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CAS No. : | 52287-51-1 | MDL No. : | MFCD00040750 |
Formula : | C8H7BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LFCURAJBHDNUNG-UHFFFAOYSA-N |
M.W : | 215.04 | Pubchem ID : | 104141 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.01 |
TPSA : | 18.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.06 cm/s |
Log Po/w (iLOGP) : | 2.4 |
Log Po/w (XLOGP3) : | 2.18 |
Log Po/w (WLOGP) : | 2.22 |
Log Po/w (MLOGP) : | 1.83 |
Log Po/w (SILICOS-IT) : | 2.85 |
Consensus Log Po/w : | 2.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.95 |
Solubility : | 0.241 mg/ml ; 0.00112 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.2 |
Solubility : | 1.35 mg/ml ; 0.00629 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.29 |
Solubility : | 0.111 mg/ml ; 0.000515 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.32 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
100% | With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 24 h; | 35 g of 1,4-benzodioxane and 200 ml of anhydrous dimethylformamide are placed under argon at 0° C. 54.9 g of N-bromosuccinimide are then added in portions. After it has returned gradually to room temperature, the reaction mixture is stirred for 24 hours. The solvents are evaporated off under reduced pressure and the white solid obtained is washed with dichloromethane. The filtrate is treated with 50 ml of saturated aqueous sodium sulfate solution, washed with 50 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, a yellow oil is obtained (quantitative yield). [0098] EI mass spectrum: M+=214 [0099] 1H NMR (200 MHz) CDCl3: 4.25 (4H, s); 6.74 (1H, d); 6.93 (1H, dd); 7.02 (1H, d) |
90% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In tetrahydrofuran at 20℃; for 18 h; | Compound V can also be prepared by the following procedure: [0103] 5 g of 1,4-benzodioxane and 100 ml of anhydrous tetrahydrofuran are placed under argon in the dark. 5.12 g of 1,3-dibromo-5,5-dimethylhydantoin are then added. The reaction mixture is stirred at room temperature in the dark for 18 hours. After half of the tetrahydrofuran has been evaporated off, 50 ml of pentane are added. After filtration, the operation is repeated three times and the solvents are then evaporated off under reduced pressure. The oily residue obtained is purified by chromatography on a silica gel column using a cyclohexane/ethyl acetate mixture (8/2, v/v) as the eluent (yield=90percent). |
85.5% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 2.5 h; | (1) in 1L three flask 60.0g (0.44mol) benzo-dioxane, 40.0gDMF, the 78.5g (0.44mol) NBS was dissolved in 200.0g of DMF formulated as a light yellow solution at room temperature 20 , mechanical stirring the solution was slowly added dropwise three bottles, 30min addition was completed, the addition was completed at room temperature for 2h, the reaction was completed, the reaction solution was added 250g of toluene and 250g water, and extracted liquid separation operation, and the organic phase was washed with water, no over anhydrous sodium sulfate, and columned on silica gel, toluene off under reduced pressure to give 80.5g red-brown oil, that is an intermediate in a yield of 85.5percent, determined by gas mass spectrometry confirmed the molecular ion peak detected as a target. |
36.9% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 1.5 h; | The reaction route is as follows:1L three-necked flask was added 54.5g (0.4mol)1,4-benzodioxane,272.5 g DMF.71.2 g (0.4 mol) of NBS was dissolved in 142.4 g of DMF to form a pale yellow solution.Control the internal temperature 0 ~ 20 ,The above solution was slowly added dropwise into a three-necked flask under mechanical stirring,30 minutes plus finishedAnd at 0 to 20 ° C,Stir for 1 hour.Completed the reaction,To the reaction mixture was added 300 g of toluene and 500 g of water to extract the liquid fraction.The organic phase is washed with water,Dried over anhydrous sodium sulfate,Silica gel column,Decompression solvent was light yellow liquid,The above crude product from toluene,Ethanol (mass ratio of 0.2: 2) recrystallization,31.7 g of colorless liquid was obtained,Yield 36.9percent. |
83 %Chromat. | With carbon dioxide; oxygen; lithium bromide; copper(ll) bromide In water at 100℃; for 15 h; Autoclave; Green chemistry | General procedure: A mixture of substrate (1 mmol), CuBr2 (22.4 mg, 10 molpercent), LiBr (130.3 mg, 1.5 equiv.), and 0.05 mL of water was placed in a 50 mL stainless steel autoclave equipped with an inner glass tube in room temperature. CO2 (4 MPa) and O2 (1 MPa) were subsequently introduced into the autoclave and the system was heated under the predetermined reaction temperature for 15 min to reach the equilibration. Then the final pressure was adjusted to the desired pressure by introducing the appropriate amount of CO2. The mixture was stirred continuously for the desired reaction time. After cooling, products were diluted with acetone and analyzed by gas chromatograph (Shimadzu GC-2014) equipped with a capillary column (RTX-17 30 m × 25 μm and RTX-wax 30 m × 25 μm) using a flame ionization detector by comparing the retention times of authentic samples. The residue was purified by column chromatography on silica gel (200–300 mesh, eluting with petroleum ether/ethyl acetate from petroleum ether to 50:1) to afford the desired product. The isolated products were further identified with NMR spectra (Bruker 400 MHz) and GC–MS or GCD, which are consistent with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 24h; | 35 g of 1,4-benzodioxane and 200 ml of anhydrous dimethylformamide are placed under argon at 0 C. 54.9 g of N-bromosuccinimide are then added in portions. After it has returned gradually to room temperature, the reaction mixture is stirred for 24 hours. The solvents are evaporated off under reduced pressure and the white solid obtained is washed with dichloromethane. The filtrate is treated with 50 ml of saturated aqueous sodium sulfate solution, washed with 50 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, a yellow oil is obtained (quantitative yield). [0098] EI mass spectrum: M+=214 [0099] 1H NMR (200 MHz) CDCl3: 4.25 (4H, s); 6.74 (1H, d); 6.93 (1H, dd); 7.02 (1H, d) |
90% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In tetrahydrofuran; at 20℃; for 18h; | Compound V can also be prepared by the following procedure: [0103] 5 g of 1,4-benzodioxane and 100 ml of anhydrous tetrahydrofuran are placed under argon in the dark. 5.12 g of 1,3-dibromo-5,5-dimethylhydantoin are then added. The reaction mixture is stirred at room temperature in the dark for 18 hours. After half of the tetrahydrofuran has been evaporated off, 50 ml of pentane are added. After filtration, the operation is repeated three times and the solvents are then evaporated off under reduced pressure. The oily residue obtained is purified by chromatography on a silica gel column using a cyclohexane/ethyl acetate mixture (8/2, v/v) as the eluent (yield=90%). |
85.5% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2.5h; | (1) in 1L three flask 60.0g (0.44mol) benzo-dioxane, 40.0gDMF, the 78.5g (0.44mol) NBS was dissolved in 200.0g of DMF formulated as a light yellow solution at room temperature 20 , mechanical stirring the solution was slowly added dropwise three bottles, 30min addition was completed, the addition was completed at room temperature for 2h, the reaction was completed, the reaction solution was added 250g of toluene and 250g water, and extracted liquid separation operation, and the organic phase was washed with water, no over anhydrous sodium sulfate, and columned on silica gel, toluene off under reduced pressure to give 80.5g red-brown oil, that is an intermediate in a yield of 85.5%, determined by gas mass spectrometry confirmed the molecular ion peak detected as a target. |
36.9% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h; | The reaction route is as follows:1L three-necked flask was added 54.5g (0.4mol)1,4-benzodioxane,272.5 g DMF.71.2 g (0.4 mol) of NBS was dissolved in 142.4 g of DMF to form a pale yellow solution.Control the internal temperature 0 ~ 20 ,The above solution was slowly added dropwise into a three-necked flask under mechanical stirring,30 minutes plus finishedAnd at 0 to 20 C,Stir for 1 hour.Completed the reaction,To the reaction mixture was added 300 g of toluene and 500 g of water to extract the liquid fraction.The organic phase is washed with water,Dried over anhydrous sodium sulfate,Silica gel column,Decompression solvent was light yellow liquid,The above crude product from toluene,Ethanol (mass ratio of 0.2: 2) recrystallization,31.7 g of colorless liquid was obtained,Yield 36.9%. |
With bromine; sodium carbonate; sodium thiosulfate; In hexane; | Reference Example 68 To a mixture of 1,4-benzodioxane (5.0 g) and sodium carbonate (5.9 g) in hexane (100 ml) was added dropwise at room temperature a solution of bromine (1.9 ml) in hexane (20 ml) for 1 hour and the mixture was stirred for 1 hour. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give orange oil of 6-bromo-2,3-dihydro-1,4-benzodioxine (7.48 g). | |
83%Chromat. | With carbon dioxide; oxygen; lithium bromide; copper(ll) bromide; In water; at 100℃; for 15h;Autoclave; Green chemistry; | General procedure: A mixture of substrate (1 mmol), CuBr2 (22.4 mg, 10 mol%), LiBr (130.3 mg, 1.5 equiv.), and 0.05 mL of water was placed in a 50 mL stainless steel autoclave equipped with an inner glass tube in room temperature. CO2 (4 MPa) and O2 (1 MPa) were subsequently introduced into the autoclave and the system was heated under the predetermined reaction temperature for 15 min to reach the equilibration. Then the final pressure was adjusted to the desired pressure by introducing the appropriate amount of CO2. The mixture was stirred continuously for the desired reaction time. After cooling, products were diluted with acetone and analyzed by gas chromatograph (Shimadzu GC-2014) equipped with a capillary column (RTX-17 30 m × 25 mum and RTX-wax 30 m × 25 mum) using a flame ionization detector by comparing the retention times of authentic samples. The residue was purified by column chromatography on silica gel (200-300 mesh, eluting with petroleum ether/ethyl acetate from petroleum ether to 50:1) to afford the desired product. The isolated products were further identified with NMR spectra (Bruker 400 MHz) and GC-MS or GCD, which are consistent with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 11 g of compound V and 30 ml of anhydrous tetrahydrofuran are placed under argon and cooled to -78 C. 25.6 ml of 2.2 M n-butyllithium in dioxane are added dropwise and the reaction mixture is then stirred at -78 C. for 1 hour. 10.4 ml of chlorodiphenylphosphine are then added dropwise, the temperature being maintained at -60 C. The temperature of the reaction mixture then rises slowly to 0 C. and 20 ml of saturated ammonium chloride solution are added at 0 C. The organic phase is then washed with 2 times 20 ml of saturated sodium chloride solution, dried over magnesium sulfate and filtered and the solvents are evaporated off under reduced pressure to give an orange oil, which crystallizes. The solid is subsequently washed with hot hexane and then filtered off (yield=90%). [0107] 1H NMR (200 MHz) CDCl3: 4.26 (4H, m); 6.80-6.84 (2H, m); 6.85 (1H; d: J=4 Hz); 7.32 (10H, m) [0108] 31P NMR (162 MHz) CDCl3: -4.66 ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | 100.0 g of <strong>[52287-51-1]6-bromo-2,3-dihydro-1,4-benzodioxin</strong> diluted in 200 ml of anhydrous THF are added over about 1 hour, under nitrogen, to a suspension of 12.4 g of magnesium in 31 ml of anhydrous THF, the temperature being maintained below 60 C. After the reaction mixture has been maintained at 60 C. for 2 hours, 107.7 g of chlorodiphenylphosphine are added over 3 hours without exceeding 10 C. in the reaction medium. After the temperature has been maintained at 20 C. for 18 hours, 35 ml of methanol are added. The reaction medium is stirred for one hour and then cooled to 0 C. 30 ml of 35% hydrogen peroxide are then added without exceeding 5 C. in the reaction mixture. After the temperature has been maintained at 20 C. for 2 hours and the solvents have been evaporated off under reduced pressure, the solid obtained is dissolved in 900 ml of hot isopropyl acetate, then washed successively with 3 times 200 ml of 1 N HCl, 150 ml of 1 N aqueous potassium carbonate solution and 150 ml of water and then dried over magnesium sulfate. After 500 ml of solvent have been evaporated off under reduced pressure, the reaction mixture is cooled to 0 C. and filtered and the solid is rinsed with 2 times 30 ml of isopropyl acetate. After drying for 72 hours at 20 C. under reduced pressure, 113 g of a creamy-white solid are obtained (yield=72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With n-butyllithium; In tetrahydrofuran; hexane; water; ethyl acetate; | 4.6.2 Synthesis of Illustrative Compounds of the Invention 4.6.2.1 3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile A solution of <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[1,4]dioxine</strong> (1.09 g, 5.07 mmol) in anhydrous THF (10 ml) was cooled to -78 C., evacuated and refilled with nitrogen for ten cycles. To this clear solution was slowly added n-butyl lithium (2.03 ml, 5.07 mmol) and stirred for 30 min. Then a solution of 3,5-dimethoxybenzaldehyde (0.77 g, 4.61 mmol) in anhydrous THF (10 ml) was added via a syringe. The mixture was stirred at -78 C. under nitrogen for 4 h then quenched with 2-propanol (2.10 ml, 27.65 mmol) and stirred overnight. To the orange colored mixture was added 30 ml of water and extracted with ether (3*60 ml). The combined ether extracts was washed with water (2*60 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,5-dimethoxy-phenyl)-methanol as a light brown oil (1.27 g, 91%), HPLC purity was 93.4% at 3.45 min. (50/50 ACN/0.1% H3PO4): 1H-NMR (CDCl3) delta 6.88-6.79 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.65 (d, J=3 Hz, 1H, CH), 4.22 (m, 4H, 2CH2), 3.77 (s, 6H, OCH3), 2.25 (d, J=3 Hz, 1H, OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With n-butyllithium; In hexane; ethyl acetate; | 2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.87 g, 5.28 mmol), <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[1,4]dioxine</strong> (1.25 g, 5.81 mmol), and n-butyl lithium (2.33 ml, 5.81 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol as an oil (1.37 g, 86%): 1H-NMR (CDCl3) 6.87-6.82 (m, 6H, Ar), 5.63 (d, J=3 Hz, 1H, CHOH), 4.22 (s, 8H, 2CH2CH2), 2.19 (d, J=3 Hz, 1H, OH). The product was carried over to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With n-butyllithium; In hexane; ethyl acetate; | 3,4-dimethoxybenzaldehyde (2.21 g, 13.32 mmol), 6-Bromo-2,3-dihydrobenzo[1,4]dioxine (3.15 g, 14.65 mmol), and n-butyl lithium (5.86 ml, 14.65 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,4-dimethoxy-phenyl)-methanol as an oil (3.60 g, 89%): 1H-NMR (CDCl3) 6.93-6.80 (m, 6H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.24 (s, 4H, CH2CH2), 3.86 (s, 6H, 2OCH3), 2.14 (d, J=3 Hz, 1H, OH). The product was carried over to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With n-butyllithium; In hexane; ethyl acetate; | 3-ethoxy-4-methoxybenzaldehyde (0.92 g, 5.12 mmol), 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.21 g, 5.63 mmol), and n-butyl lithium (2.25 ml, 5.63 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxy-phenyl)-methanol as a yellow solid (0.91 g, 56%): 1H-NMR (CDCl3) 6.92-6.80 (m, 6H, Ar), 5.68 (d, J=3 Hz, 1H, CHOH), 4.23 (s, 4H, 2CH2), 4.07 (q, J=6.90, 14 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 2.13 (d, J=2 Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
114% | With n-butyllithium; In tetrahydrofuran; water; | 4.6.2.89 (E/Z)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3-methoxy-phenyl)-acrylonitrile A stirred mixture of 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.59 g, 7.4 mmol) and dry TRF (10 mL) was cooled to -78 C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.4 mmol) and stirred for 20 min. Then a mixture of 3-methoxy-benzaldehyde (0.92 g, 6.7 mmol) in dry THF (10 mL) was added and stirred for 1 hour at -78 C. The mixture was quenched with isopropanol (3.1 mL, 40 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3*30 mL). The combined organic phases were washed with water (2*30 mL), dried over MgSO4 and concentrated to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-methoxy-phenyl)-methanol as an oil (2.09 g, 114% crude yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sulfuric acid; In dichloromethane; at 20℃; for 2h; | To a solution of 4-bromo-1,2-ethylenedioxybenzene (500 mg, 2.28 mmol) and 1-adamantanol (347 mg, 2.28 mmol) in 1.15 mL of dichloromethane, 0.125 mL (2.28 mmol) of concentrated sulfuric acid were added. The mixture was stirred 2 h at room temperature, poured into water, neutralized with sodium bicarbonate and extracted with dichloromethane. The organic phase was evaporated to obtain a crude that was purified by flash chromatography (hexane/ethyl acetate 95:5) to give 280 mg (35%) of the pure product, mp 166-168 C. 1H NMR (300 MHz, DMSO-d6) : 1.70 (6H, s, 6Ad), 2.00 (9H, s, 9Ad), 4.23 (4H, s, OCH2), 6.74 (1H, d, 1Ar, J = 2.6 Hz), 6.88 (1H, d, 1Ar, J = 2.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 24h;Heating / reflux; | A solution of 5-formyl-2-methoxybenzeneboronic acid (1 g, 5.6 mmol), 3,4- ethylenedioxybromobenzole (1 g, 4.65 mmol) and K2CO3 (1.6 g, 11.6 mmol) in ethanol (20 mL) and toluene (40 mL) was degassed prior to addition of Pd [(PH3)] 4 (54 mg, 0.046 mmol). The mixture was refluxed for 24 hours then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, extracted with ethyl acetate, washed with water and the organic layer dried over sodium sulphate. The crude was purified by column chromatography (heptane/ethyl acetate 7/3) to give 1 g of title compound. [C16HL4O4 MASS] (calculated): [270]; (found): [[M+H+]] = 271,312 NMR (400 MHz, [CDC13)] : 3.95 (3H, s, CH30) ; 4.3 (4H, s, OCH2CH2O0 ; 6.9-7. 15 (4H, m, aryl-H); 7.9-7. 95 (2H, m, aryl-H); 10 [(1H,] s, CHO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 17h; | (B) (2, 3-DIHYDRO-BENZO [1, 4] DIOXIN-6-YL)-[2-(4-TRIFLUOROMETHYL-PHENYL)- pyridin-4-yl]-amine. To an oven-dried 100-mL, round-bottomed flask were added 2- (4-TRIFLUOROMETHYLPHENYL)-PYRIDIN-4-YLAMINE (0. 18 g, 0. 77 mmol) and 6- BROM-1, 4-benzodioxane (ALDRICH Chemical Company) (0. 17 g, 0. 77 MMOL), followed by ANHYDROUS toluene (50 ML). Nitrogen was bubbled through the above solution via needle for 1 H. Palladium acetate (ALDRICH Chemical Company) (26 mg, 0. 12 mmol) and BINAP (ALDRICH Chemical Company) (72 mg, 0. 12 mmol) were then added to the reaction in one portion, followed by sodium TERT-BUTOXIDE (ALDRICH Chemical Company) (0. 21 g, 2. 2 MMOL). The reaction mixture was heated in A 90 C oil bath for 16 H. After cooling to room temperature, the reaction mixture was taken up into ether, and washed with brine. The aqueous layer was extracted with ether (2X 20 ML) and the combined ether layers were dried over NA2S04 and concentrated. The residue was purified on A BIOTAGE 40 S column (2 : 1 hexane : EtOAc), followed by RECRYSTALLIZATION in ETOAC and hexane to provide the title compound as A light-yellow solid. MS (ESI, pos. ion) 771/Z : 373 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); triphenylphosphine; In 1,4-dioxane; water; at 110℃; for 2h; | Add to a 1-neck round-bottom flask (100 mL) under nitrogen triphenylphosphine (0.0997 g, 0.380 mmol), methyl-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2- thiophen-2-yl-phenoxy]ethyl}-amino)-acetic acid tert-butyl ester (0.600 g, 1.27 mmol), 6- bromo-1,4-benzodioxane (0.136 g, 0.634 mmmol) in 1,4-dioxane (20 mL, 0.2 mol) and 2 N aqueous potassium carbonate (20 mL). Degas reaction, add tris (dibenzylideneacetone)dipalladium (0) (0.07 g, 0.08 mmol) heat to 110 C for 2 h. Col to room temperature, filter through CeliteNo. and wash with ethyl acetate (200 mL). Wash The filtrate with water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL) dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 6: 4 hexanes:ethyl acetate) to give the title compound as a clear oil (500 mg, 82.0%). HRMS m/z Calculated: 482.2001; Found: 482.1980 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 160 - 180℃; for 1.25h;Microwave irradiation; | (d) 4-(4-tert-Butylphenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-2-(1H)-one. A glass microwave reaction vessel was charged with 4-(4-tert-butylphenyl)pyridin-2(1H)-one (0.23 g, 1 mmol), 1-bromo-3,4-(ethylenedioxy)-benzene (0.4 mL, 2 mmol), potassium carbonate, powder (0.15 g, 1.1 mmol), copper(I) iodide (19 mg, 0.1 mmol), and N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred and heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 160 C. for 15 min, then at 180 C. for 1 h. The reaction was partitioned between EtOAc (30 mL) and saturated NaCl (20 mL). The aqueous layer was back extracted with EtOAc (3×10 mL) and the combined EtOAc layers were dried (Na2SO4) and concentrated. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 40% EtOAc in hexane, to provide 4-(4-tert-butylphenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-2(1H)-one as white solid. HPLC-MS (A: 0.1% HCOOH in water, B: 0.1% HCOOH in MeCN, 10-100% B for 0.5-7 min, then 100% B through 9.5 min): 7.387 min, area %: 98% (at)215 nM; RT: 7.387 min, area %: 98% (at)254 nM. MS (ESI, pos. ion) m/z: 362.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In toluene; at 150℃; for 1.41667h;Microwave irradiation; | (b) 4-(4-tert-butylphenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidin-2-one. A glass microwave reaction vessel was charged with 4-(4-tert-butylphenyl)-piperidin-2-one (0.28 g, 1.2 mmol), 1-bromo-3,4-(ethylenedioxy)benzene (0.3 ml, 1.3 mmol), copper(I) iodide (11 mg, 0.06 mmol), and potassium carbonate (0.33 g, 2.4 mmol), briefly evacuated, and backfilled with argon. (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (17 mg, 0.12 mmol) dissolved in toulene (3 mL) was added under argon. The tube was sealed and the reaction mixture was stirred and heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150 C. for 30 min, then at the same temperature for another 55 min. The resulting dark suspension was filtered through a pad of Celite and washed with EtOAc (30 mL). The filtrate was concentrated and the residue was purified by flash chromatography on Silica gel through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 25% to 40% EtOAc in hexane, to provide 4-(4-tert-butylphenyl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidin-2-one as off-white solid. HPLC-MS (A: 0.1% HCOOH in water, B: 0.1% HCOOH in MeCN, 10-100% B for 0.5-7 min, then 100% B through 9.5 min): 7.557 min, area %: 100% (at)215 nM; RT: 7.556 min, area %: 100% (at) 254 nM. MS (ESI, pos. ion) m/z: 366.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
D) (2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-[4-(4-isopropyl-phenyl)-6-propargyloxy-quinazolin-2- yl]-methanol; A suspension of 48 mg (2.0 mmol) magnesium turnings in 2 ml THF is treated with 43 mg (2.0 mmol) 6-bromo-1 ,4-benzodioxane solution in 2 ml THF. The reaction mixture is stirred for another 20 minutes at 60 0C1 cooled to room temperature and then added to a cooled solution (5 0C) of 495 mg (1.5 mmol) of 4-(4-isopropyl-phenyl)-6-propargyloxy- quinazoline-2-carbaldehyde (in 6 ml THF). Upon complete addition stirring is continued for one hour at room temperature. The mixture is poured into 20 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The crude material is purified by chromatography on silica gel (dichloromethane/ methanol) to give the alcohol in the form of a light yellow solid.1H-NMR (400 MHz, CDCI3): 8.02 (d, 1H)1 7.73 (d, 2H)1 7.56-7.61 (m, 2H), 7.41 (d, 2H), 7.06-7.11 (m, 2H), 6.81 (d, 1H), 5.94 (d, 1 H), 5.15 (d, 1 H), 4.73 (d, 2H), 4.21 (s, 4H), 3.03 (hept, 1H), 2.58 (t, 1H), 1.33 (d, 6H). MS: 467 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 20 g (92.8 mM) of the compound obtained according to Preparation 1 and 1.2 g (9.28 mM) of nickel chloride are placed in a round-bottom flask equipped with a distillation apparatus. The mixture is stirred and brought to 160 C. and 18.8 ml (111.4 mM) of triethyl phosphite are added dropwise. The reaction mixture is stirred at 160 C. for one hour after the addition has ended, while the bromoethane formed by the reaction is collected by distillation. The reaction medium is then cooled and 50 ml of ethyl ether and 50 ml of ethyl acetate are added. The suspension obtained is filtered and the filtrate is concentrated under reduced pressure. The residue is then purified by chromatography on silica gel using ethyl acetate as the eluent to give 25 g of the expected product in the form of a colorless oil (quantitative yield). [0155] 1H NMR (400 MHz, CDCl3): delta=1.24 (t, J=7.0 Hz, 6H); 4.01 (qd, J=7.0, 9.9 Hz, 4H); 4.20-4.23 (m, 4H); 6.86 (dd, J=8.1, 4.6 Hz, 1H); 7.19-7.22 (m, 2H) [0156] 13C NMR (50 MHz, CDCl3): delta=16.1; 61.8; 64.0; 64.4; 117.5 (d, J=17.5 Hz); 120.9 (d, J=12.0 Hz); 125.3 (d, J=10.0 Hz); 125.5; 143.4 (d, J=20.8 Hz); 147.2 [0157] 31P NMR (162 MHz, CDCl3): delta=20.20 [0158] Mass spectrum (EI): M+=272 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | 602 mg (25.6 mM) of activated magnesium and 1 ml of anhydrous tetrahydrofuran (THF) are placed in a three-necked round-bottom flask under argon. Two drops of 1,3-dibromopropane are added and 5 g (23.3 mM) of compound V dissolved in 10 ml of THF are then added, the temperature being maintained at 0 C. The reaction mixture is stirred for 2 hours at room temperature and then for 1 hour at the reflux point of the solvent. The magnesium compound formed is then added slowly to a solution of 4.84 ml (23.25 mM) of diphenylphosphinic chloride in 5 ml of THF, cooled to -5 C. beforehand. The solution is stirred overnight at room temperature and then concentrated under reduced pressure. The residue is taken up in 20 ml of ethyl acetate and stirred with 10 ml of normal hydrochloric acid solution for 30 minutes. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oil obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (7/3, v/v) as the eluent to give 5 g of the expected product in the form of a pinkish-white solid (yield=59%). [0148] 1H NMR (200 MHz, CDCl3): delta=4.25-4.32 (m, 4H); 6.95 (dd, J=5.1, 8.1 Hz, 1H); 7.10-7.35 (m, 10H); 7.39-7.43 (m, 1H); 7.47 (ddd, 1H) [0149] 13C NMR (50 MHz, CDCl3): delta=64.1; 64.5; 117.7 (d, J=18.5 Hz); 120.5 (d, J=4.5 Hz); 121.6 (d, J=12.7 Hz); 124.9; 125.9 (d, J=10.6 Hz); 129.6; 143.5 (d, J=22.2 Hz); 147.9; 150.5 (d, J=7.4 Hz) [0150] 31P NMR (162 MHz, CDCl3): delta=13.11 [0151] Mass spectrum (EI): M+=368 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 1h; | EXAMPLE 128; N-Cl-Chloro-S-Cl^-dihydrobenzoIblll^ldioxin--y^pyridin-S-ylH- fluorobenzenesulfonamide; To a 50 mL round-bottomed flask was added N-(2-chloro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (62 mg, 150 mumol), 1-bromo- 3,4-(ethylenedioxy)benzene (32 mg, 150 mumol, Aldrich, St. Louis, MO), dichloro 1,1'- bis(diphenylphosphino)ferrocene palladium (II) (12 mg, 15 mumol), Cesium carbonate (98 mg, 300 mumol), dioxane (1 mL), water (0.2 mL). The reaction mixture was stirred at 100 0C for 1 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2 x 30 mL). The organic extract was washed with saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give N- (2-chloro-5-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (51 mg, 81% yield). MS (EI, pos.) calcd for Ci9H14ClFN2O4S: 420.0; found 420.9.. 1H NMR (300 MHz, CHLOROFORM-^) delta ppm 4.32 (s, 4 H) 6.88 - 7.09 (m, 4 H) 7.09 - 7.21 (m, 2 H) 7.74 - 7.87 (m, 2 H) 8.12 (d, J=2.19 Hz, 1 H) 8.30 (d, J=2.34 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With copper(II) ferrite; caesium carbonate; In dimethyl sulfoxide; at 110℃; for 30h;Inert atmosphere; | General procedure: To astirred solution of: Aryl iodide (1.0 mmol), trans-4-Hydroxy-L-proline (1.5 mmol), nano CuFe2O4 (0.01 mmol), base (2 equiv), solvent (3.0 mL), 20h, 100 oC. The progress of the reaction was monitored by TLC. After the reaction was complete CuFe2O4 nano were placed on the bottom of the flask by a neodymium magnet, and the supernatant solution was removed. The crude residue was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were extracted with water, saturated brine solution, and dried over anhydrous Na2SO4.The organic layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography to give the corresponding N-substituted pyrrole in excellent yields. The identity and purity of the product were confirmed by 1H,13C NMR, and mass spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Aluminium chloride (0.49 g, 3.7 mmol) was added to a solution of 6-bromo-1 ,4- benzodioxane (0.50 g, 2.3 mmol) and ethyl chlorooxoacetate (0.35 g, 2.5 mmol) in anhydrous dichloromethane (10 ml.) previously cooled with an ice bath. The reaction mixture was stirred at room temperature overnight and poured into ice water. The mixture was extracted with dichloromethane (2 x 20 ml.) and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to provide ethyl 2-(7- bromo-2,3-dihydro-1 ,4-benzodioxin-6-yl)-2-oxoacetate (6a) (0.71 g, 2.3 mmol, 97%) as a yellow oil which was used without further purification.1 H NMR (300 MHz, CDCI3) «51 .40 (t, J = 7.2 Hz, 3H), 4.25-4.34 (m, 4H), 4.40 (q, J = 7.2 Hz, 2H), 7.13 (s, 1 H), 7.33 (s, 1 H). | |
With aluminum (III) chloride; In dichloromethane; at 20℃; | Step 1: Preparation of intermediate ethyl 2-(7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoacetate (7a) Aluminium chloride (0.49 g, 3.7 mmol) was added to a solution of <strong>[52287-51-1]6-bromo-1,4-benzodioxane</strong> (0.50 g, 2.3 mmol) and ethyl chlorooxoacetate (0.35 g, 2.5 mmol) in anhydrous dichloromethane (10 mL) previously cooled with an ice bath. The reaction mixture was stirred at room temperature overnight and poured into ice water. The mixture was extracted with dichloromethane (2 x 20 mL) and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to provide ethyl 2-(7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoacetate (7a) (0.71 g, 2.3 mmol, 97%) as a yellow oil which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 1.40 (t, J = 7.2 Hz, 3H), 4.25-4.34 (m, 4H), 4.40 (q, J = 7.2 Hz, 2H), 7.13 (s, 1H), 7.33 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With [PhCOPd(PtBu3)I]; dtbpf In 2-methyltetrahydrofuran at 80℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With n-butyllithium; In tetrahydrofuran; at -78 - 20℃; for 0.833333h;Inert atmosphere; | Step 1: 2,3-Dihydro-1 ,4-benzodioxin-6-yltrimethylstannane[00277j n-Butyllithium (3. lml of a 1 .6M solution in hexane, 4.98mmol) was added dropwise under nitrogen to a stirred solution of <strong>[52287-51-1]<strong>[52287-51-1]6-bromo-2,3-dihydro-1,4-benzodioxin</strong>e</strong> (1.OOg, 4.65mmol) in dry THF (20m1) at -78 C. After 45mm, trimethyltin chloride (5.Oml of a 1.OM solution in THF, 5mmol) was added dropwise over 5 mm. After 20 mm the reaction mixture was allowed to warm to room temperature and left overnight. The reaction mixture was poured into brine (1 OOml), extracted with ethyl acetate (3x80m1) and the combined, dried (Na2SO4) organic extracts were evaporated in vacuo to give the title compound (1 .363g, 98%).as a colourless oil. oH (500 MHz, CDC13) 6.78 (d, J 1.1 Hz, 1H), 6.74 (dd, J 7.7, 1.1 Hz, 1H), 6.67 (d, J= 7.7 Hz, 1H), 4.06 (s, 4H), 0.06 (s, 9H). Tr = 2.42 mm; no ionisation. |
98% | Step 1, Method 5: 2,3-Dihydro-l,4-benzodioxin-6-yltrimethylstannane [00185] n-Butyllithium (3.1ml of a 1.6M solution in hexane, 4.98mmol) was added dropwise under nitrogen to a stirred solution of 6-bromo-2,3-dihydro-l,4-benzodioxine (l.OOg, 4.65mmol) in dry THF (20ml) at -78 C. After 45min, trimethyltin chloride (5.0ml of a l.OM solution in THF, 5mmol) was added dropwise over 5 min. After 20 min the reaction mixture was allowed to warm to room temperature and left overnight. The reaction mixture was poured into brine (100ml), extracted with ethyl acetate (3 x80ml) and the combined, dried (Na2S04) organic extracts were evaporated in vacuo to give the title compound (1.363g, 98%).as a colourless oil. deltaEta (500 MHz, CDCb) 6.78 (d, J= 1.1 Hz, 1H), 6.74 (dd, J= 7.7, 1.1 Hz, 1H), 6.67 (d, J= 7.7 Hz, 1H), 4.06 (s, 4H), 0.06 (s, 9H). Tr = 2.42 min; no ionisation. | |
98% | Step 1, Method 4: 2,3-Dihydro-l,4-benzodioxin-6-yltrimethylstannane [00174] n-Butyllithium (3.1ml of a 1.6M solution in hexane, 4.98mmol) was added dropwise under nitrogen to a stirred solution of 6-bromo-2,3-dihydro-l,4-benzodioxine (l.OOg, 4.65mmol) in dry THF (20ml) at -78 C. After 45min, trimethyltin chloride (5.0ml of a l.OM solution in THF, 5mmol) was added dropwise over 5 min. After 20 min the reaction mixture was allowed to warm to room temperature and left overnight. The reaction mixture was poured into brine (100ml), extracted with ethyl acetate (3 x80ml) and the combined, dried (Na2S04) organic extracts were evaporated in vacuo to give the title compound (1.363g, 98%).as a colourless oil. deltaEta (500 MHz, CDCb) 6.78 (d, J= 1.1 Hz, 1H), 6.74 (dd, J= 7.7, 1.1 Hz, 1H), 6.67 (d, J= 7.7 Hz, 1H), 4.06 (s, 4H), 0.06 (s, 9H). Tr = 2.42 min; no ionisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; copper(ll) sulfate pentahydrate; sodium carbonate; sodium L-ascorbate; L-proline; In water; N,N-dimethyl-formamide; at 85℃; | General procedure: A: For aryl azides: Sodium ascorbate (59.4 mg, 0.3 mmol) and CuSO4*5H2O (23 mg, 0.12 mmol) were added to a mixture of aryl bromide (0.6 mmol), sodium azide (59.1 mg, 0.9 mmol), L-proline (13.8 mg, 0.12 mmol) and Na2CO3 (12.7 mg, 0.12 mmol) in 2 mL of DMF/H2O (2:1). The mixture was stirred overnight at 85 C. Then water (8 mL) and concentrated NH4OH (2 mL) were added and the crude mixture was extracted with ether (10 mL x 3), then the combined organic layers were washed with saturated NH4Cl solution and brine, dried over Na2SO4 (anhydrous), filtered and concentrated to give a crude azido compound, which was used as such in the subsequent step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.5% | To a solution of 6-bromo-2,3-dihydrobenzo[b][l,4]dioxine (150 mg, 0.7 mmol) in dioxane (4 ml) and H20 (1 mL) was added l-(3,4-dihydroisoquinolin-2(lH)-yl) -3-(3- (4,4,5, 5-tetramethyl -l,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (428.3 mg, 1.05 mmol), Pd(dppf)Cl2 (51.2 mg, 0.07 mmol) and K2C03 (290.3 mg, 2.1 mmol) at 16 C. The reaction mixture was stirred for 16 h at 100C until TLC indicated the reaction was completed. The mixture was concentrated to get yield a crude which was purified by HPLC separation to give the formate salt of the title compound (136.0 mg, 46.5%) as a white solid. 1HNMR (CH3OD, 400MHz) delta: 8.40 (br, IH), 7.35-7.06 (m, 9H), 6.95-6.49 (m, 2H), 4.51-4.98 (m, IH), 4.40 (s, 2H), 4.28 (s, 4H), 4.14-4.08 (m, 2H), 3.57-3.51 (m, 2H), 3.40-3.29 (m, 2H), 3.21-3.11 (m, 2H). LCMS (m/z): 418.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | [000222] To a solution of 6-bromo-2,3-dihydrobenzo[£][l,4]dioxine (4.9 g, 23 mmol) in THF (100 mL) was added n-BuLi (1.6 M, 15 mL) at -60 C under N2 and stirred for 0.5 h, before a solution of Compound A4 (3 g, 7.6 mmol) in THF (50 mL) was added slowly. The mixture was stirred at -60 C for 1 h, and followed by addition of a saturate NH4C1 solution. The mixture was extracted with ethyl acetate (100 mL x 2), brine (100 mL), and then dried over Na2S04. The crude product was purified by column chromatography on silica gel (ethyl acetate in petroleum, 10%> v/v) to give Compound A5 (3 g, yield 84%>) as a colorless liquid. LC-MS (m/z): 472 [M+l]+; 1H-NMR (CDC13, 400 MHz) peaks: delta (ppm) 0.000 (s, 3H), 0.024(s, 3H), 0.892 (s, 9H), 4.024-4.116 (m, 1H), 4.402-4.465 (m, 4H), 5.262(s, 2H), 5.421 (m, 1H), 6.066 (d, J= 8.0 Hz, 1H), 7.043 (d, J= 8.0 Hz, 1H), 7.444-7.505 (m, 5H), 7.618- 7.639 (m, 2H). | |
[000204j To a solution of <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[b][1,4]dioxine</strong> (4.9 g, 23 mmol) in THF (100 mL)was added n-BuLi (1.6 M, 15 mL) at -60C under N2 and stirred for 0.5 h, before a solution of Compound A4 (3 g, 7.6 mmol) in THF (50 mL) was added slowly. The mixture was stirred at -60 C for 1 h, and followed by addition of a saturated NH4C1 solution. The mixture was extracted with ethyl acetate (100 mL x 2), brine (100 mL), and then dried over Na2SO4. The crude product was purified by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give Compound A5. LC-MS (mlz): 472 [M+1] ?H-NMR (CDC13, 400 MHz) peaks: 5 (ppm) 0.000 (s, 3H), 0.024(s, 3H), 0.892 (s, 9H), 4.024-4.116 (m, 1H), 4.402-4.465 (m, 4H), 5.262(s, 2H), 5.421 (m, 1H), 6.066 (d, J 8.0 Hz, 1H), 7.043 (d, J 8.0 Hz, 1H), 7.444-7.505 (m, 5H), 7.6 18-7.639 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0001134] A mixture of 6-bromo-2,3-dihydrobenzo[b][l,4]dioxane (1.07 g, 5 mmol), NBS (2.1 g, 12 mmol), and AIBN (20 mg) in CC14 (60 mL) was refluxed under nitrogen for 18 h. The mixture was cooled down to room temperature and filtered. The filtrate was washed with water (50 mL x 2) and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was dissolved in acetone (50 mL) and refluxed under nitrogen for 3 h with Nal (3.75 g, 25 mmol). The mixture was cooled down to room temperature and evaporated. The residue was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic layer was washed with aqueous Na2S2C>3 solution (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to yield Compound 319A. | ||
[000839j A mixture of <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[b][1,4]dioxine</strong> (1.07 g, 5 mmol), NBS (2.1 g, 12 mmol), and AIBN (20 mg) in CC14 (60 mL) was refluxed under nitrogen for 18 h. The mixture was cooled down to room temperature and filtered. The filtrate was washed with water (50 mL x 2) and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was dissolved in acetone (50 mL) and refluxed under nitrogen for 3 h with Nal (3.75 g, 25 mmol). The mixture was cooled down to room temperature and evaporated. The residue was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The organic layer was washed with aqueous Na2S2O3 solution (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to yield Compound 143A. ?H-NMR (CDC13, 400 MHz): (5(ppm) 5.86 (s, 2H), 6.49 (d, J 8.8 Hz, 1H), 6.76 (d, J 2.8 Hz, 1H), 6.92 (dd,J= 8.8, 2.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 6-bromo-1,4-benzodioxane With n-butyllithium In tetrahydrofuran; hexane at -70℃; Inert atmosphere; Stage #2: 5-(S)-<3.3.0>-1-aza-2-thia-3-oxabicyclooctane-2,2-dioxide In tetrahydrofuran; hexane at -70 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With palladium diacetate; potassium carbonate; catacxium A; Trimethylacetic acid In 1,4-dioxane at 120℃; for 24h; Inert atmosphere; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 6-bromo-1,4-benzodioxane With magnesium; lithium chloride In tetrahydrofuran at 23℃; Stage #2: 2,2-dimethylmalononitrile In tetrahydrofuran at 0 - 23℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere; | To a screw cap vial were added <strong>[52287-51-1]6-bromo-1,4-benzodioxane</strong> (10c) (211 muL, 1.54 mmol), Pd(PPh3)2Cl2 (55.0 mg, 76.9 mumol), CuI (29.9 mg, 154 mumol), anhydrous DMF (0.31 mL) andEt3N (2.1 mL, 15.4 mmol) at rt. The solution was bubbled with argon gas for 5 min to remove the dissolved gases. Then, trimethylsilylethyne (320 muL, 2.31 mmol) was added, and the reaction mixture was stirred at 90 C for 24 h. Upon completion of the reaction, the reaction mixture was concentrated by rotary evaporation. Purification by column chromatography(hexanes) yielded 11c (108 mg, 30%) as a brown liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 97% | To a 50 mL flask, fresh magnesium ribbon (100 mg, 4.2 mmol) was added, then tetrahydrofuran (4 mL) and a small amount of iodine were added after purging with N2, and then a small amount of a solution of 6-bromine-2,3-dihydrobenzo[b][1,4]dioxine in tetrahydrofuran was added. The reaction mixture was heated to 40 C., then the remaining 6-bromo-2,3-dihydro-benzo[b][1,4]dioxine (645 mg, 3 mmol) was added dropwise after successfully initiating the reaction. The reaction mixture was stirred for about 40 minutes, then a solution of 4-benzyloxy-5-bromine-2-methylbenzaldehyde (305 mg, 1 mmol) in tetrahydrofuran was added in an ice bath. The reaction mixture was stirred for 3 hours, then inorganic substance was filtered off through short column of silica gel, and then the filtrate was concentrated. The resulting residue was purified by flash column chromatography to give (4-benzyloxy-5-bromine-2-methylphenyl)-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-methanol (430 mg, an oil, yield: nearly 97%). 1H NMR (400 MHz, CDCl3): delta 7.73 (s, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.39 (dd, J=10.0, 4.7 Hz, 2H), 7.32 (t, J=7.3 Hz, 1H), 6.85-6.74 (m, 3H), 6.72 (d, J=5.6 Hz, 1H), 5.79 (s, 1H), 5.14 (d, J=7.5 Hz, 2H), 4.24 (s, 4H), 2.15 (s, 3H). | |
To a mixture of <strong>[52287-51-1]<strong>[52287-51-1]6-bromo-2,3-dihydro-1,4-benzodioxin</strong>e</strong> (679 mg, 3.15 mmol, 1.2 equiv) in THF (15 ml) was added n-BuLi (2.5 M in n-hexane) (1.26 ml, 3.15 mmol, 1.2 equiv) dropwise at -78C under N2. The reaction mixture was stirred at -78C for 30 min. 4-(Benzyloxy)-5-bromo-2-methylbenzaldehyde (800 mg, 2.63 mmol, 1.00 equiv) in THF (15 ml) was added dropwise at -78C. The reaction mixture was stirred at -78C for 1 h. Saturated NH4CI (aq) was added and the mixture was extracted with EA thrice. The combined extracts were washed with water, saturated brine and dried over anhydrous Na2SC>4. The mixture was concentrated and the resulting residue purified by chromatography on silica gel (1 :2 EA/PE) to yield (4-(benzyloxy)-5-bromo-2-methylphenyl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 4h;Inert atmosphere; | The A16-1 (73mg, 0.32mmol) was dissolved in dioxane (4mL), was added bis (pinacolato) borate (98mg, 0.39mmol), KOAc (95mg,0.97mmol), Pd (dppf) 2Cl2 (26mg, 0.032mmol), purged with nitrogen, 90 stirred for 4 hours, cooled to room temperature, suction filtered through Celite,The filtrate was spin-dried to give a crude black oil (213mg), was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.6% | With potassium tert-butylate; palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 105 - 110℃; for 6.5h;Inert atmosphere; | (5) 1L three flask was added 82.4g (0.38mol) of Intermediate 1,48.6g (0.32mol) of intermediate 3 (prepared in Example 1 through the embodiment), 59.1g (0.53mol) of potassium tert-butoxide, 500g of toluene, a nitrogen gas protection was added 0.7g (3.0 × 10-3mol) of palladium acetate, 1.7g (6.0 × 10-3) (t-Bu) 3PH · BF4, was heated to 105 ~ 110 6.5h under reflux the reaction, the reaction was completed, the reaction solution was filtered, The filtrate was washed with 300g of water, dried over anhydrous sodium sulfate, and columned on silica gel, removal of toluene to give a tan powder. The above tan powdery solid by toluene, n-hexane (mass ratio 1: 1) and recrystallized to give 41.7g light yellow powdered solid, yield: 45.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With palladium diacetate; XPhos; In 1,4-dioxane; at 100℃; for 32h;Inert atmosphere; | tert-butyl 2-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (200 mg, 0.52 mmol) was placed under argon with <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[b][1,4]dioxine</strong> (135 mg, 1.3 eq, 0.52 mmol), Pd(OAc)2 (11 mg, 0.1 eq, 0.05 mmol) and XPhos (74 mg, 0.3 eq, 0.15 mmol). Anhydrous dioxane (4 ml) was added and the reaction was stirred for16h at 100C before addition of more Pd(OAc)2 (11 mg) and XPhos (74 mg). Heating was continued for 16h before cooling to r.t. and adding water (10 ml) and EtOAc (10 ml) to the mixture. The organic phase was extracted with EtOAc (2x10 ml) and the organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2:EtOAc 95:5 to 85: 15) to afford the deprotected coupling compound as a yellow solid (40 mg, 30%). 1H-NMR (300 MHz, CDCl3): 4.34 (s, 4H), 6.66 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 7.8, 4.9 Hz, 1H), 7.32 (dd, J = 8.4, 2.2 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.92 (dd, J= 7.8, 1.5 Hz, 1H), 8.30 (dd, J= 4.9, 1.5 Hz, 1H), 11.38 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / -15 - -10 °C 1.2: 17 h / 0 - 20 °C 2.1: aluminum isopropoxide; isopropyl alcohol / toluene / 16 h / 50 °C / Inert atmosphere 3.1: hydrogenchloride / ethyl acetate; isopropyl alcohol / 3 h / 50 °C 4.1: dimethylaminoacetic acid; caesium carbonate; copper(l) iodide / 0.5 h / 110 °C 4.2: 19 h / 110 °C / Sealed tube 5.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 2.5 h / 20 °C 6.1: lithium hydroxide / methanol; water; tetrahydrofuran / 3 h 7.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.1% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; DPEphos; sodium t-butanolate; In toluene; at 100 - 108℃; for 8h;Inert atmosphere; | The reaction route is as follows:250mL three-necked flask was added 2.66g (0.01mol)1,1-bis (4-aminophenyl) cyclohexane,9.66 g (0.045 mol) of Intermediate 1 (prepared by Example VII),4.80 g (0.05 mol) sodium tert-butoxide,53.2 g toluene.Nitrogen gas protection 0.281 g (4.0 × 10 -4 mol) of Pd (dppf) Cl 2,0.430 g (8.0 × 10 -4 mol) DPEphos,The temperature was raised to 100 C to 108 C and refluxed for 8 hours.Completed the reaction,Add 50g water twice,Dried over anhydrous sodium sulfate,The solvent was removed under reduced pressure to give a tan solid.The above crude product was treated with THF,Toluene (mass ratio of 0.5: 5) recrystallization,Got 6.6g light yellow powder,Yield: 82.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 12 h / 153 °C 2.1: trifluoroacetic acid; sulfuric acid / 5 h / Reflux 2.2: Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In N,N-dimethyl-formamide; at 153℃; for 12h; | General procedure: A mixture of 0.01 mol bromo derivative 3c-3g, 4, 6a-6e, or 9 and 0.015 mol of CuCN in 5 mL of DMF was heated to 110-120C (or 153C) and was stirred for 12 h. The mixture was cooled and poured into a solution of 6 g of FeCl3 · 6 H2O and 1.5 mL of aqueous HCl in 10 mL of water, the resulting mixture was stirred for 0.5 h at 70-90C and cooled to room temperature, and the precipitate was filtered off, washed with water, and recrystallized from appropriate solvent. Oily compounds were extracted with chloroform, the extract was evaporated, and the residue was purified by chromatography on an Al2O3 plate. Compounds 7g (yield 36%) and 8 (yield 62%) were described previously [16, 17]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 1h; | To a 50 mL two-neck flask were added N-(1-((1-cyanocyclopropyl)carbamoyl)-4,4-difluorocyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)benzofuran-2-carboxamide (110 mg, 0.21 mmol), toluene (6 mL), ethanol (2 mL) and 3-(4-bromophenyl)oxetan-3-amine (50 mg, 0.22 mmol), then tetrakis(triphenylphosphine)palladium(0 (25 mg, 0.02 mmol) was added under nitrogen protection, and aqueous potassium carbonate (2 nol/L, 0.4 mL) was added into the reaction mixture. The resulting mixture was stirred at 90 C for 1 h. The reaction mixture was cooled to rt and to the mixture was added saturated brine (20 mL). The resulting mixture was extracted with EtOAc (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 (DCM:MeOH=10:1, V/V)to give white powder (60 mg, 52.6%).the title compound was prepared according to the procedure described in step 4 of example 1 using <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[b][1,4]dioxine</strong> (35 mg, 0.16 mmol), N-(1-((1-cyanocyclopropyl)carbamoyl)-4,4-difluorocyclohexyl)-6-(4,4,5,5-tetramethyl-1,3,2-dio xaborolan-2-yl)benzofuran-2-carboxamide (0.10 g, 0.19 mmol), Pd(dppf)Cl2·CH2Cl2 (14 mg, 0.017 mmol), DMF (8 mL) and aqueous potassium carbonate (0.16 mL, 0.32 mmol, 2 mol/L) to give a white solid (45 mg, 53%). MS (ESI, pos.ion) m/z:522.20 (M+1); 1H NMR (400 MHz, DMSO-d6) delta 8.77 (s, 1H), 8.46 (s, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 11.0 Hz, 2H), 6.97 (d, J = 8.2 Hz, 1H), 4.29 (s, 4H), 2.21 (s, 2H), 2.06 (d, J = 14.7 Hz, 4H), 1.45 (s, 2H), 1.24 (s, 2H), 1.07 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃; for 0.25h; | (1) Dissolving 0.01 mol of <strong>[52287-51-1]6-bromo-1,4-benzodioxane</strong> in 5 mL of DMSO,A solution was obtained, and 0.016 mol of bis(neopentyl glycol) diboron was dissolved in 4 mL of DMSO.Obtaining B solution, 0.005 mol of PbCl2 (dppf) and0.02 mol of potassium acetate is immobilized on the continuous flow reactor channel,Continuous addition of solution A and solution B at 90 CAfter 15 min, the reaction was terminated after exiting the reaction tube to obtain an intermediate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tris-(dibenzylideneacetone)dipalladium(0); C22H29O3P; lithium hexamethyldisilazane; In tetrahydrofuran; toluene; at 70℃;Inert atmosphere; Sealed tube; | General procedure: All reactions were conducted in 10 mL glass vials fitted with crimpcap septum caps. The reaction vial, equipped with a magnetic stir bar,was charged under an N2 atmosphere with 1-methylindolin-2-one (4)(73.6 mg, 0.5 mmol), Pd2(dba)3 (10 mg, 0.011 mmol, 2.5 mol%), i-Pr-BI-DIME (7) (0.022 mmol, 5 mol%), LiHMDS (1 M in toluene, 0.55 mL,0.55 mmol) and the aryl halide (1.1 equiv), then sealed with a crimpcap septum. THF (0.5 mL) and toluene (0.5 mL) were added via syringe and the reaction was heated to 70 C for 4-24 h. The reaction mixture was cooled to room temperature then filtered through a Celite pad with EtOAc (5 mL) as eluent. The filtered solution waswashed with H2O (3 mL), dried over MgSO4 and then concentrated under reduced pressure. The crude residue was purified using a 12 g silica column (30% EtOAc/hexanes) to afford the corresponding oxindole product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With palladium diacetate; caesium carbonate; ruphos; In water; toluene; at 90℃; for 4h;Inert atmosphere; | A mixture of <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[b][1,4]dioxine</strong> (1.081 g, 4.87 mmol), potassium (2-((tert- butoxycarbonyl)amino)ethyl)trifluoroborate (1.417 g, 5.36 mmol) and cesium carbonate (4.764 g, 14.60 mmol) in toluene (33 mL) and water (11 mL) is degassed three times with nitrogen. Palladium(ll) acetate (54.8 mg, 0.244 mmol) and RuPhos (239 mg, 0.48 mmol) are added and the mixture is heated to 90C,under nitrogen, for 4h. The RM is allowed to cool to RT, water is added and the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over anh. MgSO4, filtered and concentrated under reduced pressure. Purification by FC (from heptane to heptane/EtOAc = 1/1) affords tert-butyl (2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate as a pale yellow solid (1.230 g, 90%). LCMS B: tR = 0.91 mm; no ionization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | 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 |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; In tetrahydrofuran; at 70℃; for 6h; | General procedure: To a solution of 3,5-dimethoxybromobenzene (0.2 g, 0.92mmol,1.0 equiv.) in THF (20mL) was added compound 20 (192 mg,0.82mmol, 0.9 equiv.), potassiumtert-butoxide (155mg, 1.38mmol,1.5 equiv.), tris(dibenzylideneacetone)dipalladium (0.01 equiv.) andbis(2-diphenylphosphinophenyl)ether (0.01 equiv.). The mixturewas refluxed for 6 h. After the reaction was completed, the solventwas removed at reduced pressure, and the residue was treated with10 mL water and extracted with ethyl acetate (3 30 mL). Thecombined organic phases were dried (Na2SO4), and the solvent wasremoved at reduced pressure. The crude residue was purified bycolumn chromatography with petroleum/ethyl acetate (6:1) to give21a as a pale yellow solid (0.24 g, 70%). 1H NMR (300MHz, CDCl3)delta7.51 (d, J 8.6 Hz, 1H), 6.60 (m, 2H), 6.42 (d, J 2.1 Hz, 2H), 6.34 (s,1H), 5.68 (d, J 10.0 Hz, 1H), 4.20 (s, 2H), 3.76 (s, 3H), 3.77 (s, 6H),1.45 (s, 6H); 13C NMR (75 MHz, CDCl3) delta198.2, 157.3, 155.9, 148.3,147.3, 130.7, 130.1, 127.1, 124.3, 121.2, 116.0, 114.3, 112.2, 112.2, 110.6,76.4, 62.8, 55.3, 55.9, 47.7, 27.5; HRESI-MS m/z calcd for C22H24O5369.1697 [MH], found 369.1741. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; potassium hydroxide; In 2-methyltetrahydrofuran; at 75℃; for 16h;Inert atmosphere; | Step A: Compound 12 (100.00mg, 212.13umol, 1.00eq) and 6-bromo-1,4-benzodioxan (68.42mg, 318.19umol,42.76uL, 1.50eq) were weighed and dissolved in 2-methyltetrahydrofuran (4.00mL) under nitrogen atmosphere, followedby addition of potassium hydroxide (66.65mg, 1.19mmol, 5.60eq) (dissolved in 500.00uL water) and dichlorobis(triphenylphosphine)palladium(II) (7.44mg, 10.61umol, 0.05eq), the reaction solution was stirred at 75C for 16 hours. Aftercompletion of the reaction, the reaction solution was filtered through silica gel (100-200 mesh), the silica gel was washedwith ethyl acetate (30mL), the filtrate was combined and concentrated to give the crude product 75 as a dark brown oil(210.00mg), which was directly used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With palladium diacetate; sodium t-butanolate; XPhos; In toluene; tert-butyl alcohol; at 110℃; for 24h; | General procedure: Using method O, tert-butyl (1R,5S)-3-(1 ,1-dioxidothiomorpholine-4-carbonyl)-9,9-dimethyl-3,6- diazabicyclo[3.2.2]nonane-6-carboxylate (100 mg, 0.24 mmol) was reacted in dichloromethane (2 ml_) with trifluoroacetic acid (1 ml_) for 1 h. The volatile components were removed under reduced pressure to give crude ((1S,5S)-9,9-dimethyl-3,6-diazabicyclo[3.2.2]nonan-3-yl)(1,1-dioxidothiomorpholino)methanone (83 mg). fe/ -Butanol and toluene (2 ml_, 1 :3 v/v) were added, followed by X-Phos (1 1 .5 mg, 0.02 mol), palladium(ll) acetate (2.7 mg, 0.01 mol), sodium tert- butoxide (1 16 mg, 1 .20 mmol) and <strong>[52287-51-1]6-bromo-1,4-benzodioxane</strong> (39 muIota_, 0.29 mmol). The reaction mixture was heated to 110 C for 24 h. After allowing to cool, the volatile components were removed in vacuo. Workup and column chromatography (cyclohexane/ethyl acetate) gave ((1S,5S)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9,9-dimethyl-3,6-diazabicyclo[3.2.2]nonan-3-yl)(1,1-dioxidothiomorpholino)methanone (25 mg, 23%). 1H NMR (500 MHz, Chloroform-d) delta 6.79 (d, J = 9.2 Hz, 1 H), 6.16 (s, 2H), 4.31 - 4.16 (m, 6H), 3.92 (d, J = 10.0 Hz, 2H), 3.80 - 3.71 (m, 1 H), 3.69 - 3.58 (m, 1 H), 3.36 (d, J = 1 1 .8 Hz, 3H), 3.26 - 3.09 (m, 1 H), 3.04 - 2.91 (m, 1 H), 2.53 (t, J = 7.5 Hz, 2H), 2.18 (s, 2H), 1 .67 (d, J = 13.9 Hz, 2H), 1 .44 (dd, J = 13.9, 6.6 Hz, 1 H), 0.96 (s, 3H), 0.90 (s, 3H). HRMS calculated for C22H32N3O5S [M+H]+450.2063; found 450.2047. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17 g | Tetrahydrofuran (75 ml) was added to 6-bromo-2,3-dihydrobenzo[&][l,4]dioxine (15.4 gms) at 25-30C. Cooled the reaction mixture to -75 C and added n-BuLi (81.7 ml) and stirred for 30 min at the same temperature. To this reaction mixture slowly added a solution of tert-b ty 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (15 gms in 75 ml of THF) at -75C and stirred for 20 min at the same temperature. Heated the reaction mixture to 25-30C and stirred for 10 hrs. 5% Aqueous ammonium chloride solution (3.5 gms in 75 ml of water) was added to the reaction mixture at 0-5 C and stirred for 20 min at the same temperature. Heated the reaction mixture to 25-30C. Ethyl acetate (150 ml) was added to the reaction mixture and stirred for 15 min. Separated the both aqueous and organic layers and extracted the aqueous layer with ethyl acetate. Combined the total organic layers and distilled off the solvent completely from the organic layer under reduced pressure to provide the title compound. (Yield: 17.0 gms). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.7% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In ethanol; water; toluene; at 95℃; for 12h;Inert atmosphere; | To a solution of 6-bromo-2,3-dihydrobenzo[b][l,4]dioxine (6 g, 0.027 mol) and (2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (8.3 g, 33 mmol) in Toluene:Ethanol:water (1: 1: 1) (120 mL) at room temperature, potassium carbonate (11.5 g, 83 mmol) was added and degassed the mixture at room temperature for 15 min using nitrogen. To this mixture, Pd(dppf)Ci2- DCM complex (1.4 g, 1.3 mmol) was added and the reaction mixture was degassed again for 10 min using nitrogen. After stirring the reaction mixture at 95C for 12 h, the mixture was cooled to room temperature and filtered through celite pad. The filtrate was diluted with water (100 mL) and the aqueous mixture was extracted with EtOAc (2 x 500 mL). The organic layer was washed with brine (500 mL), dried over sodium sulfate and concentrated to get crude compound. The resulting crude was purified by column chromatography (silica gel, 100-200 mesh) using hexanes as eluent to afford (3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylphenyl)methanol (Yield: 7 g, 97.9%) as light red liquid. lH NMR (400 MHz, DMSO-d6): delta 2.12 (s, 3H), 4.27 (m, 4H), 4.52 (m, 2H), 5.75 (s, 1H), 6.90 (m, 2H), 7.05 (m 1H), 7.16 (m, 1H), 7.20 (m, 1H), 7.36 (m, 1H). |
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In ethanol; water; toluene; at 90℃; for 8h;Inert atmosphere; Sealed tube; | A mixture of 6-bromo-2,3-dihydrobenzo[b][l,4]dioxine (5 g, 0.023 mol), (2- methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (8.6 g, 0.034 mol), potassium carbonate (9.5 g. 0.069 mol), toluene (50 mL), water (50 mL) and EtOH (50 mL) was degassed with nitrogen gas for 15 minutes. To this mixture, PdCl2(dppf)DCM (0.93 g, 1.15 mmol) was added and degassed for another 5 minutes with nitrogen. After sealing the vessel, the mixture was heated at 90C for 8h. After completion, the reaction was diluted with water (300 mL) and extracted with EtOAc (3 x 300 mL). The organic layer was dried over sodium sulphate and concentrated. The crude was purified by column chromatography (silica gel, 100-200 mesh) using 0-30% EtOAc in hexanes to obtain (3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- methylphenyl)methanol (Yield: 5.8 g, 97%) as yellow sticky liquid. 1H NMR (400 MHz, DMSO-de) d ppm: 2.11 (s, 3H), 4.27 (s, 4H), 4.51 (m, 2H), 5.10 (m, 1H), 6.69-6.74 (m, 2H), 6.89 (d, J= 7.6 Hz, 1H), 7.04 (d, J= 7.6 Hz, 1H), 7.18 (t, J= 7.6 Hz, 1H), 7.35 (d, J= 7.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With tetrakis(triphenylphosphine) palladium(0); triethylamine; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; Sealed tube; | To a solution of 4-ethynyl-2-methylpyridine (1 g, 8.5mmol) in DMF were added 6- bromo-2,3-dihydrobenzo[b][1 ,4]dioxine (1.82g, 8.5mmol) and triethylamine (7.2ml_, 51.2mmol) at rt. The reaction mixture was purged with N2 gas for 10 min and Pd(PPh3)4 was added to it. The reaction mixture was again purged with N2 gas for 5 min. The reaction vessel was sealed and stirred at 80C for 16h. The TLC showed the reaction to be complete. The reaction mixture was diluted with ice-cold water (50ml_) and extracted with EtOAc (3x25ml_). The organic layer was dried (Na2S04), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel (100-200 mesh), eluting with 22% EtOAc in hexane to afford 4-((2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)ethynyl)-3-methylpyridine as a yellow solid. Yield: 880mg (41 %); MS (ESI+) for CHNOS m/z 252.09 [M+H]+. 1 H NMR (400 MHz, DMSO-d6): 5 8.45 (d, J = 4.9Hz, 1 H), 7.23-7.53 (m, 2H), 7.05-7.10 (m, 2H), 6.92 d, J = 8.2Hz, 1 H), 4.28 (bs, 4H), 2.47 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of <strong>[52287-51-1]6-bromo-2,3-dihydrobenzo[b][1,4]dioxine</strong> (3.7 g, 17.21 mmol, 1.11 equiv) in THF (80 ml_) was added n-BuLi (2.5 M in hexane, 7.5 ml_, 1.20 equiv) dropwise at -78C. The reaction mixture was stirred for 1 h at - 78C. To the reaction mixture was added a solution of 4-(benzyloxy)-5-bromo-2-methoxybenzaldehyde (5.0 g, 15.57 mmol, 1.00 equiv) in THF (20 ml_) dropwise at -78C. The reaction mixture was stirred for 3 h at -78C. NH4CI/H2O was added and the mixture was extracted with EtOAc thrice. The combined extracts were washed with brine and dried over Na2S04. The filtrate was concentrated to yield (4-(benzyloxy)-5-bromo-2-methoxyphenyl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol as a yellow oil. MS (ES) m/z 441.1 [M-OH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | To an oven-dried round bottom flask containing Mg turnings (2.56 g, 0.10 mol) and LiCI (3.70, 0.087 mol) was added dry THF (100 mL) at RT and the mixture was stirred for 5 min. DIBAL-H (0.7 ml_, 0.69 mmol, 1 mol%, 1 M in THF) was added dropwise at RT and the mixture was further stirred for 5 minutes. It was then cooled to 0 C and 6-bromo-2, 3-dihydrobenzo[b][1 ,4]dioxine (15 g, 0.07 mol, 1.0 equiv.) in dry THF (15 mL) was added dropwise. After the initial heat evolution the reaction mixture was removed from the ice bath and allowed to stir for 1 h at RT. (0367) To the stirred solution of tert-butyl 2-oxopyrrolidine-1 -carboxylate (1 1.66 g, 0.06 mol) in dry THF (100 mL), above Grignard reagent was added at -78 C dropwise and stirred at same temperature for 2 h. After completion of reaction the reaction mixture was warmed to RT and quenched with 1.5M HCI (50 mL). The aqueous phase was extracted with EtOAc (2 x 250 mL). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 25% EtOAc in pet ether) to give the title compound. Yield: 86% (19 g, Pale yellow solid). 1H NMR (400 MHz, DMSO-cfe): d 7.46 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1 H), 6.85 (s, 1 H), 4.29 (s, 4H), 2.99-2.90 (m, 4H), 1.71 -1.66 (m, 2H), 1.37 (s, 9H). LCMS: (Method A) 222.1 (M-Boc), Rt. 2.72 min, 75.31 % (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.2 % | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In 1,4-dioxane Reflux; Inert atmosphere; | 51.4 The preparation method of acridine compound 3 adopts steps 1) and 2) of Example 1 to obtain the compound of formula V, which also includes the following steps: 3) dissolving the compound of formula V (107mg, 0.5mmol) in phenol (5mL), Ammonium carbonate (192.18mg, 1mmol) was added, heated to 120°C for reaction, and the reaction progress was monitored by TLC.After the reaction was completed, ethyl acetate and water were added to the reaction system for extraction, the organic phase was dried with anhydrous magnesium sulfate, filtered, and after the solvent was removed by rotary evaporation, the intermediate compound of formula VI was obtained by column chromatography with a yield of 83.2%. .4) Compound of intermediate formula VI (214mg, 1.1mmol), 6-bromo-1,4-benzoxane (215mg, 1mmol), bis(dibenzylideneacetone) palladium (35mg, 0.06mmol), tetrafluoro Tri-tert-butylphosphine borate (17mg, 0.06mmol) and sodium tert-butoxide (111mg, 1.15mmol) were dissolved in dry 1,4-dioxane (10mL), refluxed for 10 hours under nitrogen protection, and cooled To room temperature, deionized water (50mL), saturated sodium sulfite (15mL) and dichloromethane (50mL) were successively added to the reaction system, and stirred for about 30 minutes. Dry over magnesium sulfate, filter, spin evaporate to remove the solvent, and separate by column chromatography to obtain acridine compound 3 with a yield of 63.2%. |
63 % | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In 1,4-dioxane at 100℃; Inert atmosphere; | 4.4. Synthesis of compounds 6f-h, 6aa General procedure: To a solution of compound 5 (1.0 mmol) in 1,4-dioxane (10 mL) wasadded different substituted alkyl bromide (1.2 mmol), bis(dibenzylideneacetone)palladium (0.06 mmol), tri-tert-butylphosphonium tetrafluoroborate(0.06 mmol) and t-BuONa (1.15 mmol), the reactionmixture was stirred under nitrogen protection at 100 C. After completionof the reaction, the solvent was removed in vacuo, and the residuewas diluted with DCM (25 mL) and washed with brine (3 × 25 mL). Theorganic layer was dried over anhydrous MgSO4, filtered, and concentratedunder vacuum. The residue was purified by column chromatographyto give the compounds 6f-h, 6aa.N-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)acridin-9-amine (6f), redsolid; mp 108.8-110.3 C; yield, 63%; 1H NMR (400 MHz, DMSO-d6) 10.73 (s, 1H), 7.93-7.42 (m, 1H), 7.00 (s, 2H), 6.78 (d, J = 8.4 Hz, 1H),6.25 (dd, J = 14.9, 6.4 Hz, 2H), 4.23 (s, 4H). 13C NMR (100 MHz,DMSO-d6) 144.0, 138.1, 131.0, 117.7, 111.0, 106.5, 64.2, 63.9. HRMS(ESI) calcd for C21H16N2O2 [M + H]+, 329.1285; found, 329.1289. |
63 % | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In 1,4-dioxane at 100℃; Inert atmosphere; | 4.4. Synthesis of compounds 6f-h, 6aa General procedure: To a solution of compound 5 (1.0 mmol) in 1,4-dioxane (10 mL) wasadded different substituted alkyl bromide (1.2 mmol), bis(dibenzylideneacetone)palladium (0.06 mmol), tri-tert-butylphosphonium tetrafluoroborate(0.06 mmol) and t-BuONa (1.15 mmol), the reactionmixture was stirred under nitrogen protection at 100 C. After completionof the reaction, the solvent was removed in vacuo, and the residuewas diluted with DCM (25 mL) and washed with brine (3 × 25 mL). Theorganic layer was dried over anhydrous MgSO4, filtered, and concentratedunder vacuum. The residue was purified by column chromatographyto give the compounds 6f-h, 6aa.N-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)acridin-9-amine (6f), redsolid; mp 108.8-110.3 C; yield, 63%; 1H NMR (400 MHz, DMSO-d6) 10.73 (s, 1H), 7.93-7.42 (m, 1H), 7.00 (s, 2H), 6.78 (d, J = 8.4 Hz, 1H),6.25 (dd, J = 14.9, 6.4 Hz, 2H), 4.23 (s, 4H). 13C NMR (100 MHz,DMSO-d6) 144.0, 138.1, 131.0, 117.7, 111.0, 106.5, 64.2, 63.9. HRMS(ESI) calcd for C21H16N2O2 [M + H]+, 329.1285; found, 329.1289. |
63.2 % | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In 1,4-dioxane Reflux; Inert atmosphere; | 51.4 The preparation method of acridine compound 3 adopts steps 1) and 2) of Example 1 to obtain the compound of formula V, which also includes the following steps: 3) dissolving the compound of formula V (107mg, 0.5mmol) in phenol (5mL), Ammonium carbonate (192.18mg, 1mmol) was added, heated to 120°C for reaction, and the reaction progress was monitored by TLC.After the reaction was completed, ethyl acetate and water were added to the reaction system for extraction, the organic phase was dried with anhydrous magnesium sulfate, filtered, and after the solvent was removed by rotary evaporation, the intermediate compound of formula VI was obtained by column chromatography with a yield of 83.2%. .4) Compound of intermediate formula VI (214mg, 1.1mmol), 6-bromo-1,4-benzoxane (215mg, 1mmol), bis(dibenzylideneacetone) palladium (35mg, 0.06mmol), tetrafluoro Tri-tert-butylphosphine borate (17mg, 0.06mmol) and sodium tert-butoxide (111mg, 1.15mmol) were dissolved in dry 1,4-dioxane (10mL), refluxed for 10 hours under nitrogen protection, and cooled To room temperature, deionized water (50mL), saturated sodium sulfite (15mL) and dichloromethane (50mL) were successively added to the reaction system, and stirred for about 30 minutes. Dry over magnesium sulfate, filter, spin evaporate to remove the solvent, and separate by column chromatography to obtain acridine compound 3 with a yield of 63.2%. |
[ 39255-23-7 ]
1-Bromo-4-(2-methoxyethoxy)benzene
Similarity: 0.92
[ 79440-34-9 ]
6-(Bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine
Similarity: 0.69
[ 10288-36-5 ]
2,3-Dihydrobenzo[b][1,4]dioxin-5-ol
Similarity: 0.65
[ 39270-39-8 ]
(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methanol
Similarity: 0.63
[ 493-09-4 ]
2,3-Dihydrobenzo[b][1,4]dioxine
Similarity: 0.60
[ 823225-66-7 ]
Methyl 8-bromo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate
Similarity: 0.60
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