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CAS No. : | 84459-33-6 | MDL No. : | MFCD09056792 |
Formula : | C7H4BrClO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AJOAHIKYBSZIEV-UHFFFAOYSA-N |
M.W : | 219.46 | Pubchem ID : | 13154710 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.54 |
TPSA : | 17.07 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) : | -5.3 cm/s |
Log Po/w (iLOGP) : | 1.93 |
Log Po/w (XLOGP3) : | 3.29 |
Log Po/w (WLOGP) : | 2.92 |
Log Po/w (MLOGP) : | 2.79 |
Log Po/w (SILICOS-IT) : | 3.3 |
Consensus Log Po/w : | 2.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.65 |
Solubility : | 0.049 mg/ml ; 0.000223 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.32 |
Solubility : | 0.104 mg/ml ; 0.000475 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.82 |
Solubility : | 0.0331 mg/ml ; 0.000151 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.33 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridinium chlorochromate In dichloromethane for 2 h; | Add pyridinium chlorochromate (432 mg, 2 mmol) to a solution of 2-bromo-4- chlorobenzyl alcohol (200 mg, 0.9 mmol) in dichloromethane (4 mL). Stir the resulting mixture for 2 h. Add diethyl ether (4 mL) and stir for 20 "min. Decant the diethyl ether solution. Wash the remaining solids with diethyl ether twice. Combine the diethyl ether solutions and concentrate. Chromatograph on silica gel, eluting with 20:80 to 1:1 ethyl acetate:dichloromethane to give 2-bromo-4-chlorobenzaldehyde as a white solid (167 mg, 85percent). |
81% | With sulfur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1 h; | To a 0 °C solution of (2-bromo-4-chloro-phenyl)-methanol (5.57 g, 0.025 mol), dichloromethane (250 ml_), diisopropylethylamine (22 ml_, 0.126 mol), and dimethyl sulfoxide (15 ml_, 0.211 mol) was added sulfur thoxide-pyhdine (12.0 g, 0.075 mol), in portions, over 15 minutes. The resulting solution was stirred at 0 °C for 45 minutes. The reaction mixture was diluted with 250 ml_ dichloromethane, then washed with saturated aqueous NaHCO3 (500 ml_). The organic phase was washed with saturated aqueous sodium thiosulfate (500 ml_) to reduce excess oxidant. The organic phase was dried over Na2SO4, filtered and concentrated to afford a yellow oily solid. A solution of this crude product and CH2CI2 (200 ml_) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes-ethyl acetate). 2-Bromo-4-chloro-benzaldehyde was isolated as 4.43 g (81percent yield) of a white solid. 1H NMR (300 MHz, CDCI3) δ ppm 10.31 (s, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 1.6 Hz, 1 H), 7.44 (dd, J = 8.2, 1.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridinium chlorochromate; In dichloromethane; for 2h; | Add pyridinium chlorochromate (432 mg, 2 mmol) to a solution of 2-bromo-4- chlorobenzyl alcohol (200 mg, 0.9 mmol) in dichloromethane (4 mL). Stir the resulting mixture for 2 h. Add diethyl ether (4 mL) and stir for 20 "min. Decant the diethyl ether solution. Wash the remaining solids with diethyl ether twice. Combine the diethyl ether solutions and concentrate. Chromatograph on silica gel, eluting with 20:80 to 1:1 ethyl acetate:dichloromethane to give 2-bromo-4-chlorobenzaldehyde as a white solid (167 mg, 85%). |
81% | With sulfur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | To a 0 C solution of (2-bromo-4-chloro-phenyl)-methanol (5.57 g, 0.025 mol), dichloromethane (250 ml_), diisopropylethylamine (22 ml_, 0.126 mol), and dimethyl sulfoxide (15 ml_, 0.211 mol) was added sulfur thoxide-pyhdine (12.0 g, 0.075 mol), in portions, over 15 minutes. The resulting solution was stirred at 0 C for 45 minutes. The reaction mixture was diluted with 250 ml_ dichloromethane, then washed with saturated aqueous NaHCO3 (500 ml_). The organic phase was washed with saturated aqueous sodium thiosulfate (500 ml_) to reduce excess oxidant. The organic phase was dried over Na2SO4, filtered and concentrated to afford a yellow oily solid. A solution of this crude product and CH2CI2 (200 ml_) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes-ethyl acetate). 2-Bromo-4-chloro-benzaldehyde was isolated as 4.43 g (81% yield) of a white solid. 1H NMR (300 MHz, CDCI3) delta ppm 10.31 (s, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 1.6 Hz, 1 H), 7.44 (dd, J = 8.2, 1.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Add <strong>[84459-33-6]2-bromo-4-chloro-benzaldehyde</strong> (3.5 g, 16 mmol) in DCM (6 mL) to a flask that contains zinc iodide (8 mg). Stir the mixture at RT for 30 min. Cool the mixture to 0 0C with an ice-water bath. Add trimethylsilylcyanide (2.14 mL, 15.99 mmol) to the vigorously stirred mixture. Remove the cooling bath and stir at RT for 18 h. Add DCM (20 mL) and cool the mixture to 0 0C. Add a solution of diethylaminosulfurtrifluoride (2.32 mL, 18 mmol) in DCM (8 mL) to the previous reaction mixture and stir the mixture overnight. Pour the reaction mixture into ice- water (50 mL) and separate the organic layer. Wash the organic layer with water, 0.5 N HCl, water, saturated NaHCO3, and water. Dry over magnesium sulfate. Remove the organic solvent to give the crude product. Purify by column chromatography(hexane/ethyl acetate, 10: 1) to give the title compound (2.40 g, 74 %). MS (GC) 249 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonium acetate; acetic acid; for 1.5h;Reflux; | 6.83 g (31.1 mmol) of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> and 5.52 g (71.6 mmol) of ammonium acetate were partly dissolved in 78 ml of acetic acid. Subsequently, 4.80 ml (80.7 mmol) of nitromethane were added and the reaction mixture was heated under reflux for 90 min. The mixture was cooled down to room temperature, 80 ml of water were added and the mixture was extracted with dichloromethane. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. Yield: 6.86 g (82% of theory) (0555) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=8.29 (d, 1H), 8.17 (d, 1H), 8.06 (d, 1H), 7.99 (d, 1H), 7.62 (dd, 1H). |
With methylamine hydrochloride; sodium acetate; at 20℃; for 19h; | A suspension of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (2.2 g; 10.0 mmol), methylamine hydrochloride (0.43 g; 6.4 mmol) and sodium acetate (0.53 g; 6.4 mmol) in 3.8 mL of nitromethane (70.1 mmol) was stirred at ambient temperature. After stirring for 19 hours the mixture was diluted with 20 mL water and 40 mL dichloromethane, and the mixture was transferred to a separatory funnel. After shaking, the organic layer was separated, dried over sodium sulfate and evaporated to give 2.56 g of a light brown solid. The crude material was purified by silica gel chromatography on a Biotage 4OS column, eluting with 95/5 hexane/EtOAc to give 1.18 g of 2-bromo-4-chloro-l-(2-nitrovinyl)benzene as a light yellow solid. MS(apci, neg) m/z = 261. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium tetrahydroborate; In tetrahydrofuran; methanol; at 0 - 20℃; for 1h;Inert atmosphere; | Step 1: (2-bromo-4-chloro-phenyl)methanol. [001019] To a solution of <strong>[84459-33-6]2-bromo-4-chloro-benzaldehyde</strong> ( 10.1 g, 46.1 mmol) in tetrahydrofuran (101 mL) and methanol (50.6 mL) at 0 C under argon was added sodium tetrahydroborate (2.31 g, 60.9 mmol). The reaction was allowed to warm to room temperature and stirred for l h. The mixture was evaporated to dryness, and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to provide 10.0 g (98%) of the title compound as an off-white solid. NMR (400MHz, CDC13) delta 7.57 (d, J=2.0 Hz, 1 H), 7.45 (d, J=8.3 Hz, 1 H), 7.33 (dd, J-2.0, 8.3 Hz, 1 H), 4.73 (d, J=6.0 Hz, 2H), 1.95 (t, J=6.1 Hz, 1H). |
79% | With methanol; sodium tetrahydroborate; for 1h;Inert atmosphere; Cooling with ice; | To a solution of 10.0 g (44.2 mmol) of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> in 90 ml of methanol in a baked-out flask were added in portions, under argon and while cooling with an ice bath, 836 mg (22.1 mmol) of sodium borohydride and the mixture was stirred while cooling with an ice bath for 1 h. After adding 200 ml of water, the methanol was removed under reduced pressure. The aqueous phase was extracted three times with in each case 80 ml of ethyl acetate. The combined organic phases were dried (magnesium sulphate), filtered and concentrated under reduced pressure. Yield: 7.75 g (79% of theory) (0568) GC/MS [Method 9]: Rt=4.91 min; MS: m/z=220 (M)+, (0569) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=7.70 (d, 1H), 7.54 (d, 1H), 7.48 (dd, 1H), 5.51 (t, 1H), 4.48 (d, 2H) |
With sodium tetrahydroborate; In methanol; for 1h;Cooling; | A solution of 2- bromo-4-chlorobenzaldehyde (21.95 g; 100.0 mmol) in 200 mL methanol was stirred and cooled in an ice bath for 15 minutes, and solid sodium borohydride (1.9 g; 50.0 mmol) was added. A yellow color formed and there was copious gas evolution. Stirring was continued in the bath for 1 hour. The solution was diluted with 200 mL water, and then the methanol was <n="69"/>evaporated on a rotary evaporator. The residual mixture was extracted with 200 mL EtOAc. The organic layer was washed with 50 mL brine, then dried over sodium sulfate and evaporated. The residual solid was washed out of the flask with hexane and collected by filtration, ground with a mortar and pestle to break up the chunks, then washed with hexane and air-dried on the filter to give 17.8 g of (2-bromo-4-chlorophenyl)methanol as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; In dichloromethane; at 0℃; for 1h; | General procedure: To a solution of substituted arylaldehyde (4.0 mmol) in DCM (15 mL) were added CBr4 (2.65 g, 8.0 mmol) and PPh3 (2.10 g, 8.0 mmol) at 0 C and stirred for 60 min. After completion, DCM was evaporated and the residue was purified by column chromatography affording pure 1-bromo-2-(2,2-dibromovinyl)benzene. A solution of 1-bromo-2-(2,2-dibromovinyl)benzene (3 mmol) in DMSO (40 mL) was added Cs2CO3 (2.4 g, 7.5 mmol) and the mixture was stirred at 115 C for 8 hours. The reaction was poured into water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4. DCM was evaporated and the residue was purified by column chromatography. Substrates 1d, 1e, 1f, 1g, 1h2, 1i5, 1j6, 1k7 and 1l8 were prepared following the general procedure B |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; for 5h;Reflux; | After <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (15.1 g, 69.1 mmol) and 2-chlorophenylboronic acid (11.9 g, 76 mmol) were dissolved in tetrahydrofuran (THF) (200 mL), 2M potassium carbonate aqueous solution (70 mL) was added thereto, and tetrakistriphenylphosphino palladium (Pd(PPh3)4 (1.6 g, 2 mol%) was put thereinto, agitated and refluxed for 5 hours. The temperature was lowered to normal temperature, the water layer was removed, and the organic layer was dried with anhydrous magnesium sulfate and filtered. The filtered solution was concentrated under the reduced pressure, and columned with tetrahydrofuran:hexane = 1:10 to prepare the compound A-11 (13.0 g, 80%). MS: [M+H]+=251 |
76% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; | Starting material(2-chlorophenyl) boronic acid (CAS Registry Number: 3900-89-8) (28.56 g, 182.64 mmol)Was dissolved in THF (640 ml) in a round bottom flask, <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (CAS Registry Number: 84459-33-6) (44.09 g, 200.91 mmol)Pd (PPh3) 4 (8.44 g, 7.31 mmol), K2CO3 (75.73 g, 547.93 mmol),Water (320 ml)And the mixture was stirred at 80 C.After the reaction was completed, the reaction mixture was extracted with CH 2 Cl 2 and water. The organic layer was dried over MgSO 4 and concentrated. The resulting compound was purified by silicagel column and recrystallized to obtain 34.86 g (yield: 76%) of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1 g, 4.56 mmol) in DCM (15 mL) was added DAST (0.903 mL, 6.83 mmol) at 0 C. The reaction was allowed to warm to rt and stir overnight. The reaction mixture was diluted with EtOAc, washed with sat NaHCC^ and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give Intermediate 19A (0.88g. 80% yield) as a clear oil. MS (ESI) m/z: 261.2 (M+Na)+. |
80% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1 g, 4.56 mmol) in DCM (15 mL) was added DAST (0.903 mL, 6.83 mmol) at 0 C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 and brine. The organic phase was dried over MgS04, filtered and concentrated to give Intermediate 14A (0.88 g. 80%) as a clear oil. MS (ESI) m/z: 261.2 (M+Na)+. |
80% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1 g, 4.56 mmol) in DCM (15 mL) was added DAST (0.903 mL, 6.83 mmol) at 0 C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with EtOAc, washed with saturated aHC03 and brine. The organic phase was dried over MgS04, filtered and concentrated to give Intermediate 14A (0.88 g.80% yield) as a clear oil. MS (ESI) m/z: 261.2 |
80% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1 g, 4.56 mmol) in DCM (15 mL) was added DAST (0.903 mL, 6.83 mmol) at 0 C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHC03 and brine. The organic phase was dried over MgSO4, filtered and concentrated to give Intermediate 14A (0.88 g.80% yield) as a clear oil. MS (ESI) m/z: 261.2 |
79% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | [0957] At oo C., 0.9 ml (6.83 mmol) of diethylaminosulphurtrifluoride was added to a solution of 1.0 g ( 4.56 mmol)of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> in 12 ml of dichloromethane.The reaction mixture was stirred at RT overnightand then added dropwise to a saturated sodium bicarbonatesolution until no more evolution of carbon dioxide wasnoticeable. After addition of ethyl acetate and phase separation,the aqueous phase was extracted twice with ethylacetate. The combined organic phases were washed withsaturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and briefly () concentrated under reducedpressure and dried. Yield: 872 mg (79% of theory)[0958] GC/MS [Method 7]: R,=2.98 min; MS (EI):m/z=240 (Mt |
872 mg | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | At 0 C, 0.9 ml (6.83 mmol) of diethylaminosulphurtrifluoride was added to a solution of 1.0 g (4.56 mmol) of<strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> in 12 ml of dichloromethane. The reaction mixturewas stirred at RT overnight and then added dropwise to a saturated sodiumbicarbonate solution until no more evolution of carbon dioxide was noticeable.After addition of ethyl acetate and phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried (sodium sulphate),filtered and briefly () concentrated under reduced pressure and dried. Yield:872 mg (79% of theory) |
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 3h; | 2-Bromo-4-chloro-1-(difluoromethyl)benzene 1.50 g (6.84 mmol) of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> were initially charged in 18 ml of dichloromethane, 1.36 ml (10.25 mmol, 1.5 eq.) of N-ethyl-N-(trifluoro-lambda4-sulphanyl)-ethanamine were added at 0 C. and the mixture was stirred at RT for 3 h. Subsequently, 80 ml of saturated aqueous sodium hydrogencarbonate solution were added dropwise and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. Yield: 1.6 g (92% purity, 89% of theory). LC/MS [Method 9]: Rt=3.22 min; MS (ESIpos): m/z=241 (M+H)+, 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=7.95 (s, 1H), 7.72-7.61 (m, 2H), 7.13 (s, 1H) | |
With dimethylaminosulphur trifluoride; In dichloromethane; at 0 - 20℃; for 3h; | [0855] 1.50 g (6.84 mmol) of 2-bromo-4-chlorobenzalde- hyde were initially charged in 18 ml of dichloromethane, 1.36 ml (10.25 mmol, 1.5 eq.) of N,N-diethylaminosulphur trifluoride were added at 0 C. and the mixture was stirred at RT for 3 h. Subsequently, 80 ml of saturated aqueous sodium hydrogencarbonate solution were added dropwise and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. Yield: 1.6 g (92% purity, 89% of theory).10856] LC/MS [Method 9]: R=3.22 mm; MS (ESIpos):mlz=241 (M+H), 10857] ?H-NMR (400 MHz, DMSO-d5): oe [ppm]=7.95 (s, 1H), 7.72-7.61 (m, 2H), 7.13 (s, 1H) | |
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.08 g, 4.92 mmol) in DCM (15 ml) was added DAST (0.975 ml, 7.38 mmol) at 0C. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was diluted with EtOAc (50 ml), washed with saturated aq. NaHCO3 (50 ml) and brine (40 ml). The organic phase was dried over MgSO4, filtered and concentrated to afford the title compound. The crude was used in the next step without further purification.1H NMR (CDCl3, 5000+]^^^^7.55-7.63 (m, 2H), 7.39 (br s, 1H), 6.84 (t, J = 54.8 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 4,4,-(lZ,l*Z)-2,2,-(2,5-dibromo-l,4-phenylene)bis(ethene-2,l-diyl)bis(l- bromo-4-chlorobenzene) (25b). A solution of phosphonium salt 23 (2.79 g, 2.94 mmol) in THF (30 mL) was cooled to 0 C in a 100 mL 2-neck round bottom under nitrogen with stirring. Potassium 'butoxide (808 mg, 7.06 mmol) was added portionwise and the resulting mixture was held at 0 C for 30 min. A solution of benzaldehyde 24b (1.23 g, 5.58 mmol) in THF (30 mL) was added dropwise at 0 C and the reaction was allowed to warm up to room temperature and left stirring for 24 h. The reaction mix was partitioned between 1 : 1 water: EtOAc and washed with brine (2x). The aqueous layer was removed and extracted with EtOAc (3x) and the organics were dried with MgS04, filtered and the solvent removed under reduced pressure to a yellow solid that was rinsed with ethanol and filtered to yield 1.46 g (2.19 mmol, 74%) of 25b as a yellow solid that was used without further purification. -NMR (400 MHz, CD2C12) delta: 7.64 (d, 2H, J= 2.1 Hz), 7.18 (s, 2H), 7.10 (dd, 2H, J-= 2.1, 8.3 Hz), 6.92 (d, 2H, J= 8.4 Hz), 6.72 (dd, 4H, J= 17 Hz); C-NMR (100MHz, CDCb) delta: 137.6, 135.0, 134.3, 134.2, 132.7, 131.3, 131.2, 129.9, 127.5, 124.5, 122.5; HRM *]; 667.6988, found 667.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); potassium fluoride dihydrate; tri tert-butylphosphoniumtetrafluoroborate / tetrahydrofuran / Inert atmosphere 2: methanol / 0.17 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With tris-(dibenzylideneacetone)dipalladium(0); potassium fluoride dihydrate; tri tert-butylphosphoniumtetrafluoroborate In tetrahydrofuran Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; 3-(diphenylphosphino)benzoic acid; palladium diacetate; potassium carbonate; In tetrahydrofuran; water; at 50℃; for 2h;Green chemistry; | General procedure: In a 10 mL round bottom flask containing 2 mL of (1 : 4) THF-H2O, Pd(OAc)2 (0.02 mmol), 3-(diphenylphosphino)benzoic acid (L 4 ), (0.04 mmol), CuI (0.05 mmol), 2-bromo benzaldehyde (1 mmol), phenylacetylene (1.2 mmol). K2CO3 (2 mmol), were added and the reaction mixture was stirred at 50 C for 2 h until the completion of the starting materials as monitored by TLC. Then NH4OAc (1.5 mmol) was added and again the whole reaction mixture was stirred at same temperature for additional 2 hours. After the formation of desired product 4a as confirmed by TLC, the reaction mixture was extracted with ethyl acetate (10 mL) and water (10 mL) and the organic layer was washed with aqueous saturated brine solution and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel using ethyl acetate/ hexanes as the eluent to afford the desired product 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In tetrahydrofuran; at -78 - 20℃; for 20h; | Cyclopropylmagnesium bromide (0.5M solution in THF, lOO.OmL, 50.0mmol) was added portion wise over 1 hour to a cold (-78oC), stirred solution of 4-bromo-2-chlorobenzaldehyde (5.5g,25.0mmol) in THF (lOOmL) and the mixture was stirred for 1 hour before being allowed to warm to room temperature and stirred for a further 18 hours. After this time, the reaction was quenched by the addition of saturated ammonium chloride (lOOmL) and the mixture extracted with ethyl acetate (3 x lOOmL). The combined organic extracts were combined, washed with water (lOOmL) and brine (lOOmL) before being dried (MgS04), filtered and concentrated. The resulting residue was purified by flash columnchromatography (elution: 10% ethyl acetate, 90% heptanes) to give the desired compound (5.05g, 77% yield) as a pale yellow oil. ?? (500 MHz, DMSO) 7.66 (d, J=1.89 Hz, 1 H) 7.50 - 7.60 (m, 2 H) 5.43 (br. s., 1 H) 4.59 (d, J=5.20 Hz, 1 H) 1.04 - 1.15 (m, 1 H) 0.29 - 0.46 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide; In dichloromethane; water;Inert atmosphere; | General procedure: The SBOs were prepared by the base-catalysed condensation of the appropriate 5-halogeno-2-methylbenzoxazole with the requisite aromatic aldehyde under phase transfer conditions. In a typical experiment, equimolar quantities (5 mmol) of the starting materials were dissolved in dichloromethane (20-50 ml) in the presence of benzyltriethylammonium chloride (3 mmol) and stirred magnetically under a nitrogen atmosphere as an aqueous solution of sodium hydroxide (50%, w/v, 5 ml) was added dropwise over a period of 10 min. After being stirred for 2-36 h until analytical thin layer chromatography indicated that the reaction was complete, the mixture was diluted with water (50 ml) and the SBO was extracted with dichloromethane (3×20 ml), dried (MgSO4), filtered, evaporated under reduced pressure and recrystallized from aqueous methanol or ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Step 1: Preparation of tert-butyl 4-[(2-bromo-4-chlorophenyl)methyl]piperazine-l- carboxylate rt, 3h [00299] A 500-mL round-bottom flask was charged with <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (30.0 g, 137 mmol, 1.00 equiv), tert-butyl piperazine-l-carboxylate (23.2 g, 124 mmol, 0.910 equiv), and 1,2-dichloroethane (300 mL). The mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (52.8 g, 249 mmol, 1.82 equiv) was added. The resulting solution was stirred for 3 h at room temperature and washed with H20 (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to provide 40.0 g (75% yield) of tert-butyl 4-[(2-bromo-4-chlorophenyl)methyl]piperazine-l-carboxylate as a light yellow solid. XH NMR (300 MHz, CDC13): delta 7.56-7.57 (m, 1H), 7.43-7.46 (m, 1H), 7.29-7.30 (m, 1H), 3.61 (br, 2H), 3.46 (br, 4H), 2.49 (br, 4H), 1.46 (s, 9H). LCMS (ESI, m/z): 390 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; at 80℃; under 3800.26 Torr; | Step 1: Pre aration of methyl 5-chloro-2-formylbenzoate [00464] A 250-mL pressure tank reactor was charged with 2-bromo-4- chlorobenzaldehyde (20.0 g, 91.1 mmol, 1.00 equiv), methanol (120 mL), triethylamine (18.5 g, 183 mmol, 2.01 equiv), and Pd(dppf)Ci2 (731 mg, 1.00 mmol, 0.01 equiv). To the above, CO (5 atm) was introduced. The resulting solution was stirred overnight at 80 C and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (10/90) to provide 1.60 g (9% yield) of methyl 5-chloro-2- formylbenzoate as a yellow oil. XH NMR (300 MHz, Chloroform-if) delta 10.47 (s, 1H), 7.78-7.88 (m, 2H), 7.50-7.52 (m, 1H), 3.90 (s, 3H). GCMS (EI, m/z): 198 M+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 2h;Inert atmosphere; Reflux; | [0143] The following reagents and solvents were charged into a 200-ml recovery flask. <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> : 3.00 g (13.7 mmol) FL-Bpin: 4.47 g (13.9 mmol) Tetrakis (triphenylphosphine) palladium(O) : 474 mg (0.41 mmol) Toluene: 60 mL Ethanol: 30 mL 10-wt% aqueous sodium carbonate solution: 30 mL [0144] Next, the reaction solution was refluxed by heating for 2 hours with stirring under nitrogen. After the reaction was completed, to the reaction solution was added toluene and water and the mixture was stirred, and an organic layer was then separated by a liquid separation operation. Subsequently, after being washed with a saturated aqueous sodium chloride solution, the organic layer was dried over sodium sulfate. The organic layer was then concentrated under reduced pressure, so that a crude product was obtained. This crude product was then purified by a silica gel column chromatography (eluent: heptane/chloroform=2/l ) , so that 4.33 g (yield: 95%) of the intermediate 1 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | To a degassed mixture of toluene (60 mL) and water (9 mL) was added potassium cyclopropyl-trifluoroborate (0.91 g, 6.2 mmol) and tribasic potassium phosphate (6.37 g, 30 mmol). The resulting mixture was stirred for 15 min at rt, thereafter, <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.50 g, 6.84 mmol, WO2006044454), palladium(II) acetate (0.11 g, 0.5 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.48 g, 1.0 mmol) were added and the mixture was heated under reflux, overnight. After cooling to rt, water (50 mL) and ethyl acetate (50 mL) were added and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/hexanes 1:3) to give 4-chloro-2-cyclopropyl-benzaldehyde (0.48 g, 2.6 mmol, 39%) as a colorless semi solid: 1H-NMR (CDCl3, Bruker 400 MHz) delta 0.80 (2H, m), 1.08-1.17 (2H, m), 2.58 (1H, m), 7.10 (1H, d, J=2 Hz), 7.29 (1H, dd, J=8 Hz, 2 Hz), 7.75 (1H, d, J=8 Hz), 10.6 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxyammonium sulfate; In 2,2,2-trifluoroethanol; water; at 20℃; for 1h; | General procedure: One-Pot Synthesis of Isoxazolines 3; General ProcedureTo a mixture of TFE (2.2 mL) and H2O (0.8 mL), an aldehyde 1 (0.5mmol) and hydroxylamine sulfate (0.3 mmol) were first added, andthe mixture was stirred at r.t. for 1 h. Then, m-CPBA (0.7 mmol) andPhI (0.1 mmol) were added and stirring was continued. After 30min, an alkene 2 (1 mmol) was added to the mixture which wasstirred for another 5 h, until the reaction was completed. Then, H2O(10 mL), sat. aq Na2S2O3 (2 mL) and sat. aq Na2CO3 (2 mL) wereadded, and the mixture was stirred for 10 min. The mixture was extractedwith CH2Cl2 (3 × 4 mL) and the combined organic phasewas dried over anhydrous Na2SO4, filtered and concentrated underreduced pressure. The residue was purified by TLC on a silica gelplate (petroleum ether-EtOAc, 3:1) to provide the correspondingpure isoxazoline 3. | |
With hydroxylamine hydrochloride; sodium acetate; In methanol; at 20℃; for 2h; | 8.00 g (36.4 mmol) of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> were dissolved in 80 ml of methanol, and5.38 g (65.6 mmol, 1.8 eq.) of sodium acetate were added, 2.79 g (40.1 mmol) of hydroxylamine hydrochloride were then added a little at a time, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in 200 ml of dichloromethane. The organic phase was washed with 100 ml of water and 100 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered. The filtratewas concentrated under reduced pressure. The crude product was reacted in the next step without further purification. Yield: 6.50 g (72% of theory).LC/MS [Method 18]: R = 0.92 mm; MS (ESIpos): m/z = 236 (M+H),?H-NMR (400 MHz, DMSO-d6): oe [ppm] = 11.74 (s, IH), 8.29 (s, 1H), 7.78-7.72 (m, 2H), 7.50- 7.43 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In N,N-dimethyl acetamide; at 130℃;Inert atmosphere; | Step B: Ethyl 5-(5-chloro-2-formylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdCl2(PPh3)2 (3.14 mmol). The reaction mixture is then heated at 130 C. overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane. Animal charcoal is added (30 g) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over magnesium sulphate and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid. 1H NMR: delta (400 MHz; dmso-d6; 300K): 9.8 (s, 1H, formyl); 7.91-7.69-7.61 (d, 3H, aromatic Hs); 6.5 (s, 1H pyrrole); 4.2 (q, 2H, OCH2CH3); 3.4 (s, 3H, CH3-N-pyrrole); 2.55 (s, 3H pyrrole); 1.28 (t, 3H, OCH2CH3) | |
Step B: Ethyl 5-(5-chloro-2-formylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdC12(PPh3)2 (3.14 mmol). The reaction mixture is then heated at 130 C. overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane. Animal charcoal is added (2 g per g of product) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid. 1H NMR: delta (400 MHz; dmso-d6; 300K): 9.8 (s, 1H, formyl); 7.91-7.69-7.61 (d, 3H, aromatic Hs); 6.5 (s, 1H pyrrole); 4.2 (q, 2H, OCH2CH3); 3.4 (s, 3H, CH3-N-pyrrole); 2.55 (s, 3H pyrrole); 1.28 (t, 3H, OCH2CH3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 10h;Reflux; | General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 12h;Reflux; | General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 16h;Reflux; | General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sulfuric acid; at 20℃; for 16h;Cooling with ice; | 2-(2-bromo-4-chlorophenyl)tetrahvdro-2H-pyran-4-ol Concentrated H2S04 was added drop wise to an ice-cold mixture of 3-buten-1 -ol (6.2 mL, 68.5 mmol, 2.0 eq) and <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (7.5 g, 34.25 mmol, 1.0 eq) and the RM was allowed to warm to RT slowly and stirred for 16 h. Then the RM was poured into ice water, basified with sat. NaHC03 solution and extracted with DCM (2x100 mL), combined organic layer was dried over anhydr. Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by CC to afford 2-(2-bromo-4- chlorophenyl)tetrahydro-2H-pyran-4-ol (3.6 g, 36%) as deep brown liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In ethanol; at 80℃; for 11h; | General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (1.0 mmol), 1H-indazol-6-amine (2a; 133 mg, 1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 8-11 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 5 was collected by filtration without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 0℃; for 3h;Inert atmosphere; | General procedure: To a solution of 2-bromo-4-fluorobenzaldehyde (1.0 g, 5.0 mmol, 1.0 equiv.) in dry ether (10 mL, 0.5 M) at 0 C was added dropwise a solution of methylmagnesium bromide in Et2O (10 mmol, 2.0 equiv.) under N2 atmosphere. The resulting reaction mixture was stirred at 0 C for 3 hours, then quenched with saturated aqueous NH4Cl solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford the corresponding 1- (2-bromo-4-fluorophenyl)ethan-1-ol. To a solution of 1-(2-bromo-4-fluorophenyl)e- than-1-ol (1.0 equiv.) in dry CH2Cl2 (0.2 M) was added a homogeneous mixture of pyridinium chlorochromate (PCC, 3.2 g, 15 mmol, 3.0 equiv.) and silica gel (3.2 g, 1:1 by mass). The resulting suspension was stirred at room temperature for 2 hours, then filtered through a pad of silica gel, washed with CH2Cl2 and concentrated in vacuo. The crude product was used for the next step without further purification. From 1-(2- bromo-4-fluorophenyl)ethan-1-one, the corresponding benzamide was synthesized by the same method of 1a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In methanol; at 75℃; | At RT, 12.7 g (91.8 mmol) of potassium carbonate were added to a mixture of 10.0 g (45.9 mmol)of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> and 9.8 g (50.5 mmol) of isocyanomethyl 4-methylphenylsulphone in 100 ml of methanol, and the mixture was stirred at 75C overnight. After cooling to RT, the reaction mixture was concentrated under reduced pressure. After addition of water, the residue was stirred and the precipitate was filtered off, dried under reduced pressure and triturated with hexane. Yield: 9.8 g (83% of theory)LC/MS [Method 12]: R = 2.18 mm; MS (ESIpos): m/z = 259 (M+H),?H-NMR (400 MHz, DMSO-d6): oe [ppm] = 8.57 (s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.75 (d, 1H), 7.58 (d, 1H). |
With potassium carbonate; In methanol; at 70℃; for 7h; | 5-(2-Bromo-4-chlorophenyl)oxazole 2-Bromo-4-chlorobenzaldehyde (3 g, 14 mmol) was mixed with tosylmethyl isocyanide (3.20 g, 16 mmol) and potassium carbonate (2.3 g, 16 mmol) in MeOH (24 ml). The resulting mixture was heated to 70C for 7 hours. The mixture was concentrated, and water was added. The product was taken up with ethyl acetate, and washed with water and brine. After it was dried over anhydrous sodium sulfate, the solution was concentrated. The crude was purified by column chromatography on silica gel Isolute Flash Si; 100 g prepacked, eluting with gradient 0 ~ 30% EtOAc/isohexane to give the product. | |
With potassium carbonate; In methanol; at 70℃; for 3h; | Step 3 : 5-(2-bromo-4-chlorophenyl)oxazole To a round bottom flask was added 2-bromo-4- chlorobenzaldehyde (8 g, 36.5 mmol), MeOH (200 mL), l-((isocyanomethyl)sulfonyl)-4- methylbenzene (10.68 g, 54.70 mmol) and potassium carbonate (15.11 g, 109 mmol). The mixture was stirred for 3 h at 70C. LCMS showed the reaction was complete. The mixture was concentrated in vacuo then added water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by normal phase chromatography (Si02, 0-10% EtOAc/PE, 50 min, dry loaded) to give the title compound. MS (ESI) m/z 260.1 (M+H). |
With potassium carbonate; In methanol; at 70℃; for 3h; | To a round bottom flask were added 2-bromo-4- chlorobenzaldehyde (8.00 g, 36.5 mmol), MeOH (200 mL), 1-((isocyanomethyl)sulfonyl)-4- methylbenzene (10.68 g, 54.7 mmol) and K2CO3 (15.11 g, 109 mmol). The mixture was stirred at 70C for 3 h. The mixture was concentrated in vacuo and water (200 mL) was added. The mixture was extracted with ethyl acetate (150 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0-10% ethyl acetate/petroleum ether) to give the title compound. MS (ES+) m/z: 258, 260 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With diethylamine; In ethanol; at 60℃; for 6h;Green chemistry; | General procedure: The reaction was performed in a 20 mL V-type tube equipment with a triangle magnetic stirring bar. In a typical reaction, 4-hydroxyindole (0.4 mmol) was mixed with malonodinitrile (0.4 mmol) and aldehydes (0.4 mmol) in 2.0 mL of ethanol. KF (0.08 mmol) was then added. The mixture was subsequently heated to 60 C under stirring for 6 h. After the reaction, the mixture was cooled to room temperature, and the target product was isolated using a preparative thin-layer chromatograph (TLC) with eluting solution [petroleum ether/ethyl acetate 3/1 (v/v)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.5 g | Example 9: l-(2-Bromo-4-chlorophenyl)-N-methylmethanamine Int-11 Int-11 [00317] To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (3.00 g, 13.7 mmol) in ethanol ( 10.0 mL, 171 mmol) was added 8.4 M of methylamine in ethanol (3.27 mL, 27.3 mmol) and the mixture was stirred for 4h at rt. The mixture was cooled at 0 C and sodium triacetoxyborohydride (3.04 g, 14.4 mmol) was added portion wise. The reaction was stirred for lh. The reaction was concentrated in vacuo, and then IN NaOH (200mL) was added to the residue and the mixture was extracted with DCM (200mLx3). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by ISCO silica gel column chromatography (40g, eluting with 5% MeOH in DCM for 5min then gradient to 10% MeOH in DCM over 15min, 40mL/min flow) to give 2.5 g of the title compound. NMR (400 MHz, DMSO-d6) delta 7.71 (d, J = 2.1 Hz, 1 H), 7.51 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.3, 2.1 Hz, 1H), 2.29 (s, 3H), 2.22 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With Tosyl isocyanate; copper(II) bis(trifluoromethanesulfonate); In 1,2-dichloro-ethane; at 80℃; for 15h;Inert atmosphere; Schlenk technique; | General procedure: To a suspension of 3,4,5-trimethoxy-biphenyl (8a, 122 mg,0.5 mmol) and 4-chlorobenzaldehyde (9a, 84 mg, 0.6 mmol),Cu(OTf)2(18 mg, 0.05 mmol) in DCE (2 mL) was added tosyl iso-cyanate (118 mg, 0.6 mmol) in a Schlenk tube under a balloon pressure of N2. The resultant mixture was stirred at 80 C for 15 h. It was directly subjected to flash chromatography [silica gel, 5% EtOAcin petroleum ether (60-90 C)] to give 170 mg (93%) of product 1a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h; | To 219 mg <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-indazol-6-amine(1.0 mmol), 213 mg tert-butyl 2,4-dioxopiperidine-1-carboxylate(1.0 mmol), 10 mg CuI (0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for12 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 380 mg (85 %) 4d as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M.p.:[300 C; 1H NMR (CDCl3, 400 MHz): d = 1.67 (s, 9H,3CH3), 3.51 (t, J = 6.0 Hz, 2H, CH2), 4.30 (t, J = 6.0 Hz,2H, CH2), 7.48 (dd, J = 9.2 Hz, 2.4 Hz, 1H, ArH), 7.89 (d,J = 8.8 Hz, 1H, ArH), 8.25 (d, J = 8.8 Hz, 1H, ArH),8.58 (s, 1H, ArH), 8.66 (d, J = 2.4 Hz, 1H, ArH), 8.73 (d,J = 9.2 Hz, 1H, ArH) ppm; 13C NMR (CDCl3, 100 MHz):d = 28.6, 34.4, 43.1, 83.9, 112.7, 114.9, 115.6, 117.6,122.2, 125.0, 126.4, 131.6, 132.4, 134.7, 136.6, 137.5,139.0, 149.0, 151.8, 160.4, 164.6 ppm; IR (KBr):v = 3090, 3030, 2988, 1725, 1692, 1664, 1637, 1610,1594, 1556, 1538, 1514, 1468, 1392, 1367, 1344, 1315,1296, 1274, 1252, 1237, 1204, 1145, 1097, 1041, 972, 957,868, 854, 820, 773 cm-1; HRMS (ESI): m/z calcd forC24H20ClN4O3 [M ? H]? 447.1224, found 447.1221. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 17h; | To 219 mg <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.0 mmol) dissolved in 10 cm3 DMSO, 133 mg 1H-benzo[d]imidazol-5-amine (1.0 mmol), 213 mg tert-butyl 2,4-dioxopiperidine-1-carboxylate (1.0 mmol), 10 mg CuI(0.05 mmol), and 652 mg Cs2CO3 were added. The mixture was heated at 100 C for 17 h. The solid was filtered off, and the solvent in filtrate was recovered by distillation under reduced pressure, and the residue was purified by chromatography over silica gel to give 371 mg(83 %) 5c as pale yellow powder using ethyl acetate and petroleum ether (1:2) as an eluent. M. p.: [300 C; 1HNMR (CDCl3, 400 MHz): d = 1.59 (s, 9H, 3CH3), 3.51 (t,J = 6.0 Hz, 2H, CH2), 4.28-4.31 (m, 2H, CH2), 7.51-7.53(m, 1H, ArH), 8.06 (d, J = 9.2 Hz, 1H, ArH), 8.14-8.15(m, 1H, ArH), 8.44 (d, J = 8.8 Hz, 1H, ArH), 8.76 (d,J = 8.8 Hz, 1H, ArH), 9.00 (s, 1H, ArH) ppm; 13C NMR(CDCl3, 100 MHz): d = 28.2, 34.4, 43.2, 83.9, 116.1,117.5, 119.0, 121.0, 122.2, 125.9, 126.4, 129.2, 133.3,134.1, 134.3, 138.5, 146.5, 151.7, 156.7, 159.2, 164.8,165.0 ppm; IR (KBr): v = 3098, 2981, 2935, 1716, 1697,1656, 1606, 1592, 1557, 1510, 1472, 1391, 1369, 1340,1320, 1308, 1279, 1249, 1187, 1147, 1096, 963, 873, 851,820, 767 cm-1; HRMS (ESI): m/z calcd for C24H20ClN4O3[M ? H]? 447.1224, found 447.1215. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux; | General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisobutylaluminium hydride; In tetrahydrofuran; at -78℃; for 1h; | Step 2: 2-bromo-4-chlorobenzaldehyde To a round bottom flask was added 2-bromo-4-chloro- N-methoxy-N-methylbenzamide (11 g, 39.50 mmol), THF (150 mL) and DIBAL-H (71.1 mL, 71.1 mmol) dropwise at -78C. The reaction mixture was stirred for 1 h at -78C. TLC (Si02, PE:EtOAc = 5: 1) showed starting material disappeared and a new spot formed. The mixture was quenched with sat. potassium sodium tartrate solution (300 mL), then EtOAc (200 mL) was added. The mixture was stirred for 20 min and filtered and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give the title compound which was directly used for next step without further purification. | |
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78℃; for 1h; | To a solution of 2-bromo-4-chloro-N-methoxy-N- methylbenzamide (11 g, 39.5 mmol) in anhydrous THF (150 mL) was added diisobutylaluminum hydride (1 M in toluene, 71.1 mL, 71.1 mmol) dropwise at -78 C. The reaction mixture was stirred for 1 h and was quenched with saturated potassium sodium tartrate solution (300 mL). The mixture was stirred for 20 min and filtered through a pad of Celite. The filtrate was extracted with ethyl acetate (200 mLx3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to the title compound. It was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In ethanol; at 80℃; for 1.5h;Sealed tube; Inert atmosphere; | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (491 mg, 2.24 mmol) in EtOH (12 mL) was added phenylboronic acid (300 mg, 2.46 mmol), PdCl2(dppf) (33 mg, 0.045 mmol), and Et3N (937 pL, 6.72 mmol). The resulting mixture was heated in a sealed tube under Argon atmosphere at 80 C for 1.5 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc = 0-15% gradient) to afford the title compound (430 mg, 88%). NMR (400 MHz, CDCh) d 9.91 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.48 (m, 5H), 7.37 (m, 2H). |
With palladium diacetate; sodium carbonate; at 20℃;Inert atmosphere; | General procedure: These compounds were synthesized according to the literature procedure.21 Typical procedure: 2-bromobenzaldehyde (0.92 g,5 mmol), phenylboronic acid (0.67 g, 5.5 mmol), sodium carbonate (0.53 g, 5 mmol), and Pd(OAc)2 (0.028 g, 0.125 mmol) were added to a flask (50 mL) equipped with a high-vacuum PTFE valve-to-glass seal. The flask was opened to the vacuum, pumped for 2-3 min and backfilled with an inert Ar gas. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with CH2Cl2 (3 20 mL) and the organic layer was dried over Na2SO4, concentrated under the reduced pressure to give a dark brown oil, which was further purified via column chromatography on Silica gel (eluent: petroleum ether: EtOAc 20:1) to give 2-phenylbenzaldehyde 1a (0.86 g, 95%). | |
With palladium diacetate; sodium carbonate; In water; N,N-dimethyl-formamide;Inert atmosphere; | General procedure: To a round bottom flask were added Pd(OAc)2 (11.2 mg, 0.050 mmol, 1.0 mol%) and Na2CO3 (788 mg, 7.5 mmol, 1.5 equiv). The flask was evacuated and backfilled with argon three times. Then, DMF (5.0 mL) and 2-bromobenzaldehyde derivative (A) (5.0 mmol) were added. After cooling to 0 C, aryl boronic acid derivative (B) (6.0 mmol, 1.2 equiv) and water (5.0 mL) were added. After the stirring for overnight at room temperature, water (40 mL) and EtOAc (20 mL) were added, and the mixture was filtered through celite. The filtrate was extracted with EtOAc (20 mL × 3). The collected organic layer was combined, washed with brine (20 mL), and dried over anhydrous MgSO4. After removal of all volatiles, the residue was purified by silica gel chromatography using hexane and acetone as eluents to give intermediate C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In tetrahydrofuran; at -70℃; for 2h; | 16.0 g (72.9 mmol) of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> were dissolved in 320 ml of THF, and 94.8 ml (c = 1 mol/l, 94.8 inmol, 1.3 eq) of a solution of vinylmagnesium bromide in THF were added dropwise with stirring at -70C. After 2 h at -70C, saturated aqueous ammonium chloridesolution was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 19.0 g (89% of theory). ?H-NMR (400 MHz, DMSO-d6): oe [ppm] = 7.70 (d, 1H), 7.56-7.46 (m, 2H), 5.94-5.83 (m, 2H), 5.35-5.32 (m, 1H), 5.28-5.22 (in, 1H), 5.14-5.09 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium ethanolate; In ethanol; at -5 - 0℃; for 12h; | Sodium ethoxide (272 mg, 4.00 mmol) Was dissolved in absolute ethanol (2 mL) Cool to -5 C. 4-Chloro-2-bromobenzaldehyde (220 mg, 0.56 mmol) And ethyl azide (527 mg, 4.00 mmol) Was dissolved in absolute ethanol (4 mL) Was added dropwise to the above solution, 0 C reaction 12h, the raw material disappears. The reaction solution was poured into an aqueous NH4C1 solution (20 mL) and precipitated Body, filtered, dried, white flocculent solid 50mg, the yield was 27%. |
27% | With sodium; In ethanol; at -15 - 0℃; | General procedure: Sodium (1.5 eq) was dissolved in absolute ethanol and cooled to -15 C. Thesolution of substituted 2-bromobenzaldehydes (1.0 eq) and ethyl azidoacetate (1.5 eq)dissolved in absolute ethanol was added dropwise to the above solution. The reactionmixture was warmed up to 0 and stirred at 0 overnight. Then the mixture waspoured into an aqueous NH4Cl solution, followed by extracting with ethyl acetate.The combined organic layer was washed with the water, dried over anhydrous Na2SO4.The organic layer was concentrated in vacuo and purified by column chromatographyto give the title compound. |
50 mg | With sodium ethanolate; In ethanol; at -5 - 0℃; for 12h; | Sodium ethoxide (272 mg, 4 mmol) was dissolved in absolute ethanol (2 mL) and cooled to -5C. Dissolve <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (220mg, 0.56mmol) and ethyl azide (527mg, 4mmol) in absolute ethanol (4mL), add dropwise to the above solution, and react at 0C for 12 hours. The raw material disappears. The reaction solution was poured into an aqueous NH4Cl solution (20 mL), and a solid was precipitated, filtered, and dried to obtain 50 mg of a white flocculent solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate; triphenylphosphine; palladium dichloride; In tetrahydrofuran; water; at 85℃; for 6h;Sealed tube; | In a modification of a literatureprocedure, a resealable tube was charged with <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (6.0 g, 27.34mmol), potassium vinyltrifluoroborate (4.76 g, 35.54 mmol), PdC12 (0.388 g, 2.19 mmol),triphenylphosphine (1.72 g, 6.56 mmol), and cesium carbonate (26.72 g, 82.02 mmol).? Asolution of THF/water (150 mL, 9:1) was added to the tube, whereupon it was sealed and stirredat 85 C for 6 h. The reaction mixture was allowed to cool to room temperature, diluted with water (30 mL), and extracted using Et20 (3 x 30 mL). The organic layer was washed with brine (1 x 30 mL), dried (Na2SO4), and concentrated under reduced pressure to provide an orange oil. The cmde residue was purified via flash chromatography (Si02), eluting with 1 hexanes/EtOAc(99:1) affording 3.18 g (70%) of MDW-1-106 as a pale yellow solid. ?H NMR (400 MHz, CDC13) oe 10.07 (s, 1 H), 7.59 (d, J 8.3 Hz, 1 H), 7.39-7.30 (m, 2 H), 7.21 (dd, J= 8.3, 2.1 Hz, 1 H), 5.58 (dd,J= 17.4, 1.0Hz, 1H), 5.41 (dd,J= 11.0, 1.0Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: (trifluoromethyl)trimethylsilane; 2-bromo-4-chlorobenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: With sodium hydrogencarbonate; Dess-Martin periodane In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylsilane; silver(I) acetate; at 10℃; for 0.416667h;Green chemistry; | A 250 mL round bottom flask was sequentially charged with 5% AgOAc (0.05 mmol, 0.08 g).<strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (100 mmol, 21.9462 g)And triethylsilane (100 mmol, 19.888 g),The reaction was stirred at 10 C for 25 minutes at room temperature. After the reaction was completed,The desired product was isolated by distillation under reduced pressure (1 mmHg, 112 C), yield 80% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium phosphate; palladium diacetate; In N,N-dimethyl-formamide; at 85℃; for 12h;Inert atmosphere; | General procedure: A two-neck round bottom is charged with Pd(OAc)2 (242.6mg, 1.1mmol) and K3PO4 (3.32g, 15.6mmol) under nitrogen atmosphere. To this mixture was added N,N-dimethylformamide (20mL), substituted 2-bromobenzaldehyde (10.8mmol) and substituted styrene (21.6mmol). After stirring at 85C for 12h, the mixture was cooled to room temperature and poured into ice water (40mL). The mixture was filtered through a celite pad and extracted with EtOAc (40mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column with petroleum ether (abbreviate to PE) as eluent to afford the desired product with (E)-configuration in 36-90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.6% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 17h; | [00375] To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (15 g, 68.5 mmol) in DMF (200 mL) under N2 was added phenol (9.5 g, 82.2 mmol) and K2CO3 (28.4 g, 205.5 mmol). The mixture was stirred at 90 C for 17 h. Concentrated and purified by chromatography (silica, DCM/petroleum ether=l/2) to afford k2 (6.1 g, 38.6 %) as a white solid. ESI-MS (EI+, m/z): 233.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 8h;Inert atmosphere; | General procedure: To an argon-charged flask, 0.34mL of 2-bromopyridine (3.6mmol) and 10mL of THF were added under a positive pressure of argon, and cooled at -78C for 5min 1.4mL of n-BuLi solution in hexane (2.5M, 3.5mmol) was added. The metal-halogen exchange step completed in 30min according to TLC. 3.6mL of corresponding 2-bromobenzaldehyde was added to 2-pyridyl lithium solution at -78C. Reaction was kept at this temperature for 2h, then stirred at an ambient temperature for another 6h. Afterwards, the reaction was quenched by adding 50mL of saturated aqueous ammonium chloride solution, then extracted by 30mL of ethyl acetate. The combined organic extract was dried (anhydrous sodium sulfate), filtered (celite plug), and concentrated under a reduced pressure. The crude alcohol was submitted to next step without purification. To the crude alcohol, 4mL benzene (44mmol) was added under an argon atmosphere, and stirred until the alcohol was completely dissolved. This benzene solution was cooled at 0C for 5min, and 2mL of trifluoromethanesulfonic acid was added. The flask was removed from ice bath, and reaction mixture was stirred at room temperature for 12h. The reaction mixture was added to 20mL of cooled saturated sodium bicarbonate solution, and extracted by 20mL of ethyl acetate. The combined organic extract was dried (anhydrous sodium sulfate), filtered (celite plug), and concentrated under a reduced pressure. A silica gel column chromatography (20:1 Hexanes/EtOAc) afforded the product 1a-g,i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a solution of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.0 equiv.) in MeOH (0.20 mol.L'1), methylamine (2M solution in THF, 1.1 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (1.2 equiv.) was slowly added and the resulting yellow mixture was stirred at room temperature for 1 hour. MeOH was removed under vacuum and the residue was dissolved in a mixture of THF (0.30 mol.L"1) and saturated aqueous sodium bicarbonate (0.30 mol.L"1). Di-rert-butyl-dicarbonate (1.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours, before being hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgS04 and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 91% yield. 1H-NM (400 MHz, DMSO-D6): 7.77 (d, J 2.1 Hz, 1 H, Ar); 7.50 (dd, J 8.3, 2.1 Hz, 1 H, Ar); 7.15 (d, J 8.3 Hz, 1 H, Ar); 4.40 (s, 2H, CH2); 2,82 (s, 3H, CH3); 1.38 (s, 9H, tert-butyl). M/Z (M[35Ci] [79Br] ertbutyl)+ = 280.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 3h;Inert atmosphere; | Under inert atmosphere, a mixture of <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.0 equiv.), bispinacolatodiboron (2.0 equiv.), potassium acetate (2.0 equiv.) and PdCI2(dppf).CH2CI2 (0.1 equiv.) in dioxane (0.10 moi.L"1) was heated at 80 C for 3 hours. After cooling, the reaction mixture was hydrolyzed and extracted twice with EtOAc. The combined organic layers were dried with brine and over MgS04, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using dichioromethane as eiuent) afforded the product as a beige solid in 55% yield. 1H-NMR (400 MHz, DMSO-D6): 10.27 (s, 1 H, CHO); 7.93 (d, J 8.2 Hz, 1 H, Ar); 7.74 (dd, J 8.2, 2.1 Hz, 1 H, Ar); 7.69 (d, J 2.1 Hz, 1 H, Ar); 1.35 (s, 12H, 4CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | General procedure: Under inert atmosphere, a mixture of benzaldehyde boronic acid or ester A2 (1.0 equiv.), (hetero)aromatic hade B2 (1.0 equiv.) and PdCI2(dppf).CH2CI2 (0.10 equiv.) in a mixture of dioxane (0.10 moLL1) and aqueous K3P04 (1.2 moLL1) was heated at 80C for 1 hour, After coong to room temperature, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4,concentrated and purified to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 70℃; for 10h;Inert atmosphere; Schlenk technique; | General procedure: To a schlenk tube (15 mL) containing a solution of <strong>[32566-01-1]2-(1H-indol-2-yl)aniline</strong> 3a (0.4 mmol) in DMSO (2 mL) was added 2-bromobenzaldehyde 4 (0.44 mmol) under nitrogen atmosphere.Then, the reaction mixture was stirred at 70C for 10 h until <strong>[32566-01-1]2-(1H-indol-2-yl)aniline</strong> 3a was consumed completely. Next, Pd(PPh3)2Cl2(0.02 mmol), [(t-Bu)3PH]BF4 (0.06 mmol) and Et3N (1.2 mmol) wereadded into the above reaction system under CO (1 atm) atmo-sphere. After being stirred at 120C for 5 h, the resulting mixturewas quenched with NH4Cl and extracted with ethyl acetate. Thecombined organic layer was washed with H2O and brine, and thendried over anhydrous Na2SO4. The solvent was removed underreduced pressure and the residue was puried by column chro-matography on silica gel (petroleum ether/ethyl acetate 5:1) toafford the corresponding indolo[1,2-c]isoindolo[2,1-a]quinazolin-5(16aH)-one 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Take a 500 ml double-necked round bottom bottle and place it in a stir bar, dry and then fill with nitrogen; first add intermediate 2-3 (35.000 g, 1.0 equivalent) and potassium t-butoxide (21.553 g, 3.0 equivalent), then add Tetrahydrofuran (150 ml) was stirred and mixed at 0 C for 10 minutes, then <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (the compound of formula B-3, 14.051 g, 1.0 eq.) in tetrahydrofuran (100 ml) was added dropwise. The solution was finally reacted at room temperature for 24 hours; after it was warmed, water (50 ml) was added, followed by extraction with diethyl ether (3×300 ml), and the obtained extract was sequentially dried over magnesium sulfate, filtered and dried. The crude product was purified by chromatography (ethyl acetate /hexane, 1 / 80).Intermediate 3-3 (24.750 g, yield 89%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,4-diaza-bicyclo[2.2.2]octane; C31H52CuN2O4; In propan-1-ol; tert-butyl methyl ether; at 10℃; | General procedure: A solution of anhydrous Cu(OAc)2 (1.8 mg, 0.01 mmol) andligand 7d (4.0 mg, 0.01 mmol) in MTBE (1 mL) in a 10mL test tubeequipped with a magnetic stirring bar was stirred at room temperaturefor 30 min. Next, 20 mL DABCO (5M dissolved in n-propanol)was added, followed by stirring for 5 min. After the aldehyde(0.2 mmol) was added to the reaction mixture, we stirred the mixture at 10 C for 2 min, and then 2-nitropropane (180 mL,2 mmol) was added to the tube. The reaction was stirred at 10 Cand monitored by TLC. After the complete reaction, the chiral product was separated by flash column chromatography (PE/EA 9/1). Enantiomeric excesses were determined by HPLC chiralcolumn. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; toluene; ethanol / Inert atmosphere; Sealed tube 1.2: 48 h / 100 °C / Inert atmosphere; Sealed tube 2.1: bis(norbornadiene)rhodium(l)tetrafluoroborate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / dichloromethane / 120 h / 50 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Add 2-ester benzimidazole (0.5 mmol) and 4-chloro-2-bromobenzaldehyde (0.6 mmol) to the dry Schlenk tube, evacuate nitrogen, and add piperidine (0.05 mmol), 1, 4-Dioxane (2 ml), and the reaction was stirred at room temperature for 3 hours. At room temperature, CuI (0.05 mmol) K2CO3 (1 mmol) and 1,10-phenanthroline (0.1 mmol) were added to the reaction system, and then the mixture was heated to 90 C. and stirred for 8 hours. After stopping the reaction, 15 ml of CH2Cl2 was added to the reaction system, filtered through a sand funnel, and washed with CH2Cl2 three times. The filtrate and washing solution were combined, dried over anhydrous Na2SO4, and concentrated and separated by silica gel column chromatography (eluent: ethyl acetate). Ester: dichloromethane = 30: 1) to obtain the pure product. The material was a yellow solid with a yield of 45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonium acetate; acetic acid; at 100℃; for 2h;Sealed tube; | To a solution of NH4OAc (1.13 g, 14.65 mmol) in AcOH (10 mL) was added CH3NO2 (2.09 mL, 38.9 mmol), <strong>[84459-33-6]2-bromo-4-chlorobenzaldehyde</strong> (1.31 g, 6.1 mmol). The reaction mixture was heated in a sealed tube at 100 C for 2 h, and then poured into water. The solid was filtered and dried under vacuum in the presence of P2O5 overnight to provide the desired product (1.43 g, 88%). NMR (400 MHz, CDCh) d 8.32 (d, J = 13.6 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.51 (m, 2H), 7.37 (dd, J= 8.4, 2.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate / toluene; ethanol; lithium hydroxide monohydrate / 5 h / 140 °C 2.1: tetrahydrofuran / 0.17 h 2.2: 3 h / 0 - 20 °C 3.1: Eaton′s reagent / chlorobenzene / 2 h / Reflux | ||
Multi-step reaction with 3 steps 1: tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate / toluene; lithium hydroxide monohydrate; ethanol / 5 h / 140 °C 2: potassium-t-butoxide / tetrahydrofuran / 3.17 h / 0 - 20 °C 3: methanesulfonic acid / chlorobenzene / 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With ammonium acetate; acetic acid at 120℃; for 4h; | 2.2 (2) Preparation of compound 2-2 Compound 2-1 (29g, 79.7mmol) and 2-bromo-4-chlorobenzaldehyde was added to a 500mL flask containing 200mL of glacial acetic acid, Ammonium acetate (12.3g, 159.4mmol) was slowly added in batches while stirring at room temperature. After the addition, the reaction was stirred and refluxed at 120°C, 4 Hours, TLC monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, it was slowly poured into 1 L of water to precipitate a large amount of solids. After suction filtration, the solids were separated and purified by column chromatography to obtain compound 2-2 (40.3 g, yield 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate / toluene; lithium hydroxide monohydrate; ethanol / 5 h / 140 °C 2: potassium-t-butoxide / tetrahydrofuran / 3.17 h / 0 - 20 °C 3: methanesulfonic acid / chlorobenzene / 1 h / Reflux |
Tags: 84459-33-6 synthesis path| 84459-33-6 SDS| 84459-33-6 COA| 84459-33-6 purity| 84459-33-6 application| 84459-33-6 NMR| 84459-33-6 COA| 84459-33-6 structure
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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