8.84 g, 112.6 mmol) in 1 ,2-dichloroethane (120 mL) is added dropwise at room temperature, tin tetrachloride (IM in dichloromethane, 112.6 mmol, 112.6 mL) under nitrogen. After the addition is completed, the reaction mixture is stirred at room temperature overnight. The mixture is poured onto an ice/water bath and extracted with dichloromethane. The organic phase is washed with saturated NaHCOs, water, and brine, dried over MgSO4, and evaporated under reduced pressure. The crude residue is purifed by flash chromatography on silica gel eluting with hexane/EtOAc 6:1 as eluent mixture. The title compound (12 g, 50%) is obtained as a 7:3 mixture of the two isomers: 3-acetyl- <strong>[17347-32-9]6-bromobenzothiophene</strong> and 2-acetyl-<strong>[17347-32-9]6-bromobenzothiophene</strong>. ES/MS m/e 256 (M+2).
A mixture of 3-bromothiophenol (25 g, 132 mmol, 1 eq.), bromoacetaldehyde diethyl acetal (25.5 g, 129 mmol, 0.98 eq.) and K2CO3 (27 g, 198 mmol, 1.5 eq.) in 200 mL of DMF was stirred at room temperature for 24 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate 2 times. The combined organic layers were washed with 1 N NaOH, water, brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 30 g of residue as an oil. 15 g of the residue was dissolved in dichloroethane (100 mL) and the solution was added dropwise into a boiling solution 35 g of PPA in 800 mL of dichloroethane. The reaction was kept at reflux for another hour. The solution was decanted from the residue and dichloroethane (100 mL×2) was added to the residue, stirred and decanted. The solution and the extracts were combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with 10% of Na2CO3 (aq.), water, brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane. The fractions containing product were combined and concentrated under reduced pressure to provide 9 g of intermediates 1A and 1B in approximate ratio of 4=6 as an oil.
[0254] Part C: A portion of the part B product (2.1 g, 10 mmol) was slowly added over 20 min to a solution of LDA (2 M in THF/hexane, 5.5 mL, 11 mmol) stirring under argon at -78 C. After stirring at -78 C. for 40 min, this solution was transferred over 10 min via cannula to a solution of carbon tetrachloride (3.0 mL, 38 mmol) in THF (40 mL) stirring at -78 C. After stirring at -78 C. for 1.5 h, the reaction was quenched with sat. ammonium chloride and allowed to warm to room temperature and, transferred to a separatory funnel with methylene chloride/water. Extraction with methylene chloride (2×100 mL) and drying the combined organic layers over magnesium sulfate afforded 3.7 g of crude product after evaporation of the solvent. Purification over silica gel gave 2.1 g (87%) of a mixture of 4-bromo-2-chlorobenzo[b]thiophene and 6-bromo-2-chlorobenzo[b]thiophene.
With boron trifluoride diethyl etherate; In acetic acid; at 20 - 120℃; for 0.0833333h;
To a room temperature solution OF 6-BROMO-2, 3-dihydro-benzo [b] thiophen-3-ol (785 mg, 3.39 mmol) in HOAC (7 mL) is added boron trifluoride diethyl etherate (1. 44 G, 10.2 mmol) and the reaction mixture is placed into a 120 C oil bath. After 5 min, the reaction is cooled to room temperature and basified to-pH 11 using 2 M NaOH. The aqueous suspension is extracted with ET2O (2 X 200 mL) and the combined organic layer is dried (MGS04), filtered and concentrated to afford the sub-title compound (689 mg, 95%) as an off-white solid. RF 0. 70 (4: 1 HEX/ETOAC). mp 48-50 C. 'H NMR (300 MHz, CDCl3) 8 7.29 (d, J= 5.4 Hz, 1H), 7.41 (d, J= 5. 4 Hz, 1H), 7.46 (dd, J= = 1. 8,8. 5 Hz, 1H), 7.66 (d, J= 8.5 Hz, 1H), 8.01 (M, 1H).
With poliphosphoric acid; In chlorobenzene; for 2h;Heating / reflux;Product distribution / selectivity;
Step B: To a solution of polyphosphoric acid (90 g) in chlorobenzene (250 mL) under reflux was added a solution of the thiophenol acetal (27.6 g, 99.6 mmol) from Step A above in chlorobenzene (120 mL) dropwise. After the addition, the reaction solution was heated under reflux for 2 hours and then cooled to room temperature. The top layer was separated; the bottom layer was diluted with water and then extracted with dichloromethane twice. The combined organic extract was washed with water and aqueous saturated sodium bicarbonate and dried concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexanes) to give a 1:1 mixture of 4-bromobenzo[b]thiophene and 6-bromobenzo[b]thiophene (15.5 g, 73%), which was used in the next step without further purification or characterization.
With PPA; at 130℃; for 4.5 - 5.5h;Heating / reflux;
[0165] Chlorobenzene (1000 mL) and PPA (280 g) were combined and heated to reflux (130 0C). The solution of compound 20 (130 g, 0.48 mol) in chlorobenzene (300 mL) was added drop wise to the mixture over 1.5 h. The reaction mixture was refluxed for 3-4 h and then cooled. The solvent was decanted from the residue and toluene (400 mLx2 ) was added to <n="44"/>the residue, stirred and decanted. The chlorobenzene/toluene extracts were combined and concentrated under vacuum, and the residue was then taken up with PE (800 mL) and water (400 mL). After layers separation the organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give a crude product, which was purified by column chromatography (silica gel, elute: PE) to afford a mixture of 21 and 22 (80 g, 70 %) as a colorless oil.
With PPA; In chlorobenzene; at 130℃; for 4.5 - 5.5h;Heating / reflux;
Chlorobenzene (1000 niL) and PPA (280 g) were combined and heated to reflux (130 0C). The solution of compound 25 (130 g, 0.48 mol) in chlorobenzene (300 mL) was added drop wise to the mixture over 1.5 h. The reaction mixture was refluxed for 3-4 h and then cooled. The solvent was decanted from the residue and toluene (400 mLx2 ) was added to the residue, stirred and decanted. The chlorobenzene/toluene extracts were combined and concentrated under vacuum, and the residue was then taken up with PE (800 mL) and water (400 mL). After layers separation the organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give a crude product, which was purified by column chromatography (silica gel, elute: PE) to afford a mixture of 26 and 27 (80 g, 70 %) as a colorless oil.
With PPA; In chlorobenzene; at 140℃; for 5.5h;Heating / reflux;
[0253] Part B: A solution of 1-bromo-3-((2,2-dimethoxyethyl)thio)benzene (23 g, 81 mmol theory) in chlorobenzene (100 mL) was slowly added over 1 h to polyphosphoric acid (62 g) in chlorobenzene (500 mL) stirring vigorously at 140 C. under nitrogen. After refluxing for 4.5 h, the reaction was slowly poured into 1.5 L of ice water. Extraction with methylene chloride (2×700 mL) and washing the combined organic layers with water and saturated sodium bicarbonate solution and drying over magnesium sulfate afforded 17 g of crude product after evaporation of the solvent. Distillation (20 mm Hg) afforded 9.7 g (156-165 C., 55%) of a 50/50 mixture of 4-bromobenzo[b]thiophene and 6-bromobenzo[b]thiophene.
With phenylpropanol amine; In chlorobenzene; for 12h;Reflux;
PPA (40.0 g) was combined with chlorobenzene (110 mL) and refluxed for 1 hr. 1-Bromo- 3-(2,2-dimethoxy-ethylsulphanyl)-benzene (11.0 g, 36.038 mmol) in chlorobenzene (40 mL) was added dropwise to the refluxing reaction mixture and continued to reflux for 12 hr. The reaction mixture was cooled to room temperature, the top-layer was separated, the bottom layer was diluted with water (200 mL) and then extracted with DCM (2 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude material which was purified by column chromatography using silica gel (100-200 mesh) and hexane as eluent to afford a mixture of 6-bromobenzo[b]thiophene and 4-bromo- benzo[b]thiophene (7.0 g, 32.849 mmol, 91%) as pale yellow liquid. GCMS: 213 (mlz).
With PPA; In 1,2-dichloro-ethane; for 1h;Heating / reflux;
A mixture of 3-bromothiophenol (25 g, 132 mmol, 1 eq.), bromoacetaldehyde diethyl acetal (25.5 g, 129 mmol, 0.98 eq.) and K2CO3 (27 g, 198 mmol, 1.5 eq.) in 200 mL of DMF was stirred at room temperature for 24 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate 2 times. The combined organic layers were washed with 1 N NaOH, water, brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 30 g of residue as an oil. 15 g of the residue was dissolved in dichloroethane (100 mL) and the solution was added dropwise into a boiling solution 35 g of PPA in 800 mL of dichloroethane. The reaction was kept at reflux for another hour. The solution was decanted from the residue and dichloroethane was added to the residue, stirred and decanted. The solution and the extracts were combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with 10% of Na2CO3 (aq.), water, brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane. The fractions containing product were combined and concentrated under reduced pressure to provide 9 g of intermediates 1A and 1B as an oil.
With sodium carbonate; In dichloromethane; for 4h;Reflux;
3-bromobenzenethiol (0.5 g, 2.64 mmol) was dissolved in 8 mL of DMF. bromoacetaldehyde diethyl acetal(0.52 g, 2.64 mmol) and K2CO3 (0.548 g, 3.97 mmol) were added thereto, and the mixture was stirred at room temperaturefor 16 hours. After addition of water, the reaction solution was extracted with EtOAc. The organic layer was dried withanhydrous magnesiumsulfate and concentrated under reduced pressure to obtain 1-bromo-3-(2,2-diethoxy-ethylsulfanyl)benzene. The obtained compound was dissolved in 8 ml of MC. 0.7 g of PPA (polyphosphoric acid) was addedthereto, and the mixture was stirred for 4 hours under reflux. After addition of Na2CO3 aqueous solution, the reactionsolution was extracted with MC. The organic layer was dried with anhydrous magnesiumsulfate and purified by columnchromatography to obtain the mixture of 4-bromo-benzo[b]thiophene and 6-bromo-benzo[b]thiophene (1:1, 0.33 g, 58 %).1H-NMR (CDCl3) delta 8.01 (1H, s), 7.80 (1H, d), 7.66 (1H, d), 7.50 (4H, m), 7.41 (1H, d), 7.29 (1H, d), 7.19 (1H, t)
With pyridine; In N,N-dimethyl-formamide; for 20h;Heating / reflux;Product distribution / selectivity;
Step C: To a solution of the isomeric bromobenzo[b]thiophene (14.2 g, 66.5 mmol) from Step B above in N,N-dimethylformamide (130 mL) were added pyridine (7.5 mL) and copper(I) cyanide (7.75 g). The reaction mixture was heated under reflux for 20 hours. The reaction solution was then cooled to 60 C. and poured into a solution of ethylene diamine in water. The resultant mixture was stirred for 30 minutes and extracted with diethyl ether and ethyl acetate. The combined organic extract was washed with 1:1 brine/water, dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (95:5 to 91:9 hexanes/ethyl acetate) to give 4-cyanobenzo[b]thiophene (4.15 g, 39%) as a light yellow solid, and 6-cyanobenzo[b]thiophene (4.34 g, 41%) as a reddish oil: 1H NMR for 4-cyanobenzo[b]thiophene (CDCl3, 500 MHz) delta 8.10 (d, J=8.2 Hz, 1H), 7.74-7.70 (m, 2H), 7.62 (dd, J=5.5, 0.6 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H); 1H NMR for 6-cyanobenzo[b]thiophene (CDCl3, 500 MHz) delta8.22 (app s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.72 (d, J=5.4 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.42 (dd, J=5.4, 0.5 Hz, 1H).
With polyphosphoric acid; In 1,2-dichloro-ethane; for 3h;Reflux;
A solution of compound B-197 (50 g, 0.16 mol) in 1 ,2-dichloroethane (500 mL) was added dropwise to a mixture of polyphosphoric acid (100 g) in 1 ,2-dichloroethane (500 mL) at reflux. The mixture was stirred at reflux for 3 hours. On completion, the reaction mixture was cooled to room temperature and quenched with water (200 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-198 (25 g, 72% yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ = 215.1 , tR= 0.945.
27%
With PPA; In chlorobenzene; for 3.5h;Heating / reflux;
Into a mixture of polyphosphoric acid (160 g) in chlorobenzene (1 L) at reflux is added a solution of the crude 3-bromobenzenethioacetaldehyde diethyl acetal (60.06 g, 196.76 mmol) in chlorobenzene (500 mL) via an addition funnel over a 1.5 h period. Upon complete addition, the mixture is heated at reflux for an additional 2 h and is then allowed to cool to room temperature. The chlorobenzene layer is decanted from the mixture and washed with saturated aqueous NaCl (500 mL). The aqueous layer is used to dilute the PPA, which is then extracted with Et2O (3 x 500 mL). The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue is then purified by silica gel chromatography (100% hexanes). The purified fractions are combined and concentrated under reduced pressure to give 6- bromobenzo[b]thiophene as a white crystal (11.59 g, 27%). mp 54.8-58.3 C. IR (KBr) 3017, 1586, 1448, 1067, 814 cm4. Ion Spray MS 211.9, 213.9 (M)+.
25%
With PPA; Polyphosphoric acid (PPA); In benzene; for 6h;Heating / reflux;
Step B: Synthesis of 6-bromobenzo[delta]thiophene as an intermediate; [0183] A mixture of (3-bromophenyl)(2,2-diethoxyethyl)sulfane (3.42 g, 11.2 mmol), PPA (1.0 g), and benzene (30 mL) was refluxed for 6 h. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and filtered. Evaporation of the solvents and purification by chromatography (silica, hexanes) gave 6- bromobenzo[6]thiophene (0.607 g, 25%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 7.63 (d, J= 8.1 Hz, IH), 7.54-7.47 (m, 3H), 7.19 (t, J= 7.8 Hz, IH).
(b) Benzo[b]thiophene-6-carboxaldehyde. A mixture of 6-bromobenzo[b]thiophene [9.6 g; prepared according to Nippon Kagaku Zasshi, 88, 758 (1967): Chem. Abstr., 69, 59018q (1968)], magnesium (1.64 g), and 1,2-dibromoethane (4.23 g) in anhydrous diethyl ether (90 ml) was stirred and gently heated for 3 hr. N-formylpiperidine (5.09 g) in anhydrous diethyl ether (15 ml) was added to the cooled mixture which was subsequently allowed to stand for 12 hr. the mixture was poured into a dilute hydrochloric acid solution. the dried (MgSO4) ether extract was evaporated and the residue was purified by column chromatography over silica gel with chloroform/hexane (1:8 v/v) elution to give benzo[b]thiophene-6-carboxaldehyde as yellow oil. Pmr spectrum (CDCl3; delta in ppm): 7.36 (1H, d); 7.68 (1H, d); 7.84 (2H, s); 8.16 (1H, s); 10.04 (1H, s).
With magnesium; In diethyl ether; hexane;
b) Benzo[b]thiophene-6-carboxaldehyde A mixture of 6-bromobenzo[b]thiophene [9.6 g; prepared according to Nippon Kagaku Zasshi, 88 , 758 (1967): Chem. Abstr., 69 , 59018q (1968)], magnesium (1.64 g), and 1,2-dibromoethane (4.23 g) in anhydrous diethyl ether (90 ml) was stirred and gently heated for 3 hr. N-formylpiperidine (5.09 g) in anhydrous diethyl ether (15 ml) was added to the cooled mixture which was subsequently allowed to stand for 12 hr. the mixture was poured into a dilute hydrochloric acid solution. the dried (MgSO4) ether extract was evaporated and the residue was purified by column chromatography over silica gel with chloroform/hexane (1:8 v/v) elution to give benzo[b]thiophene-6-carboxaldehyde as yellow oil. Pmr spectrum (CDCl3; delta in ppm): 7.36 (1H,d); 7.68 (1H,d); 7.84 (2H,s); 8.16 (1H,s); 10.04 (1H,s).
6-trimethylsilylethynylbenzo[b]thiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; triphenylphosphine;palladium diacetate; In tetrahydrofuran; N,N-dimethyl-formamide;
[Referential Example 215] 6-Trimethylsilylethynylbenzo[b]thiophene In tetrahydrofuran (15 ml) was dissolved <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (2.13 g), followed by the addition of triphenylphosphine (787 mg), triethylamine (40 ml), N,N-dimethylformamide (15 ml), trimethylsilylacetylene (1.47 g) and palladium acetate (225 mg). The resulting mixture was refluxed for 5 hours. After the reaction mixture was allowed to cool down, it was diluted with methylene chloride (150 ml). The diluted mixture was washed with water (twice) and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (only hexane), whereby the title compound (1.38 g) was obtained. 1H-NMR (CDCl3) delta: 0.27(9H,s), 7.30(1H,d,J=5.7Hz), 7.44(1H,dd,J=8.3,1.0Hz), 7.49(1H,d,J=5.7Hz), 7.73(1H,d,J=8.3Hz), 8.00(1H,s). MS (EI) m/z: 230 M+.
6-bromo-3-phenyl-2,3-dihydrobenzo<b>thiophen[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
aluminium chloride; In hexane; benzene;
Example 10 Preparation of 6-bromo-2,3-dihydro-3-phenylbenzo[b]thiophene Aluminium chloride (0.35g) was added to a solution of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (0.5g) in dry benzene (15ml). The solution was refluxed for 1 hour, cooled and poured into dilute hydrochloric acid. The aqueous solution was extracted with diethyl ether. The extracts were dried over anhydrous sodium sulphate and evaporated. The residual oil was purified on a silica gel column using hexane as eluant to give the title compound (0.2g) as a pale yellow oil.
6-bromo-benzo[b]thiophene-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
Approach 2Oxalyl chloride (717.2 g, 5.65 mol, 3.5 eq) is added to a 0-5 0C suspension of dichloromethane (3.44 L) and aluminum chloride (753.4 g, 5.65 mol, 3.5 eq). The resulting suspension is stirred for 30-60 minutes at 0-5 0C and cooled -20 to -25 C. A solution of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (344 g, 1.614 mol, 1 eq) in dichloromethane (1.72 L) is added over 1 h while maintaining the temperature at -20 to -25 0C. The reaction mixture is stirred for 30 minutes at -20 to -25 0C and warmed to 18 to 20 0C using a warm water bath. The reaction mixture is stirred for 1.5 h at this temperature. The reaction mixture is filtered and the filter cake is washed with dichloromethane (3 x 300 mL). The combined filtrate is concentrated to yield a thick black oil in the flask (600 g). This residue is dissolved in dichloromethane (1 L) and added to ethanol (3.5 L) at -10 to 0 0C in portions at such rate to maintain temperature at 10 to 20 0C. Once the addition is complete, the reaction mixture is partially concentrated to remove the dichloromethane only and then the vacuum is released. The reaction mixture is heated to 60-70 0C and stirred at this temperature for 1 h. Upon completion of the reaction, the solution is decanted from the resulting tars. The tars are discarded. The ethanol solution is evaporated to a residue. The residue is diluted with EtOAc (2 L).At this point, the current reaction mixture is combined with another reaction mixture for further work up (started with 330 g of 6-Bromobenzo[b]thiophene, 1.549 mol). The combined reaction mixture is poured into a stirred mixture of EtOAc (1 L) and brine solution (10 L). The layers are separated and the organic layer is washed with brine solution (2 L). The combined aqueous layer is extracted with EtOAc (4 L). The organic layer is washed ilh brine solution (1 L). The combined organic layers are dried over magnesium sulfate and charcoal, filtered, and concentrated under reduced pressure. The resulting oil is further concentrated in a vacuum oven for 15 h at room temperature to afford waxy solids after drying (750 g). The solids are suspended in heptane (5 L) with stirring and the suspension is heated to 70 0C. Magnesium sulfate (300 g) is added and the resulting suspension is stirred for 10 minutes at 70 0C. The <n="39"/>suspension is filtered. The solids are suspended in heptane (5 L) and heated to 70 0C. The suspension is stirred for 10-20 minutes at this temperature and filtered. The filter cake is washed with heptane (1 L). The heptane filtrates are collected and concentrated under reduced pressure to give light brown solids (550 g). The solids are dissolved in heptane (4 L) at 60 0C. The resulting solution is cooled to 35 to 50 0C. The solution is evenly loaded onto two plugs of silica gel (1.5 kg each) eluting with 0.5% EtOAc in heptane. The pure produce fractions are combined and concentrated under reduced pressure. The impure product fractions are combined, concentrated, and purified as described above. The total purified product is isolated (500 g) and crystallized from heptane (1.2 L). The solids are collected by filtration, washed with cold heptane (200 mL, -20 0C), and dried in a vacuum oven at room temperature for 15h to afford the title compound (460 g, 51%). GC analysis 98.8%; 1H NMR (DMSO-d, 500 MHz): delta. 8.65 (s, IH), 8.36 (d, IH, J = 1.5), 8.33 (d, IH, J = 8.5), 7.63 (dd, IH, J = 2, 8.5), 4.33 (q, 2H, J = 7), 1.33 (t, 3H5 J = 6.5).
(B). Preparation of 4-(6-bromobenzo[b]thiophen-2-yl)-2-chloro-5-methylpyrimidine; A solution of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (5.00 g, 23.5 mmol) in THF (50 mL) is cooled to -70 C. Lithium diisopropylamide (12.9 mL of a 2 M solution in heptane/THF/ethylbenzene, 25.8 mmol) is added dropwise over 5 minutes. After stirring for 40 minutes at -75 C., the mixture is removed from the cold bath and allowed to warm to 0 C. over 15 minutes and then recooled to -35 C. 2-Chloro-5-methylpyrimidine (3.02 g, 23.5 mmol) is added to the mixture as a solid in one portion and the resultant mixture is allowed to stir for 30 minutes at -35 C. Acetic acid (1.55 g, 25.8 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.60 g, 24.7 mmol) are added in one portion to the mixture before it is allowed to stir at room temperature for 16 hours. Then the mixture is concentrated under reduced pressure, suspended in warm dichloromethane, eluted through a pad of silica in dichloromethane (1 L) and concentrated under reduced pressure. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 50-100%. The resulting material is sonicated in ether (100 mL) and filtered to provide the title compound as an orange solid (3.08 g, 39% yield).
A solution of 10.10 gm (47.4 MMol) of a mixture of 4-bromobenzothiophene and 6-bromothiophene in 200 ML diethyl ether was treated with 2.30 gm (94.8 MMol) magnesium followed by the gradual addition of 4.1 ML (47.4 MMol) 1,2-dibromoethane.. The reaction mixture was stirred at reflux for about 2.5 hours and was then cooled to room temperature.. To this mixture was then added a solution of 10.39 gm (52.1 MMol) 1-(tert-butoxycarbonyl)piperidin-4-one in diethyl ether.. The resulting mixture was stirred at room temperature overnight and was then diluted with saturated aqueous ammonium chloride.. The reaction mixture was then extracted well with ethyl acetate.. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure.. The residue was subjected to silica gel chromatography, eluding a gradient of dichloromethane containing from 0-5% methanol.. Fractions containing product were combined and concentrated under reduced pressure to provide 3.09 gm (20%) of the desired compound. MS: m/e = 334 (M+1)
To a solution of intermediates 1A and 1B (24.1 g, 113 mmol, 1 eq.) and magnesium (5.5 g, 226 mmol, 2 eq.) in 100 mL ether was added BrCH2CH2Br (9.7 mL, 113 mmol, 1 eq.) dropwise over 30 minutes. After the addition, the reaction was headed at reflux gently for 2 hours. The reaction was allowed to cool down to room temperature and 1-(t-butoxycarbonyl)-4-piperidone (27 g, 136 mmol, 1.2 eq.) in 200 mL of THF was added into the solution. The reaction was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate 3 times. The combined organic layer was washed with water, brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a mixture of ethyl acetate and hexane (EtOAc:Hexane=1:4). The fractions containing product were combined and concentrated under reduced pressure to provide 9 g of intermediate 1C.
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90 - 100℃; for 3h;
[0166] Under Ar atmosphere, to the mixture of compound 21 and compound 22 (40 g, 0.19 mol) and Zn(CN)2 (16 g, 0.132 mol) were added Pd(PPh3)4 (10 g) and DMF (800 mL) and the mixture was stirred at 90 0C -100 0C for 3 h. The reaction solution was cooled to room temperature (30 0C) and filtered. The filtrate was concentrated under reduced pressure and the residue was then taken up with EtOAc (1000 mL) and saturated aq. NaHCO3 (500 mL), the insoluble solid was discarded via filtration. The filtrate layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a mixture product, which was purified by careful column chromatography (silica, elute; PE to EtO Ac:PE= 1:40) to afford compound 23 (14 g, 46.2 %) as an oil and compound 24 (7 g, 23%) as a solid.
46.2%; 23%
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90 - 100℃; for 3h;
Under Ar atmosphere, to the mixture of compound 26 and compound 27 (40 g, 0.19 mol) and Zn(CN)2 (16 g, 0.132 mol) were added Pd(PPh3)4 (10 g) and DMF (800 mL) and the mixture was stirred at 90 0C -100 0C for 3 h. The reaction solution was cooled to room temperature (30 0C) and filtered. The filtrate was concentrated under reduced pressure and the residue was then taken up with EtOAc (1000 mL) and saturated aq. NaHCO3 (500 mL), the insoluble solid was discarded via filtration. The filtrate layers were separated. The organic <n="90"/>layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a mixture product, which was purified by careful column chromatography (silica, elute; PE to EtO Ac:PE= 1:40) to afford compound 28 (14 g, 46.2 %) as an oil and compound 29 (7 g, 23%) as a solid.
With hydrogenchloride; In water; benzene; at 70℃; for 1h;
[00856] Part D. Preparation of 6-bromo-3-(chloromethyl)benzo[Z>]thiophene.; [00857] To a solution of the product from Part C (0.484g, 2.27mmol) in benzene (0.2OmL) was added37% aq. formaldehyde solution (ImL) and concentrated HCl (ImL). The resulting mixture was heated at700C for Ih. while HCl gas was bubbled through the mixture. The mixture was partitioned between H2O(2OmL) and CH2Cl2 (2 x 2OmL), and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using <n="161"/>CH2Cl2 to give the title compound as a waxy solid (0.49g, 82%).
82%
With hydrogenchloride; In water; benzene; at 70℃; for 1h;
Step 1) 6-bromo-3- (chloromethyl) benzo [b] thiophene To a solution of 6-bromobenzo [b] thiophene (484 mg, 2.27 mmol) in benzene (0.2 mL) were added aqueous formaldehyde (1 mL) and concentrated hydrochloric acid (1 mL) . The mixture was purged with HCl gas and heated at 70 for 1 hour. The mixture was diluted with EtOAc (40 mL) , and then washed with water (20 mL) and saturated aqueous NaCl, dried over anhydrous Na2SO4. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM to give 6-bromo-3- (chloromethyl) benzo [b] thiophene as a white solid (490 mg, 82) .
To a pre-dried flask equipped with a condenser is added magnesium (363 mg, 14.9 mmol) and ET20 (5 mL). To this is ADDED 1/10TH OF a solution of iodomethane (1. 32 g, 9.35 mmol) and 6-bromo-benzo [b] thiophene (400 mg, 1.87 mmol) in Et2O (5 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/6-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 (966 mg, 11. 2 mmol) is added dropwise. After 30 min, the ice is removed and the reaction mixture stirred for 1.5 h. Another portion of 3-PENTANONE (122 mg, 1.42 mmol) is added and the reaction is stirred for 1 h. After cooling to 0 C, the reaction is quenched with H2O (10 mL) and saturated aqueous NH4C1 (15 mL) and is diluted with Et2O (100 mL). The organic layer is dried (MGS04), filtered and concentrated. The reaction residue is subjected to flash chromatography (silica gel, 90: 10 petroleum ETHER/ET20) to afford impure sub-title compound. Most of the impurity is removed under high vacuum (-24 h) to afford slightly impure sub-title compound (243 MG, #59x0025;). APOS;HNMR (300 MHZ, CDCIS) S 0. 77 (T, J= 7. 4 HZ, 6H), 1. 70 (S, 1H), 1.80-2. 00 (sym m, 4H), 7.29-7. 34 (M, 2H), 7. 40 (D, J= 5. 4 Hz, 1H), 7.76 (D, J = 8. 4 HZ, 1H), 7.95 (s, 1H).
To a solution of intermediates 1A and 1B (241 g, 113 mmol, 1 eq) and magnesium (5.5 g, 226 mmol, 2 eq.) in 100 mL ether was added BrCH2CH2Br (9.7 mL, 113 mmol, 1 eq.) dropwise over 30 minutes. After the addition, the reaction was headed at reflux gently for 2 hours. The reaction was allowed to cool down to room temperature and 1-(t-butoxycarbonyl)-4-piperidone (27 g, 136 mmol, 1.2 eq.) in 200 mL of THF was added into the solution. The reaction was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate 3 times. The combined organic layer was washed with water, brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a mixture of ethyl acetate and hexane (EtOAc:Hexane=1:4). The fractions containing product were combined and concentrated under reduced pressure to provide 11 g of intermediate 1C.
A solution of lithium diisopropylamide (2.0 M, 1.41 mL, 2.8 mmol) was added dropwise to a solution of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (500 mg, 2.4 mmol) in tetrahydrofuran (10 mL) at -78 C under argon. After 30 minutes a solution of iodine (716 mg, 2.8 mmol) in tetrahydrofuran (3 mL) was added dropwise. The iodine quickly decolorized. After 30 minutes the reaction was quenched with an aqueous solution of sodium sulfite (1.0 M, 10 mL). Brine (50 mL) was added and the mixture was extracted with dichloromethane (3 x 25 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to provide 6-bromobenzo[6]thiophene (702 mg, 2.07 mmol, 88 %).
5-Bromobenzo[b]thiophene (700 mg; 3.3 mmol) was dissolved in dry Et2O (14 mL) and placed under nitrogen flow. 1.6 M nBuLi in hexanes (2.25 mL, 3.6 mmol) was added dropwise, and the mixture was stirred at rt for 5 min. The reaction was cooled to -70 C and N,N-dimethyl-trifluoroacetamide (0.42 mL; 3.6 mmol) was added dropwise. The mixture was stirred at -70 C for 2 h, then allowed to warm up to rt, acidified with 1 M HCl to pH = 1, extracted with MTBE (3 × 50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by chromatography using 5% EtOAc in heptane to afford the desired material as a yellow solid. Yield: 717 mg (73%). 1H NMR (CDCl3), delta: 7.68 (d, J = 1.83 Hz, 1H, ArH), 7.79 (s, 1H, ArH), 8.15 (d, J = 1.83 Hz, 2H, ArH).
With N-Bromosuccinimide; acetic acid; In chloroform; at 20℃;Cooling with ice;
Compound 24 (1.5 g, 7.0 mmol) was dissolved in chloroform (11 mL). Acetic acid (11 mL) was added and the mixture cooled on ice before adding N-bromosuccinimide (1.57 g, 8.8 mmol) portionwise over 1 h. The reaction was allowed to warm to rt then stirred at rt for 16 h before washing with saturated sodium thiosulfate (22 mL), saturated sodium bicarbonate (2 × 22 mL) and water (22 mL). The solution was dried (Na2SO4) before filtration and evaporation in vacuo. The product was purified by chromatography on silica gel with pentane to afford the desired material (1.49 g) as a crystalline solid. Yield: 73%. 1H NMR (CDCl3), delta: 7.42 (s, 1H, ArH), 7.58 (dd, J = 8.6, 1.4, 1H, ArH), 7.69 (d, J = 8.4, 1H, ArH), 8.01 (d, J = 1.4, 1H, ArH).
In a 25 mL three-necked flask, magnesium (257 mg, 10.6 mmol) was suspended in THF,(1.7 mL) and heated to reflux. A solution of 6-bromobenzo[b]thiophene (1.5 g, 7.04 mmol) in THF (8.3 mL) was added dropwise. The reaction mixture was stuffed at reflux for 2 h, thencooled to 0C. N,N-Dimethylformamide (1.03 g, 1.09 ml, 14.1 mmol) was added dropwise and the reaction allowed to warm up to room temperature. The resulting green suspension was stirred overnight then concentrated. The residue was purified by chromatography over silica gel. One fraction was isolated and dried in vacuo, affording 821 mg (72%) of benzo[b]thiophene-6- carbaldehyde as a yellow oil.
With copper(l) iodide; potassium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 16h;Inert atmosphere;
To a previously degassed solution of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (i.0 g, 4.694 mmol) in toluene (30 mL) was added tert-butyl carbamate (0.824 g, 7.042 mmol), followed by potassium carbonate (i.290 g, 9.388 mmol), CuT (0.044 g, 0.234 mmol) and N,,N2-dimethylcyclohexane-i,2-diamine(0.066 g, 0.469 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for i6 h at ii0 C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL).Filtrate was concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = iO/90) togive the titled compound (0.570 g, 48 %) as a solid. LCMS: m/z i50.2 [M-iOO] ?H NMR (400 MHz, DMSO-d6) 9.52 (s, iH), 8.i7 (s, iH), 7.74 (d, J= 8.6 Hz, iH), 7.57 (d, J= 5.5 Hz, iH), 7.4i - 7.3i (m, 2H), i.50 (s, 9H).
2-(benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 2h;Reflux; Inert atmosphere;
5-Bromobenzo[b]thiophene (10.0 parts), bis(pinacol)diboron (14.3 parts),Potassium acetate (9.2 parts) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloride adduct (1.1 parts) are mixed in toluene (200 parts) The mixture was stirred at reflux temperature for 2 hours under a nitrogen atmosphere.After cooling the obtained reaction liquid to room temperature, the solid matter was separated by filtration to obtain a filtrate containing the product.Then, it was refined by a short ruthenium column chromatography (developing solution: toluene), and the solvent was removed under reduced pressure.2-(Benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.7 parts, yield 96%) was obtained. .
87%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 4h;Reflux;
Preparation 42 2-(Benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6-Bromobenzo[b]thiophene (3.09 g, 14.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.42 g, 17.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) chloride (0.54 g, 0.74 mmol), and potassium acetate (2.89 g, 29.4 mmol) in anhydrous dioxane (48 mL) was refluxed at 80 C. for 4 h. The reaction was cooled and diluted with ethyl acetate, filtered through a pad of Celite, and washed with brine. The aqueous layer was extracted with ethyl acetate. The organic layers were dried, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-30% ethyl acetate/hexanes) provided 2-(benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oily solid: (3.266 g, 87%): 1H NMR (400 MHz, CDCl3) delta 8.38 (d, J=0.7 Hz, 1H), 7.79 (ddd, J=20.2, 8.0, 0.8 Hz, 2H), 7.51 (d, J=5.5 Hz, 1H), 7.34 (dd, J=5.4, 0.7 Hz, 1H), 1.37 (s, 12H); 13C NMR (101 MHz, CDCl3) delta 141.78, 129.75, 129.58, 128.18, 123.87, 122.94, 83.89, 24.92; EIMS m/z 260.
To a solution of diisopropylamine (9.5 g, 94 mmol) in dry tetrahydrofuran (100 mL) was added n-BuLi (34mL, 2.5M in n-hexane) dropwise at -65 C during which the temperature was not allowed to exceed -55 C. The mixture was stirred at -30 C for 30 minutes and then re- cooled to -65 C. <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (8.0 g, 38 mmol) was added in one portion, and the reation was stirred at -50 C for 1 hour and then cooled to -65 C. A solution of N-fluoro-N- (phenylsulfonyl)benzenesulfonamide (12 g, 38 mmol) in dry tetrahydrofuran (20 mL) was added dropwise at -65 C. The reaction temperature was allowed to rise slowly to room temperature, and the reaction was stirred at this temperature for 4 hours, at which time GCMS analysis showed about 30% desired product. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether] to give B-234 (2.2 g, 25% yield) as a white solid.
j00388j To a solution of <strong>[17347-32-9]6-bromobenzothiophene</strong> (5.0 g, 23 mmol) in tetrahydrofuran (50 mL) at - 60 C was added slowly lithium diisopropylamide (2 M in tetrahydrofuran, 23 mL, 46 mmol). The mixture was stirred at -30 C for 1 hour, and then N-fluorobenzenesulfonimide (22 g, 70 mmol) in tetrahydrofuran (30 mL) was added at -60 C. The mixture was stirred at room temperature for 15 hours, then quenched with water (20 mL) and extracted with ethyl acetae (2 x 100 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography [100% petroleum etherl to give compound B-58 (1.2 g, crude) as a white solid.
In 1-methyl-pyrrolidin-2-one; at 200℃; under 5171.62 Torr; for 1h;Microwave irradiation;
A mixture of compound B-198 (4.0 g, 0.019 mol) and cuprous cyanide (2.5 g, 28 mmol) in l-methylpyrrolidin-2-one (20 mL) was stirred at 200 C for 1 hour under microwave irradiation (150 W, 100 psi). On completion, the mixture was filtered, and the filtrate was diluted with dichloromethane (60 mL). This solution was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-199 (2.6 g, 87% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 160.1, tR= 0.795.
(6-bromobenzo[b]thiophen-2-yl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
To a mixture of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (1.0 g, 4.7 mmol) in anhydrous tetrahydrofuran (10 mL) was added LDA (2.8 mL, 2.0 M in THF) dropwise at -70 C. The mixture was stirred at this temperature for 1 hour. Then triisopropyl borate (1.1 g, 5.6 mmol) was added at -70 C, and the reaction stirred at this temperature for 2 hours. Sulfuric acid (0.92 g, 9.4 mmol) was added slowly, and the reaction stirred at room temperature for another 2 hours. On completion, the reaction mixture were diluted with water (10 mL) and extracted with dichloromethane (3 x20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 5: 1] to give B-230 (0.8 g, 67% yield) as a yellow solid.
(6-bromobenzo[b]thiophen-2-yl)trimethylsilane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With lithium diisopropyl amide; In tetrahydrofuran;
(6-bromobenzo[b]thiophen-2-yl)trimethylsilane Lithium diisopropylamide (2.0 M in THF, 31.0 cm3, 62 mmol) is added dropwise to a solution of <strong>[17347-32-9]6-bromo-benzo[b]thiophene</strong> (12.0 g, 56 mmol) in anhydrous tetrahydrofuran (150 cm3) under a nitrogen atmosphere at -30 C. over 30 minutes. The resulting solution is stirred at -20 C. for 2 hours and then quenched with chlorotrimethylsilane (6.7 g, 62 mmol). The ice bath is removed and the reaction mixture is warmed to 23 C. and stirred for 17 hours. The reaction mixture is diluted with water (75 cm3) and extracted with diethyl ether (5*50 cm3). The combined organic layer is washed with brine (50 cm3) and dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The crude product is purified using silica gel column chromatography (40-60 petroleum) to give (6-bromobenzo[b]thiophen-2-yl)trimethylsilane (8.9 g, 55%). MS (m/e): 286 (M+, 96.5%). 1H NMR (300 MHz, CDCl3) 8.01 (1H, s, ArH), 7.65 (1H, d, ArH, J 8.4), 7.45-7.41 (1H, dd, ArH, J 1.8, 8.4), 7.40 (1H, s, ArH), 0.37 (9H, s, CH3).
j00386j To a solution of 6-bromobenzo[blthiophene (1.0 g, 4.7 mmol) in tetrahydrofuran (10 mL) at -78 C was added lithium diisopropylamide (2 M in THF and n-heptane, 2.6 mL, 5.2 mmol). The mixture was stirred at -78 C for 0.5 hour, and then N-chlorosuccinimide (0.94 g, 7.0 mmol) was added. The mixture was stirred at -78 C for another 1.5 hours, then quenched with water (20 mL) at 0 C and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (2 x 30 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC [Instmment: GX-C; Column: Daiso 250 x 50mm, particle size: 10 .im; Mobile phase: 50-75% acetonitrile in H20 (add 0.1%TFA, v/v)1 and lyophilized to give compound B-57 (0.3 g, 26%) as a brown solid.?H-NMR (CD3OD, 400 MHz): 8.00 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.51 (dd, J=8.4 Hz, 1H), 7.31 (s, 1H)
[0006631 To a mixture of LDA (7.8 mL, 15.5 mmol) in tetrahydrofuran (10 mL) was added Compound 76A (3.0 g, 14.1 mmol) in tetrahydrofuran (5 mL) dropwise at -78 C and the mixture was stirred under nitrogen protection for 1 h. The solution was added to a mixture of carbon tetrachloride (5.5 mL, 56.6 mmol) in tetrahydrofuran (15 mL) at -78 C and the reaction mixture was stirred under nitrogen protection for 1.5 h. It was quenched with ammonium chloride solution (50 mL), warmed to room temperature, extracted with DCM (100 mL x 2), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, evaporated and purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to furnish Compound 76B. ?H-NMR (DMSO-d6, 400 MHz) 5 (ppm) 7.55- 7.58 (m, 2H), 7.72-7.74 (d, J 8.0 Hz, 1H), 8.27 (m, 1H).
(R)-ethyl 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxooxazolidin-5-yl)propanoate[ No CAS ]
(R)-ethyl-3-((S)-3-(benzo[b]thiophen-6-yl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With copper(l) iodide; trans-1,2-Diaminocyclohexane; caesium carbonate; In 1,4-dioxane; at 125℃; for 4h;
6.le (0.25 g, 0.9 mmol, 1.0 equiv), 6- bromobenzo[b]thiophene (0.23 g, 1.0 mmol, 1.1 equiv) were dissolved in 1 ,4-dioxane (5 mL). GuI (0.20 g, 1.1 mmol, 1.2 equiv), trans-cyclohexane-1,2-diamine (0.14 g, 1.2 mmol, 1.4 equiv) and Cs2CO3 (0.44 g, 1 .3 mmol, 1 .5 equiv) were added and the reaction mixture was stirred at 125 C for 4 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (20-30 % EtOAc in Hexane) to afford product 2.6a which was used for next step (0.35 g, 79 % yield). LCMS (mlz): 412.3 [M+H].
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,2-dimethoxyethane; at 100℃;Inert atmosphere;
General procedure: In a nitrogen atmosphere, substitute phenylboronic acid (12mmol), <strong>[17347-32-9]6-bromobenzothiophene</strong> (10mmol),Cesium fluoride (30 mmol) and palladium tetrakistriphenylphosphorus (0.9 mmol) were dissolved in 30 mL of dry ethylene glycol dimethyl ether solvent, and the reaction mixture was heated to reflux in an oil bath at 100C.The reaction was monitored by TLC until <strong>[17347-32-9]6-bromobenzothiophene</strong> was no longer detected.The reaction mixture was then cooled, extracted with ethyl acetate and water, and the organic layer was dried and concentrated.The crude product (petroleum ether) was then separated by column chromatography to obtain the product 6-phenylbenzothiophene compound 1.
With caesium carbonate; triphenylphosphine; palladium dichloride; In tetrahydrofuran; water; at 85℃;
6-vinylbenzo[b]thiophene A mixture of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (217 mg, 1.02 mmol), potassium vinyltrifluoroborate (137 mg, 1.02 mmol), Cs2CO3 (983 mg, 3.02 mmol), Ph3P (17 mg, 0.066 mmol) and PdCl2 (5 mg, 0.028 mol) in THF (1.8 mL)/H2O (0.2 mL) was heated at 85 C. After overhight stirring, H2O (5 mL) and saturated NH4Cl solution (50 mL) were added and the resulting mixture was extracted with CH2Cl2 (3*25 mL). The combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (67 mg, 41%).
To a mixture of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (5.0 g, 23 mmol) in diethyl ether (50 mL) at - 90 C under nitrogen was added dropwise tert-butyllithium (1.3 M in pentane solution, 27 mL, 35 mmol). The mixture was stirred at -90 C for 0.5 hour, and diethyl carbonate (4.1 g, 35 mmol) was added dropwise. The reaction was stirred at -90 C for another 0.5 hour, then quenched at 0 C with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (3 chi 20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 50: 1] to give compound B-276 (1.0 g) as a yellow oil. LCMS (B): tR=0.863min., (ES+) m/z (M+H)+ = 207.1.
To a solution of <strong>[17347-32-9]6-bromobenzothiophene</strong> (3.0 g, 14 mmol) in THF (10 mL) was added lithium diisopropylamide (2 M in tetrahydrofuran/n-heptane , 8.4 mL 17 mmol). The mixture was stirred at -70 C for 30 min, and then iodomethane (17.98 g, 126.71 mmol) was added dropwise. The mixture was stirred at 15 C for 15.5 hours, then quenched at -70 C with saturated aqueous ammonium chloride (2 mL), diluted with water (10 mL) and extracted with ethyl acetate (3 chi 80 mL). The combined organic phases were concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate= 1 :0] to give compound B-273 (1.60 g, 50% yield). -NMR (CD3OD, 400 MHz): delta 7.94 (s, 1H), 7.42-7.39 (m, 1H), 7.20-7.14 (m, 1H), 3.39 (s, 1H), 3.18-3.19 (m, 2H), 1.55 (s, 9H).
j00346j To a solution of 6-bromobenzo[bjthiophene (2.0 g, 9.4 mmol) in tetrahydrofuran (10 mL) at -70 C under nitrogen was added dropwise lithium diisopropylamide (2 M in tetrahydrofuran, 5.6 mL, 11 mmol). The solution was stirred at -70 C for 0.5 hour, and then iodomethane (12 g, 85 mmol) was added. The resulting solution was stirred at 15 C for 15.5 hours, then quenched by saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography [100% petroleum etherj to give compound B-37 (1.2 g, cmde) as a white solid. GCMS (B): tR=9.386 mi (ES) mlz = 227.9.
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; for 12h;Reflux;
Drying the reactor in 6-bromo benzothiophene 50 g (235 mmol), benzophenone hydrazone 46 g (235 mmol), tris (dibenzylideneacetone) dipalladium 4.30 g (4.7 mmol), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 2.9 g (5 mmol), sodium tert-butoxide, 45.1 g into a (469 mmol) and 500 mL of toluene was refluxed for 12 hours the reaction was terminated If the filtered under reduced pressure and in the hot state. after drying under reduced pressure to remove the solution by column chromatography to obtain a 40 g. (53% yield)
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane;Reflux;
General procedure: 3-Chloroperbenzoic acid (2.5 mmol) was added to the stirredsolution of compound 4a or 4b (1.0 mmol) in dichloromethane(50 mL) in portions over a 20-30 min period. The mixture washeated to reflux for about 5 h and monitored by TLC. Aftercompletion, the mixture was cooled to room temperature and sodiumhydrogen sulfite (20 mL) was added. The solution was stirredfor 15 min and extracted with dichloromethane. The organic phasewas washed with aqueous sodium bicarbonate (2 x 30 mL). Theorganic phase was separated, washed with brine and dried withsodium sulfate, filtered, and the solvents were removed underreduced pressure to give the sulfone compound 5a or 5b.
3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one[ No CAS ]
1-(benzo[b]thiophen-6-yl)-3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With copper(l) iodide; potassium carbonate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 20h;Inert atmosphere; Sealed tube;
In a reaction tube, <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (126 mg, 592 mupiiotaomicron, Eq: 1.5) was added to a suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 mupiiotaomicron, Eq: 1.00, W02( 114/202493 Al) in acetonitrile (3.00 ml ) . The mixture was treated with a steady stream of nitrogen that was bubbled at 22 C through the suspension for 10 minutes. Then potassium carbonate (136 mg, 987 mupiiotaomicron, Eq: 2.5) was added followed by copper (I) iodide (7.52 mg, 39.5 mupiiotaomicron, Eq: 0.1) and Nu,Nu'- dimethylethylenediamine (6.96 mg, 8.5 mu, 79.0 mupiiotaomicron, Eq: 0.2). The tube was inerted, sealed and the mixture was heated to 100 C for 20h. The mixture was treated with 20 ml water (pH 14) and extracted with ethyl acetate (2 x 20 ml). The organic layers were dried, filtered and evaporated to vacuo. (0188) The residue was purified by chromatography on silica gel to afford the desired product as a light yellow solid (124 mg, 81 %). MS (m/z) = 386.2 [(M+H)+].
(S)-1-tert-butyl 3-methyl 5-oxopiperazine-1,3-dicarboxylate[ No CAS ]
1-tert-butyl 3-methyl 4-(benzo[b]thiophen-6-yl)-5-oxopiperazine-1,3-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 70℃; for 16h;Inert atmosphere;
A mixture of 1-tert-butyl 3-methyl 5-oxopiperazine-1,3-dicarboxylate (5.0 g, 19.36 mmol), <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (5.36 g, 25.17 mmol), CuI (1.84 g, 9.68 mmol), Cs2CO3 (12.62 g, 36.72 mmol), and DMEDA (N1,N2-dimethylethane-1,2-diamine) (1.70 g, 19.36 mmol) in dioxane (80 mL) was degassed with N2 for three times. The reaction mixture was stirred at 70 C for 16 h. The reaction mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether:EtOAc = 10:1 to 2:1) to afford 1-tert-butyl 3-methyl 4-(benzo[b]thiophen-6-yl)-5-oxopiperazine-1,3-dicarboxylate (3.5 g, 33 %). LC-MS: m/z 335.0 (M+H-56)+.
A nitrogen gas atmosphere was prepared in a reaction vessel, then, diisopropylamine (13.3 mL, 93.9 mmol) and dehydrated THF (196 mL) were added, and a uniform solution was prepared. Thereafter, into this was dropped a 1.65 M n-butyllithium hexane solution (58.9 mL, 93.9 mmol) over a period of 10 minutes, and the mixture was stirred at -50 C. for 0.5 hours, then, <strong>[17347-32-9]6-bromobenzothiophene</strong> (10.0 g, 46.9 mmol) was added, and the mixture was stirred at -50 C. for 3 hours. To this was added 1,2-dibromoethane (17.6 g, 93.9 mmol), and the mixture was heated up to room temperature. After stirring for 2 hours, water (20 mL) was added to stop the reaction, and the reaction product was extracted using toluene. The resultant organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtrated.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation;
To a solution of 6-bromobenzothiophene (500 mg, 2.35 mmol) in DMF (6 ml) was added Zn(CN)2 (413 mg, 3.52 mmol) and Pd(PPh3)4 (136 mg, 0.117 mmol). The reaction was heated in the microwave to 100 C for 30 min. The mixture was filtered through a pad of Celite with EtOAc, the solvents were removed in vacuo and the crude product was purified by flash chromatography using 10-20%) EtOAc in n- heptane as eluent. Yield: 325 mg (87%); yellow solid. HPLC purity: 100 %.
With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 90℃; for 16h;
Pd(OAc)2 (0.070 g, 0.31 mmol), <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (0.70 g, 3.08 mmol), DPPP (0.128 g, 0.31 mmol), methanol (2.50 mL, 61.60 mmol), TEA (0.86 mL, 6.16 mmol) and DMF (30 mL) were combined and stirred under a CO atmosphere at 90 C for 16 hrs. The reaction was cooled to rt and diluted with EtOAc and brine. The organics were washed with water (3X), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue, containing methyl benzo[b]thiophene-6- carboxylate was used without further purification.
To a solution of <strong>[17347-32-9]6-bromo-benzo[b]thiophene</strong> (9.09 g, 42.6 mmol) in anhydrous tetrahydrofuran (150 cm3) at -30 C is added dropwise lithium diisopropylamide (23.5 cm3, 46.9 mmol, 2.0 M in tetrahydrofuran/heptane/ethylbenzene). The mixture is stirred at -30 C for 1 hour before triisopropylsilyltrifluoromethanesulfonate (14.4 g, 46.9 mmol) is added in one portion. The mixture is allowed to warm to 23 C and stirred for 15 hours. Water (150 cm3) is added and the mixture diluted with diethyl ether (100 cm3). The aqueous layer is extracted with diethyl ether (2 x 50 cm3). The combined organic layer is washed with brine (50 cm3), dried over anhydrous magnesium sulphate, filtered and the solvent removed in vacuo. The residue slowly crystallises which is triturated in ethanol (150 cm3) to give intermediate 45 (1 1 .5 g, 72%) as an off-white solid. 1H NMR (400 MHz, CDCIs) 8.04 (1 H, d, J 1 .8), 7.69 (1 H, d, J 8.5), 7.46 (1 H, s), 7.46 (1 H, dd, J 8.6, 1 .9), 1 .37 - 1 .47 (3H, m), 1 .16 (18H, d, J 7.5).
8-(6-bromobenzo[b]thiophen-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.2%
To a solution of 6-bromobenzo [b] thiophene (2.1 g, 10.0 mmol) in THF (10 mL) was added LDA (7.5 mL) at -70. Stirred at -70 for 2 hours. Added a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (2.0 g, 12.0 mmoL) in THF (10 mL) dropwise and the mixture was warmed to room temperature. Stirred at room temperature for 20 hours, then quenched the reaction with H2O (100 mL) and extracted with EA (100 mL) . Concentrated the organic phase under reduced pressure and the residue was purified by column chromatography (PE: EA=2: 1) to give product as white solid (2.3 g in 62.2%yield) . 1HNMR (400 MHz, DMSO-d6) deltaH8.18-8.17 (m, 1H) , 7.70 (d, J= 8.4 Hz, 1H) , 7.47 (dd, J = 8.4, 2.0 Hz, 1H) , 7.26 (s, 1H) , 5.69 (s, 1H) , 3.90 (s, 4H) , 2.07-1.86 (m, 6H) , 1.59 (d, J = 11.2 Hz, 2H) .
Under a nitrogen atmosphere, compound (T-1) (3 g) and THF (100 mL) were put in a reaction vessel, and the resulting mixture was cooled down to 0C. Magnesium (0.36 g) was added thereto, and the resulting mixture was stirred for 2 hours. Propanal (0.98 g) was added thereto, and the resulting mixture was stirred for 1 hour while returning to room temperature. The resulting reaction solution was poured into water, and subjected to extraction with toluene. Combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, p-toluenesulfonic acid monohydrate (1 g) was added thereto, and the resulting mixture was refluxed for 1 hour while water was removed. The solution was returned to room temperature, and purified by silica gel column chromatography (toluene), and concentrated into a 100 mL solution. Palladium on carbon (1 g) and Solmix (100 mL) were added thereto, and the resulting mixture was stirred overnight under a hydrogen atmosphere. The resulting reaction solution was filtrated, and the resulting material was concentrated to obtain compound ( T-2 ) (2.8 g).
Compound TDI01106-1 (2.50 g, 7.04 mmol) and cuprous cyanide (1.58 g, 17.6 mmol) were dissolved in Nmethylpyrrolidone(25 mL), the reaction was performed under microwave radiation at 200C for 1 hour. Thin layerchromatography (petroleum ether : ethyl acetate=5: 1) indicated the reaction was complete. The reaction solution wascooled to room temperature, followed by addition of water (100 mL), and was extracted with ethyl acetate (50 mL X 3).The combined organic phase was washed with saturated brine (80 mL X 3), dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether : ethylacetate= 20:1), to afford compound TDI01106-2 (1.00 g, yellow solid, yield: 54.1%).1H NMR (400 MHz, CDCl3) delta 8.22 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.4, 1.2 Hz,1H), 7.42 (d, J = 5.6 Hz, 1H).
6,6'-(butane-2,3-diyl)bis(benzo[b]thiophene)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
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).
With palladium diacetate; sodium t-butanolate; In toluene; at 70 - 75℃;Inert atmosphere;
Under the protection of nitrogen, are weighing 30 g raw material C (177 mmol), 37.8 g raw material D (177 mmol), 42.6 g sodium tert-butanol (443 mmol), 0.40 g Pd (OAc) 2 (1.77 mmol), 1.55 g C10104 R3 (3.54 mmol), toluene for stirring and mixing, heating to 70 - 75 C, reflux reaction for 2 - 3 hours, sampling [...], display without material remaining C; natural cooling to room temperature, water washing, over silica gel column, toluene for refining, and dried to obtain the 43 g intermediate B, yield: 80.4%, HPLC: 99.6%. C raw material, the raw material D, [...] molar ratio of 1:1: 2.5.
70%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In toluene; at 110℃; for 18h;
Diphenylamine (2 g, 11.82 mmol), <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (2.52 g, 11.82 mmol), 5 mol % Pd(dba)2, 5 mol % P(tBu)3, and NaOtBu (1.36 g, 14.18 mmol) are dissolved in 100 mL of toluene and then, stirred at 110 C. for 18 hours. When a reaction is complete, the toluene is evaporated so that the mixture is concentrated, and the resultant is separated with a dichloromethane:hexane (1:1 v/v) column to obtain 2.5 g of N,N-diphenylbenzo[b]thiophen-6-amine (Compound I-4). A yield is 70%. (0290) NMR (300 MHz, CDCl3): 7.68 (d, 1H), 7.55 (s, 1H), 7.31 (d, 1H), 7.28 (d, 1H), 7.22 (d, 4H), 7.15 (d, 1H), 7.10 (d, 4H), 7.01 (t, 2H).
70%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In toluene; at 110℃; for 18h;
Diphenylamine (2 g, 11.82 mmol), <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (2.52 g, 11.82 mmol), 5 mol % of Pd(dba)2, 5 mol % of P(tBu)3, and NaOtBu (1.36 g, 14.18 mmol) are dissolved in 100 mL of toluene and then, stirred at 110 C. for 18 hours. When a reaction is complete, the toluene is concentrated, and then, 2.5 g of Intermediate 1-1 is obtained through a separation with a dichloromethane:hexane (1:1 v/v) column. Herein, a yield is 70%. NMR (300 MHz, CDCl3): 7.68 (d, 1H), 7.55 (s, 1H), 7.31 (d, 1 H), 7.28 (d, 1H), 7.22 (d, 4H), 7.15 (d, 1H), 7.10 (d, 4H), 7.01 (t, 2H).
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; at 80℃; for 3h;Inert atmosphere;
In the nitrogen substituted reaction vessel,40 mL of toluene, 2.00 g of 6-bromobenzo [b] thiophene, 4.06 g of bis (4-t-octylphenyl) amine,Sodium-t-butoxide 1.36 g,Add 0.44 g of tris (dibenzylideneacetone) dipalladium (0), 0.66 mL of a 0.29 g / mL tri-t-butylphosphine / toluene solution,Stir at 80 C. for 3 hours. The reaction solution is allowed to cool to 25 C.,The solution is suction filtered, washed with 20 mL of toluene, and concentrated under reduced pressure.A brownish oily crude product (6.76 g) was obtained. The crude product is purified by column chromatography (carrier: silica gel, solvent: n-hexane / chloroform = 7/3 (volume ratio)),The white solid (4.90g) of the compound represented by following formula (14) was obtained.
To a suspension of AlC (9.4 g, 70 mmol) in anhydrous DCM (213 mL) at room temperature was added phthalic anhydride (3.5 g, 24 mmol) in one portion. The suspension was allowed to stir at room temperature for 15 mins. The suspension was then cooled to 0 C and compound 14 (5.0 g, 24 mmol) in DCM (10 mL) was added drop-wise. The reaction mixture was stirred overnight at room temperature. After 15.5 h, the reaction mixture was poured into ice water and acidified with 10% HCI. The suspension was filtered through celite, washing with DCM. The filtrate was concentrated to obtain the precipitate. The crude solid was then recrystallized with toluene to yield compound 13 as a pale yellow solid (4.2 g, 50%).1H NMR (400 MHz, DMSO) delta 8.39 (s, 1 H), 7.99 (m, 1 H), 7.89 (m, 1 H), 7.75 (m, 2H), 7.57 (m, 1 H), 7.23 (m, 1 H), 7.15 (m, 1 H).
A 20 mL dried Schlenk tube containing a stirring bar and CsF (60.8 mg, 0.4 mmol, 2 equiv) was dried with a heat gun under reduced pressure and filled with Ar after cooling to room temperature.To this vessel, were added with NiCl2 (1.3 mg, 0.01 mmol, 5 mol %), toluene (1 mL), benzoyl fluoride(1a) (24.8 mg, 0.2 mmol), and trimethyl(tributylstannyl)silane (2) (87.2 mg, 0.24 mmol, 1.2 equiv).The mixture was heated at 140 C with stirring for 24 h. The solution was then cooled to room temperature. 6-Bromobenzo[b]thiophene (42.6 mg, 0.2 mmol, 1 equiv), palladium acetate (0.4 mg,0.002 mmol, 1 mol %), tricyclohexylphosphine (1.1 mg, 0.004 mmol, 2 mol %), and anhydrous cesiumfluoride (45.6 mg, 0.3 mmol, 1.5 equiv) were added to the reaction mixture. The mixture was heated at110 C with stirring. After 24 h, the reaction mixture was cooled, the volatiles were evaporated under reduced pressure. The product was purified by flash chromatography on silica gel by elution with hexane, compound 4 was obtained in 71% yield (30 mg, 0.14 mmol) as white solid [31].
With bromine; potassium acetate; at 20℃;Cooling with ice;
Compound 32 (0.43 g, 2 mmol) was dissolved in 50 ml of dry dihalomethane, in which potassium acetate (0.4 g, 4 mmol) was added, and bromine (0.32 g, 2 mmol) was added in an ice bath. The mixture was slowly waiiiied at room temperature. After the completion of the reaction, 100 ml of saturated sodium thiosulfate solution was added so that the organic phases were separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, and then subjected to column chromatography after rotary evaporation to obtain a product (0.64 g, 81%). 1H-NMR(400 MHz, CDCl3): delta=7.81 (s, 1H), 7.68 (d, J=9.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H).
With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; ethylene glycol; triethylamine Inert atmosphere; Heating;
1.21.1; 1.22.1 Step 1:
A round-bottom flask is charged with 21-1, 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 21-2 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 21-3. 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.
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