* 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.
Reference：
[1] Canadian Journal of Chemistry, 1989, vol. 67, p. 1472 - 1479
3
[ 33696-00-3 ]
[ 6358-77-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With ammonium chloride; zinc In ethanol at 20℃; for 2 h;
[00169] Intermediate 1 1 A. 4-Bromo-l-methoxy-2-nitrobenzene: The mixture of 4- bromo- 1 -methoxy-2 -nitrobenzene (2.00 g, 8.62 mmol), zinc (5.64 g, 86.0 mmol), and ammonium chloride (4.61 g, 86.0 mmol) in ethanol (65 mL) was stirred together at room temperature for 2 h. The reaction was then diluted with EtOAc, filtered through CELITE®, and evaporated to give Intermediate 11A (1.74 g, 100percent) as a grayish-white solid. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 0.70 min (Method J).
60%
Stage #1: With tin(II) chloride dihdyrate In ethanol at 70℃; for 2 h; Inert atmosphere Stage #2: With water; sodium hydrogencarbonate In ethanolCooling with ice
A mixture of 11d (515 mg, 2.2 mmol) and SnCl2·2H2O (2.1 g, 10 mmol) in absolute ethanol (30 mL) was heated at 70 °C under argon for 2 h. The reaction mixture was allowed to cool to room temperature and then poured into ice. The pH was adjusted to 7–8 by addition of 5percent aqueous NaHCO3, and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (cyclohexane/EtOAc/Et3N: 85/15/0.5) to give aniline 11e51 as a pink powder (260 mg, 60percent).
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, p. 1651 - 1652[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 8, p. 1807 - 1808
[3] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, p. 1651 - 1652[4] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 8, p. 1807 - 1808
7
[ 33696-00-3 ]
[ 1826-67-1 ]
[ 436091-59-7 ]
Yield
Reaction Conditions
Operation in experiment
11%
Stage #1: at -40℃; for 4 h; Stage #2: With ammonium chloride In tetrahydrofuran
Step i :To a solution of 4-bromo-1-methoxy-2-nitro-benzene 52a (6 g, 25.9 mmol) in dry THF (250 mL) at -40°C is added dropwise the vinylmagnesium bromide solution (1 M in THF, 90.5 mL, 90.5 mmol). The reaction mixture is stirred at -4O0C for 4 h then poured into saturated NH4CI solution. The reaction mixture is extracted with Et2O (2x); the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting EtOAc/hexanes (10percent to 40percent) affording 52b (620 mg, 11percent yield).
8%
at -60 - -40℃; for 2 h;
Example 13 Synthesis of 4-bromo-7-methoxyindole (LII) To a -60° C. solution of 4-bromo-2-nitroanisole (7.89 g, 33.3 mmol) in THF (300 was added vinylmagnesium bromide (1 M in THF, 100 ml, 0.1 mol) while maintaining the reaction temperature below -40° C. The resulting mixture was stirred allowing the temperature to rise to -40° C. in 2 hours. The reaction mixture was then quenched with a saturated solution of NH4Cl (700 ml) and extracted with Et2O (200 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified through flash chromatography affording 4-bromo-7-methoxyindole LII (594 mg, 8percent yield).
With bismuth (III) nitrate pentahydrate; In 1,2-dichloro-ethane; at 80 - 85℃; for 23h;
General procedure: A mixture of aromatic compound (1 mmol) and Bi(NO3)3·5H2O (1.5 mmol) in 1,2-DCE (4 mL) was stirred at 80-85 C. On completion (as monitored by GC-MS), the contents were cooled to rt and dissolved in DCM (5 mL). The combined organic layers were washed with 10% NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to give the crude product. Isomer distributions were determined by GC-MS, and/or by 1H NMR.
With N-Bromosuccinimide; iodine; In acetonitrile; at 50℃; for 48h;Darkness;
General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 mol%, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
With ammonium chloride; zinc; In ethanol; at 20℃; for 2h;
[00169] Intermediate 1 1 A. 4-Bromo-l-methoxy-2-nitrobenzene: The mixture of 4- bromo- 1 -methoxy-2 -nitrobenzene (2.00 g, 8.62 mmol), zinc (5.64 g, 86.0 mmol), and ammonium chloride (4.61 g, 86.0 mmol) in ethanol (65 mL) was stirred together at room temperature for 2 h. The reaction was then diluted with EtOAc, filtered through CELITE, and evaporated to give Intermediate 11A (1.74 g, 100%) as a grayish-white solid. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 0.70 min (Method J).
60%
A mixture of 11d (515 mg, 2.2 mmol) and SnCl2·2H2O (2.1 g, 10 mmol) in absolute ethanol (30 mL) was heated at 70 C under argon for 2 h. The reaction mixture was allowed to cool to room temperature and then poured into ice. The pH was adjusted to 7-8 by addition of 5% aqueous NaHCO3, and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (cyclohexane/EtOAc/Et3N: 85/15/0.5) to give aniline 11e51 as a pink powder (260 mg, 60%).
With iron; acetic acid; In acetonitrile; at 0℃;
A solution of 1 (1 eq), acetonitrile, and glacial acetic acid (15 eq) was stirred in an ice bath. Iron powder (7 eq) was added slowly portion-wise. The reaction was left to stir overnight. The reaction solution was filtered, diluted with ethyl acetate, and neutralized with 3N sodium hydroxide. The organic phase was separated and the aqueous phase was washed once more with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and the solvent was removed by evaporation under reduced pressure to afford the product as a solid 2. MS: MH+=202
With triethylamine;aluminum nickel; In ethanol;
5-Bromo-2-methoxy-aniline A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20 C. After this time the theoretical amount of hydrogen had been absorbed (2.5 1), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+). intermediates for the preparation of benzylic amines
With tin(ll) chloride; In ethanol; at 20℃;
Example 159 2,6-Difluoro-N-(2-(methyloxy)-5-{3-[2-(1,2,3,4-tetrahydro-7-isoquinolinylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)benzamide Step A: N-[5-Bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide; To a solution of 4-bromo-2-nitroanisole (2.0 g, 0.009 mol) in absolute ethanol (100 mL) was added SnCl2.2H2O (11.68 g, 0.051 mol) and the resulting mixture was allowed to stir overnight at ambient temperature. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (100 mL), washed with 1M NaOH (100 mL) and filtered through a celite pad. The organic layer was removed, concentrated by rotary evaporation, and dried under high vacuum. The resulting residue was then dissolved in DCM (150 mL) followed by the addition of triethylamine (5.19 g, 0.051 mol) and trifluoroacetic anhydride (4.52 g, 22 mmol). After overnight stirring, the reaction was washed with 1M HCl (50 mL), organic layer concentrated and purified by column chromatography (1-10% gradient of EtOAc in hexanes) to yield the title compound (1.53 g, 60%) as a white solid. ESIMS (M-H)-=297.
With tin(ll) chloride; In ethanol; at 20℃;
Step A: N-[5-Bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide To a solution of 4-bromo-2-nitroanisole (2.0 g, 0.009 mol) in absolute EtOH (100 mL) was added SnCl2.2H2O (11.68 g, 0.051 mol) and the resulting mixture was allowed to stir overnight at rt. The solvent was removed under reduced pressure, residue suspended in EtOAc (100 mL), washed with 1M NaOH (100 mL), and filtered through a celite pad. The organic layer was removed, concentrated by rotary evaporation, and dried under high vacuum. The resulting residue was then dissolved in DCM (150 mL) followed by the addition of TEA (5.19 g, 0.051 mol) and TFAA (4.52 g, 0.022 mol). After overnight stirring, the reaction was washed with 1M HCl (50 mL), organic layer concentrated and purified by column chromatography (1-10% gradient of EtOAc in hexanes) to yield the title compound (1.53 g, 60%) as a white solid. ES-LC/MS m/z=297 [M-H]+.
With hydrogenchloride; tin; In ethanol; water; at 20℃; for 5h;
Step 2; Reduction of Nitro Group: Synthesis of 5-bromo-2-methoxyaniline 28.3 To a stirred solution of 28.2 (0.95 g, 4.09 mmol) in ethanol (30 mL) was added concentrated HCl (15 mL) and tin powder (0.95 g, 8 mmol). The reaction was stirred for 5 h. The solvent was then removed in vacuo and the acid was neutralised by the slow addition of 2.5M NaOH solution (13 mL) at 0 C. The aqueous mixture was then extracted with diethyl ether (3*50 mL). The organic fractions were dried over MgSO4, filtered and concentrated in vacuo to yield 28.3 as a brown solid (0.86 g, 100%). The product was not purified further. 1H NMR (CDCl3, 400 MHz) deltaH ppm: 3.85 (3H, s, OMe), 6.65 (1H, dd, J1=2 Hz, J2=10.12 Hz, ArH), 6.83 (1H, dd, J1=2.44 Hz, J2=8.2 Hz, ArH), 6.85 (1H, s, ArH) 13C NMR (CDCl3, 400 MHz) deltac ppm: 55.18 (ArC), 111.14 (ArCH), 112.75 (ArC), 116.87 (ArCH), 117.72 (ArC), 120.23 (ArCH), 137.15 (ArC), 145.90 (ArC); vmax (DCM)/cm-1: 3460.96, 3370.98, 1611.91, 1573.81; HRMS: calculated 201.9862, found 201.9855, molecular formula (C7H9BrNO).; Melting Point: 110 C.
With potassium phosphate; copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; at 140℃; for 3h;Microwave irradiation;
Description 6; 3,3-Dimethyl-l-[4-(methyloxy)-3-nitrophenyl]-2-piperazinone (D6)A stirred mixture of 4-bromo-l-(methyloxy)-2-nitrobenzene (696 mg, 3 mmol), 3,3- dimethyl-2-piperazinone (D5) (460 mg, 3.6 mmol), potassium phosphate (1.27 g, 6 mmol), copper (I) iodide (57 mg, 0.3 mmol) and trans- 1 ,2-cyclohexanediamine (69 mg, 0.6 mmol) in dioxane (18 mL) was heated at 14O<0>C for 3 hours in a microwave reactor. A solution of 0.880 ammonia (2 mL) and water (20 mL) was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried and evaporated. The residue was purified by column chromatography (silica gel) eluting with dichloromethane/2M ammonia in methanol: (20:1 to 10:1) to afford the title product (D6). MS (ES+) m/e 280 [M+H]<+>.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;
To a stirred solution of 1.30 g (5.60 mmol) <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> (VI) in 25 ml DMSO were added 1.57 g (6.16 mmol) bis(pinacolato)diboron, 123 mg (0.17 mmol) dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct and 1.65 g (16.8 mmol) potassium acetate. The mixture was heated at 80o C. for 2 h and then cooled to room temperature, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1 ethyl acetate/hexane then ethyl acetate) afforded 1.39 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (VII) as an off-white solid. ES-MS m/e (%): 280 (M+H+, 100).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 2h;
a 2-(4-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,21 dioxaborolane To a stirred solution of 1.30 g (5.60 mmol) <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> in 25 ml DMSO were added 1.57 g (6.16 mmol) bis(pinacolato)diboron, 123 mg (0.17 mmol) dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct and 1.65 g (16.8 mmol) potassium acetate. The mixture was heated at 80 C. for 2 h and then cooled to room temperature, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/2 ethyl acetate/hexane then ethyl acetate) afforded 1.39 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as an off-white solid. ES-MS m/e (%): 280 (M+H+, 100).
With caesium carbonate; johnphos;palladium diacetate; at 100℃; for 8h;
To A solution of 5-BROMO-1-METHOXY-2-NITROBENZENE (300 mg, 1. 29 mmol) in dioxane, 1-acetyl piperazine (400mg, 3.12 MMOL), cesium carbonate (1. 0g, 3. 07 MMOL), palladium diacetate (29.0 mg, 0. 129 MMOL) and 2-(DI-T-BUTYLPHOSPHINO) BIPHENYL (77 mg, 0. 258 MMOL) are added and stirred at 100C for 8 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporate in vacuo. The residue is purified by silica gel column chromatography (n-hexane : ethyl acetate gradient) to afford 1- [4- (4-METHOXY- 3-NITRO-PHENYL)-PIPERAZIN-1-YL]-ETHANONE (319MG, 44%) as yellow solids. 1H-NMR (400MHZ, CDCl3, 6, ppm): 2. 14 (s, 3H), 3.63 (ddd, 4H), 3.63 (t, 2H), 3.78 (T, 2H), 3.92 (s, 3H), 7.03 (d, 1H), 7.12 (d, 1H), 7.41 (d, 1H). RF (ETHYL acetate): 0. 18
With potassium phosphate;palladium diacetate; CyJohnPhos; In 1,2-dimethoxyethane; at 80℃; for 96h;
4-Bromo-2-nitroanisol (8.5 g, 36 mmol), morpholine (3.8 ml, 44 mmol), potassium phosphate (11 g, 51 mmol), 2-biphenyl-dicyclohexyl phosphine (960 mg, 2.7 mmol) and palladium(II)acetate (411 mg, 1.8 mmol) are dissolved in dimethoxyethane (80 ml) and stirred at 80 C. for 96 hours. The mixture is then cooled to room temperature, diluted with ethyl acetate (50 ml) and filtrated through dicalite. Flash chromatography on silica (eluent dichloromethane/methanol 99:1) affords the product as red solid (6.0 g, 69%). MS: m/e=238 (M+).
53%
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 5h;
<strong>[33696-00-3]4-bromo-1-methoxy-2-nitrobenzene</strong> (1.19 g, 5.13 mmol), morpholine (0.447 ml, 5.13 mmol), cesium carbonate (3.34 g, 10.2 mmol), palladium (II) acetate (0.092 g, 0.41 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.356 g, 0.62 mmol) in 1,4-dioxane (10 ml) were stirred at 90 C. for 5 hours. After dilution with dichloromethane and filtration, the reaction mixture was washed with water and the organic layer dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 100% EtOAc/petroleum ether to afford 4-(4-methoxy-3-nitrophenyl)morpholine (0.652 g, 53%) as a solid; NMR spectrum: (CDCl3) 3.08-3.14 (m, 4H), 3.84-3.89 (m, 4H), 3.92 (s, 3H), 7.03 (d, 1H), 7.12 (dd, 1H), 7.32 (d, 1H).
With dipotassium hydrogenphosphate; CyJohnPhos;palladium diacetate; In 1,2-dimethoxyethane; at 80 - 130℃;Inert atmosphere; Microwave irradiation;
(i) 4-Bromo-1-(methyloxy)-2-nitrobenzene (4.71 g, 20.3 mmol) was dissolved in 1 ,2- dimethoxyethane (50 ml) and the solution degassed under argon. Morpholine (2.12 ml, 24.4 mmol), potassium phosphate dibasic (4.95 g, 28.4 mmol), 2- biphenylyl(dicyclohexyl)phosphane (0.53 g, 1.52 mmol) and palladium (II) acetate (0.23 g, 1.02 mmol) were added sequentially and the reaction mixture stirred at 800C for 36 hours. A 5 mL aliquot of the mixture was removed and heated to 120 0C for 2 hours in the microwave. This mixture was diluted with ethyl acetate (5 mL), filtered through celite and concentrated in vacuo. The residue was purified by flash-silica gel chromatography, eluting with a 50-100% gradient of dichloromethane in isohexane to yield a bright orange gum that crystallised upon standing. The remainder of the reaction mixture was heated to 130 0C in the microwave for 4 hours. The mixture was diluted with ethyl acetate, filtered through celite and concentrated in vacuo. At this point the crude residue was divided into two; one half was not purified and was used no further. The remaining half was purified by flash-silica gel chromatography, eluting with a 0-1% gradient of methanol in dichloromethane. The two batches of purified material were combined to yield 4-[4-(methyloxy)-3-nitrophenyl]morpholine (0.63 g).
With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 2h;
Into a 20 ml vial was charged 4-bromo-l-methoxy-2-nitrobenzene (0.3 g, 1.293 mmol), morpholine (0.338 ml, 3.88 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.059 g, 0.065 mmol), xantphos (0.037 g, 0.065 mmol) and sodium te/t-butoxide (0.311 g, 3.23 mmol) in 1,4-dioxane (12.93 ml). The reaction mixture was heated at 100 0C on a hot plate for 2 hours. The solution was allowed to cool and stir overnight at room temperature. The mixture was concentrated and the residue was loaded onto a silica gel column. The compound was eluted using a gradient starting with 100% dichloromethane to 1: 1 dichloromethane/methanol over 50 minutes to provide the title compound. MS (DCI(+)) m/e 239.0 (M+H)+.
Palladium (II) acetate (941 mg, 4.2 mmol) and rac-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (3.93 g, 6 mmol) were heated to 50C in dioxane (200 ml) for 30 minutes. Cesium carbonate (20.48 g, 63 mmol), <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> (9.75 g, 42 mmol) and cis-2,6-dimethylpiperazine (14.39 g, 126 mmol) were added and the mixture heated at reflux for 18 hours. The solids were filtered through celite and washed with ethyl acetate. The residue was concentrated and dissolved in ethyl acetate and extracted with 2N hydrochloric acid (x5). The combined extracts were washed in ethyl acetate (x3), basified with 0.880 ammonia and extracted with dichloromethane (x5). The combined organic extracts were concentrated, redissolved in ethyl acetate and washed with water (x3), saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (Biotage Horizon, dichloromethane to 1:9 2M ammonia in methanol:dichloromethane) to afford the titleproduct (D3). MS (ES+) m/e 266 [M+H]+.
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane;
a 4-Cyclohex-1-enyl-1-methoxy-2-nitro-benzene To a stirred solution of 2.1 g (0.0091 Mol) <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> in 50 ml dioxane were added 1.05 g (0.00091 Mol) tetrakis(triphenylphosphine)palladium, 4.03 g (0.011 Mol) tri-n-butyl-(1-cyclohex-1-enyl)-stannane and 18.3 ml 2 M aqueous Na2CO3 solution. The mixture was heated for 16 h at reflux and then poured onto water. After extraction with dichloro methane, drying of the combined organic phases over sodium sulfate and evaporation of the solvent the crude material was subjected to column chromatography (ethyl acetate/hexane 1:10) to yield 1.57 g of 4-cyclohex-1-enyl-1-methoxy-2-nitro-benzene as a yellow liquid. El-MS m/e (%): 233 ([M]+, 100).
a) 5-bromo-2-methoxyaniline. A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100 C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100 C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3*25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3*25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) delta 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 mum, 200A, 250*4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443.
In n-heptane; water; acetic acid; ethyl acetate;
a) 5-bromo-2-methoxyaniline (1) A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100 C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100 C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3*25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3*25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 m, 200A, 250*4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443.
With hydrogenchloride; sodium hydrogencarbonate; In ethanol;
REFERENCE EXAMPLE 50 5-bromo-2-methoxyaniline A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder (113.7 g) in ethanol (1.51) was heated to reflux and treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for a further 3 hours the reaction mixture was cooled to room temperature then filtered through hyflosupercel. The filtrate was evaporated and the residue was treated with saturated sodium bicarbonate solution (21) then filtered. The solid was washed with water then recrystallized from cyclohexane to give the title compound (61.98 g) as a pale brown solid, m.p. 93-93 C.
a. 5-Bromo-2-methoxyaniline To a solution of 4-bromo-2-nitroanisole (500 mg, 2.15 mmol) in anhydrous ethanol (15 ml) was added slowly anhydrous tin chloride (1.6 g, 8.62 mmol). The mixture was refluxed for 1 h, then rotary evaporated to leave a brown oil which was neutralized with aqueous 2N NaOH (5 ml). The resulting solid was filtered and washed with ethyl acetate. The aqueous and ethyl acetate solutions were combined and washed with water. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified column chromatography to give a white solid (46 mg, 11%). 1H NMR (CDCl3): 6.79 (dd, J=2.1, 9.0 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 6.61 (d, J=9.3 Hz, 1H), 3.84 (s, 2H), 3.80 (s, 3H).
4-(4-benzyloxy-3-nitro-phenyl)-morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
4-(4-Benzyloxy-3 -nitro-phenyl)-morpholine The title compound was prepared using morpholine and 1-benzyloxy-4-bromo-2-nitro-benzene (prepared from 4-bromo-2-nitro-anisol and benzyl bromide) using the general method of example "4-(4-methoxy-3 -nitro-phenyl)-morpholine" as yellow solid (58%),. MS: m/e=315(M+H+).
4-(4-Methoxy-3-nitro-phenyl)-morpholine 4-Bromo-2-nitroanisol (8.5 g, 36 mmol), morpholine (3.8 ml, 44 mmol), potassium phosphate (11 g, 51 mmol), 2-biphenyl-dicyclohexyl phosphine (960 mg, 2.7 mmol) and palladium(II)acetate (411 mg, 1.8 mmol) are dissolved in dimethoxyethane (80 ml) and stirred at 80 C. for 96 hours. The mixture is then cooled to room temperature, diluted with ethyl acetate (50 ml) and filtrated through dicalite. Flash chromatography on silica (eluent dichloromethane/methanol 99:1) affords the product as red solid (6.0 g, 69%). MS: m/e=238 (M+).
4-Fluoro-N-(4-methoxy-7-pyrrolidin-1-yl-benzothiazol-2-yl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
4-Fluoro-N-(4-methoxy-7-pyrrolidin-1-yl-benzothiazol-2-yl)-benzamide The title compound was prepared strarting from <strong>[33696-00-3]4-bromo-1-methoxy-2-nitro-benzene</strong> and pyrrolidine as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light brown solid in about 10% overall yield, MS: m/e=372 (M+H+).
N-(7-Azepan-1-yl-4-methoxy-benzothiazol-2-yl)-4-nitro-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
N-(7-Azepan-1-yl-4-methoxy-benzothiazol-2-yl)-4-nitro-benzamide The title compound was prepared using <strong>[33696-00-3]4-bromo-1-methoxy-2-nitro-benzene</strong>, azepane and 4-nitro-benzoyl chloride as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=427 (M+H+).
4-{4-Methoxy-2[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}-piperazine-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
EXAMPLE 64 4-{4-Methoxy-2[(5-methyl-thiophene-2-carbonyl)-amino]-benzothiazol-7-yl}-piperazine-1-carboxylic acid benzyl ester The title compound was synthesised starting from N-benzyloxycarbonylpiperazine and <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and obtained as a white solid in 12% overall yield, MS: m/e=523 (M+H+).
5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide[ No CAS ]
[ 383865-47-2 ]
Yield
Reaction Conditions
Operation in experiment
10%
EXAMPLE 65 5-Methyl-thiophene-2-carboxylic acid [7-(3-dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl]-amide The title compound is synthesised starting from 3-(dimethylamino)pyrrolidine and <strong>[33696-00-3]4-bromo-2-nitroanisole</strong> as described for 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide and was obtained as yellow solid in 10% overall yield, MS: m/e=417 (M+H+).
7-(3-Dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl-amine Following the general method of example 403 the title compound was synthesised from [5-(3-dimethylamino-pyrrolidin-1-yl)-2-methoxy-phenyl]-thiourea (synthesised from <strong>[33696-00-3]4-bromo-1-methoxy-2-nitro-benzene</strong> and dimethyl-pyrrolidin-3-yl-amine as described for (2-methoxy-5-morpholin-4-yl-phenyl)-thiourea) as a white solid (25%), MS: m/e=293 (M+H+).
morpholine-4-carboxylic acid [4-methoxy-7-(4-methoxy-piperidin-1-yl)-benzothiazol-2-yl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
Morpholine-4-carboxylic acid [4-methoxy-7-(4-methoxy-piperidin-1-yl)-benzothiazol-2-yl]-amide The title compound was prepared strarting from <strong>[33696-00-3]4-bromo-1-methoxy-2-nitro-benzene</strong> and 4-methoxy-piperidine as described for morpholine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (Example 136) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=407 (M+H+).
4-Fluoro-N-(4-methoxy-7-[1,4]oxazepan-4-yl-benzothiazol-2-yl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
4-Fluoro-N-(4-methoxy-7-[1,4]oxazepan-4-yl-benzothiazol-2-yl)-benzamide The title compound was prepared strarting from <strong>[33696-00-3]4-bromo-1-methoxy-2-nitro-benzene</strong> and [1.4]Oxazepane as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=402 (M+H+).
Step i :To a solution of 4-bromo-1-methoxy-2-nitro-benzene 52a (6 g, 25.9 mmol) in dry THF (250 mL) at -40C is added dropwise the vinylmagnesium bromide solution (1 M in THF, 90.5 mL, 90.5 mmol). The reaction mixture is stirred at -4O0C for 4 h then poured into saturated NH4CI solution. The reaction mixture is extracted with Et2O (2x); the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting EtOAc/hexanes (10% to 40%) affording 52b (620 mg, 11% yield).
8%
In tetrahydrofuran; at -60 - -40℃; for 2h;
Example 13 Synthesis of 4-bromo-7-methoxyindole (LII) To a -60 C. solution of 4-bromo-2-nitroanisole (7.89 g, 33.3 mmol) in THF (300 was added vinylmagnesium bromide (1 M in THF, 100 ml, 0.1 mol) while maintaining the reaction temperature below -40 C. The resulting mixture was stirred allowing the temperature to rise to -40 C. in 2 hours. The reaction mixture was then quenched with a saturated solution of NH4Cl (700 ml) and extracted with Et2O (200 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified through flash chromatography affording 4-bromo-7-methoxyindole LII (594 mg, 8% yield).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;
Intermediate B63: 2-(methyloxy)-5-(4-methyl-1 -piperazinyl)aniline; Step A/Intermediate B64: 1-methyl-4-[4-(methyloxy)-3-nitrophenyl]piperazine; To an N2 degassed solution of 1 ,4-dioxane (20 ml_), was added 4-bromo-1-(methyloxy)-2-nitrobenzene (0.5 g, 2.16 mmol), XANTPHOS (0.37g, 0.65 mmol, Aldrich), Pd2(dba)3 (0.39g, 0.43 mmol, Aldrich), Cs2CO3 (1.4 g, 4.3 mmol, Aldrich), and 1-methylpiperazine (0.43 g, 4.3 mmol, Aldrich). After heating overnight at 9O0C, the reaction was diluted with ethyl acetate (50 ml_), washed with water (50 ml_), the organic layer adsorbed to silica gel and purified by column chromatography <n="114"/>(dichloromethane to 5% methanol/dichloromethane) to afford 1-methyl-4-[4- (methyloxy)-3-nitrophenyl]piperazine (0.4 g, 74%) as a tan solid. ESIMS (M+H)+ = 252.
59%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 21h;
To a solution of <strong>[33696-00-3]4-bromo-1-methoxy-2-nitrobenzene</strong> (1 g, 4.31 mmol), N-methyl piperazine (956 jiL, 8.62 mmol), Xantphos (748 mg, 1.29 mmol) and Cs2CO3 (2.81 g, 8.62 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3 (788.00 mg, 0.86 mmol) andthe reaction mixture was stirred at 90 C for 21 h. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was dried over sodium sulfate and concentrated in vacuo to give 638 mg of intermediate 147 (59% yield, orange oil) which was used in the next step without further purification.
55%
With potassium phosphate;palladium diacetate; DavePhos; In tetrahydrofuran; for 72h;Heating / reflux;
Example 31; 2-Methoxy-5-(4-methyl-piperazin-l-yl)-phenylamine; Step 1. l-(4-Methoxy-3-nitro-phenyl)-4-methyl-piperazine; Pd(OAc)2 (85 mg, 0.38 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)- biphenyl (225 mg, 0.57 mmol), K3PO4 (2.26 g, 10.68 mmol), 4-bromo-l-methoxy-2- nitro-benzene (1.77 g, 7.63 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. N- methylpiperazine (1.01 mL, 9.15 mmol) was added and the reaction mixture was refluxed for 72 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 1.05 g (55% yield) of the title compound. <n="92"/>1H NMR (400 MHz, DMSO-J6) delta ppm 2.22 (s, 3 H) 2.45 (m, 4 H) 3.09 (m, 4 H) 3.83 (s, 3 H) 7.22 (d, J= 9.27 Hz, 1 H) 7.26 (dd, J= 9.27 and 2.93 Hz, 1 H) 7.35 (d, J= 2.93 Hz, 1 H).
55%
With potassium phosphate; DavePhos;palladium diacetate; In tetrahydrofuran; for 72h;Reflux;
Pd(OAc)2 (85 mg, 0.38 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)- biphenyl (225 mg, 0.57 mmol), K3PO4 (2.26 g, 10.68 mmol), 4-bromo-l-methoxy-2- nitro-benzene (1.77 g, 7.63 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. N- methylpiperazine (1.01 mL, 9.15 mmol) was added and the reaction mixture was refluxed for 72 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel(eluant: DCM/EtOH 90/10) to afford 1.05 g (55% yield) of the title compound.1H NMR (400 MHz, DMSO-d6) delta ppm: 2.22 (s, 3 H) 2.45 (m, 4 H) 3.09 (m, 4 H) 3.83(s, 3 H) 7.22 (d, J= 9.27 Hz, 1 H) 7.26 (dd, J= 9.27 and 2.93 Hz, 1 H) 7.35 (d, J= 2.93Hz, 1 H).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 60℃; for 16h;
5-(4-Methoxy-5-nitro-phenylethynyl)-pyrimidin-2-ylamine A mixture of 1-bromo-4-methoxy-3-nitro-benzene (5.0 g), 5-ethynylpyrimidin-2-amine (Intermediate 2) (2.8 g), copper (I) iodide (33 mg) and bis(triphenylphosphine)palladium (II) chloride (212 mg) in DMF (90 mL) was stirred under an inert atmosphere. TEA (18 mL) was added and the reaction was stirred at 60 C. for 16 hours. The DMF was removed in vacuo to give a black solid. DCM (100 mL) was added and the solid was filtered and dried (10 g, impure); MS m/e MH+271.
Compound II-1 (1.09 g, 5 mmol)Soluble in acetone (12.5mL, 0.4M),Methyl iodide (933 muL, 15 mmol) was added in sequence.Potassium carbonate (2.073 g, 15 mmol).Reacted overnight,TLC monitoring showed the end of the reaction.Filtering,The filtrate was evaporated under reduced pressure.The residue was subjected to column chromatography ( petroleum ether: ethyl acetate = 50:1)Purification of Compound II-2 (yellow solid, 1.134 g, yield 97%).
61.8%
4-Bromo-2-nitrophenol (1.00 g, 4.59 mmol) was added in small portions to a suspension of sodium hydride (400 mg, 9.17 mmol) in dimethylformamide (12 ml) at room temperature under argon atmosphere, then the mixture was stirred at room temperature for 30 minutes. A solution of methyl iodide (1.30 g, 9.174 mmol) in dimethylformamide (4 ml) was added to this mixture, and stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (658 mg, 61.8%) as a pale yellow solid. 1H-NMR (CDCl3) delta: 3.96 (3H, s), 6.99 (1H, d, J=9.1 Hz), 7.65 (1H, dd, J=2.5, 9.1 Hz), 7.98 (1H, d, J=2.5 Hz).
With potassium carbonate; In [(2)H6]acetone; for 3h;Reflux;
Methylation of Phenol: Synthesis of 4-bromo-1-methoxy-2-nitrobenzene 22.2 To a stirred solution of 4-bromo-2-nitrophenol 28.1 (5.46 g, 25.04 mmol) in acetone (60 mL) was added potassium carbonate (10.38 g, 75.13 mmol) and iodomethane (15.59 mL, 250.45 mmol). The reaction was heated under reflux for 3 h. The reaction was quenched by the addition of 2M HCl aqueous solution (200 mL) and extracted with diethyl ether. The organic fractions were dried over MgSO4, filtered and concentrated in vacuo. The product was not purified further and afforded 28.2 as an off white solid (5.78 g, 99%). 1H NMR (CDCl3, 400 MHz) deltaH ppm: 3.98 (3H, s, OMe), 7.01 (1H, d, J=8.92 Hz, ArH), 7.65 (1H, dd, J1=2.48 Hz, J2=9 Hz, ArH), 7.98 (1H, d, J=2.5 Hz, ArH) 13C NMR (CDCl3, 400 MHz) deltac ppm: 56.29 (OMe), 111.35 (ArC), 114.74 (ArCH), 127.89 (ArCH), 136.50 (ArCH), 139.51 (ArC), 151.69 (ArC) numax (DCM)/cm-1: 3105.13, 2980.33, 2948.81, 2845.25, 1906.06, 1605.52, 1516.15 HRMS: [M+1] calculated 231.9609, found 231.9254, molecular formula (C7H7BrNO3).; Melting Point: 86 C.
To 4-bromo-2-nitroanisole (2.02 g, 8.72 mmol) and 1,4'-bipiperidine (3.49 g, 20.7 mmol) in dioxane (80 mL) was added sequentially, cesium carbonate (6.74 g, 20.7 mmol), palladium (II) acetate (0.196 g, 0.870 mmol) and di-tert-butylphosphino-biphenyl (0.527 g, 1.77 mmol). The reaction was heated at 100° C. for 24 hours, filtered through Celite.(R)., concentrated and purified by flash chromatography. The residue was taken up in EtOAc (100 mL) and Pd on carbon was added in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite.(R). and concentrated to provide the title compound of step A (0.667 g, 2.31 mmol, 26percent over two steps). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.32-1.40 (m, 2H), 1.43-1.54 (m, 6H), 1.73 (d, J=12.1 Hz, 2H), 2.18-2.28 (m, 1H), 2.41-2.47 (m, 6H), 3.43 (d, J=12.5 Hz, 2H), 3.65 (s, 3H), 4.52 (s, 2H), 6.06 (dd, J=8.6, 2.7 Hz, 1H), 6.28 (d, J=2.9 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H).
With water; sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 80℃;
Intermediate B21 : 2-(methyloxy)-5-(1-propyl-1,2,5,6-tetrahydro-3- pyridinyl)aniline; Step A/Intermediate B22: 3-[4-(methyloxy)-3-nitrophenyl]pyridine; Nitrogen was bubbled through dioxane (100 mL) followed by the addition of 4-bromo- 1-(methyloxy)-2-nitrobenzene (5.0 g, 21.55 mmol, Transworld). To the solution were added 3-pyridinylboronic acid (3.16 g, 25.90 mmol, Boron Molecular), dichloro(triphenylphosphine)palladium (0.76 g, 1.08 mmol, Strem) and degassed aqueous Na2CO3 (65 mL, 1 M, 65 mmol). The reaction mixture was heated at 80 0C overnight. The reaction mixture was diluted with ethyl acetate (100ml) and washed with water (100 mL). The organic layer was concentrated under reduced pressure and the crude product was recrystallized from hexanes/ethyl acetate to afford 3-[4- (methyloxy)-3-nitrophenyl]pyridine (1.5 g, 76%). ESIMS (M+H)+ = 231.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;
Intermediate B65: 5-[4-(1 -methylethyl)-1 -piperazinyl]-2-(methyloxy)aniline; Step A/Intermediate B66: 1-(1-methylethyl)-4-[4-(methyloxy)-3- nitrophenyl]piperazine; To an N2 degassed solution of 1 ,4-dioxane (50 mL, Aldrich) was added 4-bromo-1- (methyloxy)-2-nitrobenzene (1.0 g, 4.31 mmol, Aldrich), XANTPHOS (0.74 g, 1.28 <n="115"/>mmol, Aldrich), Pd2(dba)3 (0.79 g, 0.86 mmol, Aldrich), Cs2CO3 (2.8 g, 8.63 mmol, Aldrich), and <strong>[4318-42-7]1-isopropylpiperazine</strong> (1.10 g, 8.6 mmol, Oakwood Chemicals). After heating overnight at 9O0C, the reaction was diluted with ethyl acetate (50 ml_), washed with water (50 ml_), organic layer adsorbed to silica gel and purified by column chromatography (dichloromethane to 5percent methanol/dichloromethane) to afford 1-(1-methylethyl)-4-[4-(methyloxy)-3-nitrophenyl]piperazine (0.66 g, 55percent). ESIMS (M+H)+ = 280.
With hydrogen;5%-palladium/activated carbon; In tetrahydrofuran; ethanol; at 20℃; under 1551.49 Torr; for 3h;
Into a 50 ml pressure bottle was charged EXAMPLE 52A (0.2476 g, 1.039 mmol), tetrahydrofuran (2 ml), ethanol (2ml), hydrogen (30 psi), and 5% Pd-C, wet (0.050 g, 0.465 mmol). The mixture was stirred for 3 hours at room temperature, filtered through a nylon membrane and concentrated to provide the title compound. MS (DCI(+)) m/e 209.0 (M+H)+.
N′-(1-(3,5-dimethoxyphenyl)ethylidene)-4-methylbenzenesulfonohydrazide[ No CAS ]
[ 33696-00-3 ]
C17H17NO5[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With lithium tert-butoxide;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 70℃; for 6h;
To a solution of XI-2 (1.2 mmol; 1.2 eq.), 196 mg f t-BuOLi (2.4 mmol; 2.4 eq.), 52 mg Pd2 dba3 (0.005 mmol; 10 mold), 98 mg X-Phos in 20 ml of dioxane is added a solution of 5-bromo-2-methoxy-nitrobenzene (1 mmol; 1 eq.) in 5 ml dioxane at room temperature. The reaction medium is then heated to 70 C. and the reaction is followed by TLC. After 6 h, the reaction medium is cooled to room temperature and diluted with CH2Cl2, filtered through celite and concentrated under reduced pressure. The crude product is purified on silica gel column (Cyclohexane/ethyl acetate-7:3). (Yield 80%).1H NMR: delta, ppm, CDCl3, 300 MHz: 3.77 (s, 6H), 3.98 (s, 3H), 5.46 (d, J=5.33 Hz, 2H), 6.44 (m, 3H), 7.04 (d, J=8.73 Hz, 1H), 7.50 (dd, J=2.31 and 8.72 Hz, 1H), 7.86 (d, J=2.31 Hz, 1H)
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 16h;Reflux;
Example 46 4-(2,6-dichlorobenzyl)-6-[2-methoxy-5-( iperazin-l -yl)phenyl]amino}-l H-imidazo[4,5- c]pyridine-7-carboxamide Example 46A tert-buty 4-(4-methoxy-3-nitrophenyl)piperazine- l -carboxylate A mixture of 4-bromo-l -methoxy-2-nitrobenzene (232 mg, 1 mmol), fer/-butyl piperazine-l -carboxylate (224 mg, 1.2 mmol), palladium diacetate (23 mg, 1 ,2 mmol), (+/-)- 2,2'-bis(diphenylphosphino)-l, -binaphthalene (93 mg, 0.15 mmol) and cesium carbonate (978 mg, 3 mmol) in 1,4-dioxane (15 mL) was heated at reflux for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 4/1 petroleum ether/ethyl acetate to give the title compound.
With bismuth (III) nitrate pentahydrate; for 1.5h;Schlenk technique; Ionic liquid; Inert atmosphere; Heating;
General procedure: The ionic liquid (3.5-4.0 mL) was charged into an oven-dried Schlenk tube under a nitrogen atmosphere and Bi(NO3)3·5H2O (1.5 mmol) was added. The respective aromatic compound (1 mmol) was then introduced into the Schlenk tube under a nitrogen atmosphere. The reaction mixture was magnetically stirred, initially at rt for about 10 min followed by stirring in a pre-heated oil bath at 80-85 C, until completion (as monitored by GC-MS). Once the reaction was over, the contents were cooled to rt and extracted with EtOAc-Hexane (2:3 vol/vol), until the final extraction did not show a spot corresponding to the starting material or to the product. The combined organic extracts were washed with 10% NaHCO3 solution, dried with MgSO4, and concentrated to give the crude product. Isomer distributions were determined by GC-MS, and/or by 1H NMR.
With sodium t-butanolate;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃; for 3h;
Step 1 : A degassed suspension of <strong>[33696-00-3]2-nitro-4-bromoanisole</strong> (2.32 g, 10 mmol), N,N-dimethyl- 1 ,3-propanediamine (1.1 eq), Pd2(dba)3 (0.02 eq), dppf (0.04 eq) and sodiumt-butoxide ( 1.5 eq) in dioxane (20 mL) was heated at 1 10 C overnight. Upon cooling the reaction was quenched with water. The volatile components were removed on rotavap and the residue was partitioned between EtOAc and water. Extraction and concentration followed by silica gel column chromatograph ( 15% MeOH in DCM as eluents) furnished 55 (0.66 g, 26%).
26%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; In 1,4-dioxane; at 110℃;
A degassed suspension of <strong>[33696-00-3]2-nitro-4-bromoanisole</strong> (2.32 g, 10 mmol), N,N-dimethyl-1 ,3- propanediamine (1.1 eq), Pd2(dba)3 (0.02 eq), dppf (0.04 eq) and sodium t-butoxide (1.5 eq) in dioxane (20 mL) was heated at 110 C overnight. Upon cooling the reaction was quenched with water. The volatile components were removed on rotavap and the residue was partitioned between EtOAc and water. Extraction and concentration followed by silica gel column chromatograph (15% MeOH in DCM as eluents) furnished 55 (0.66 g, 26%).
(±)-2-(4-methoxy-3-nitrophenyl)-1-(3',4',5'-trimethoxyphenyl)cyclopropane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; toluene; at 100℃; for 1h;Inert atmosphere;
General procedure: Preparation of (±)-12: A pressure glass tube charged with trifluoroborate (±)-10 (31 mg, 0.10 mmol), Cs2CO3 (98 mg, 0.30 mmol) and PdCl2(dppf)·CH2Cl2 (4 mg, 5 mol %) was alternatively evacuated and sparged with argon three times. A solution of 4-bromoanisol (21 mg, 0.11 mol) in toluene (1.5 mL) previously flushed with argon, then water (0.5 mL) were added by syringes. The reaction mixture was stirred at 100 C for 18 h and then cooled to room temperature. Water (5 mL) was added and the mixture extracted with EtOAc (5 mL × 2). The combined organic layers were washed with water (5 mL × 2), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (cyclohexane/EtOAc 9:1), affording 12 as a colorless oil (24 mg, 75%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
