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{4-[6-bromo-1-(4-fluoro-benzyl)-1H-indazol-3-yl]-piperidin-1-yl}-acetic acid tert-butyl ester[ No CAS ]
[ 3375-31-3 ]
[ 6163-58-2 ]
[ 180307-57-7 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; triethylamine; lithium chloride; In N,N-dimethyl-formamide;
(x) 4-{2-[3-(1-tert-Butoxycarbonylmethyl-piperidin-4-yl)-1-(4-fluoro-benzyl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester A stirred mixture of {4-[6-bromo-1-(4-fluoro-benzyl)-1H-indazol-3-yl]-piperidin-1-yl}-acetic acid tert-butyl ester (286 mg, 0.57 mmol), <strong>[180307-56-6]4-vinyl-piperidine-1-carboxylic acid tert-butyl ester</strong> (120 mg, 0.57 mmol), lithium chloride (24 mg, 0.57 mmol), triethylamine (0.24 ml, 1.71 mmol), palladium (II) acetate (8 mg 0.03 mmol), tri-o-tolylphosphine (35 mg, 0.11 mmol), and DMF (5 ml) was heated at 105 (oil-bath temperature) under nitrogen for 18 h. When cool, the mixture was evaporated in vacuo, treated with aqueous saturated sodium bicarbonate (20 ml), and extracted with ethyl acetate (2*20 ml). The combined, dried (Na2 SO4) organic extracts were evaporated, and the residue purified by flash chromatography over silica gel (Merck 9385). Elution with ethyl acetate --cyclohexane (1:2) afforded impure fractions and pure fractions (I). The impure fractions were purified by flash chromatography over silica gel (Merck-9385) eluding with ethyl acetate--cyclohexane (gradient 1:4 to 1:2) to give pure fractions (II). The pure fractions (I) and (II) were combined to give the title compound as a pale yellow oil (195 mg).
With potassium tert-butylate; In tetrahydrofuran; diethyl ether;
(ix) 4-Vinyl-piperidine-1-carboxylic acid tert-butyl ester A solution of 4(2-bromo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (81.5 g 0.279 mol) in dry tetrahydrofuran (1000 ml) under nitrogen at 20 was treated portionwise, over 30 min, with potassium tert-butoxide (63.2 g 0.563 mol). The mixture was stirred at 25 for 3 h and partitioned between saturated aqueous ammonium chloride (1000 ml) and diethyl ether (500 ml). The aqueous phase was extracted with diethyl ether (4*500 ml) and the combined, dried (MgSO4) extracts were evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (Merck 9385) eluant cyclohexane: diethyl ether (19:1) to give the title compound as an orange oil (37.1 g, 0.176 mol, 63%). Mass spectrum m/z=212 ?MH+!
palladium diacetate; In diethyl ether; at 0 - 20℃; for 5.0h;
1-M ethyl-3-nitro-1-nitrosoguanidine (3.00 g, 20.4 mmol) was added in small portions with agitation to a mixture of 5M aqueous NaOH solution (14 ml) and ether (70 ml), cooled to 0 C. The yellow ether layer was decanted into a flask precooled in an ice bath and containing a few KOH pellets for drying. To a solution of olefin 20 (0.20 g, 0.95 mmol) in ether (5 ml) cooled to 0 C. was added Pd(OAc)2 (0.006 g, 0.03 mmol), followed by the ethereal CH2N2 solution in portions (prepared as described above), and the reaction mixture was stirred at rt for 5 hr. It was quenched with AcOH and diluted with saturated aqueous NaHCO3 solution. The product was extracted with CH2Cl2 and the organic layer was dried over Na2SO4. Purification by flash chromatography (CH2Cl2) provided 0.16 g of 21 as a clear liquid.
In tetrahydrofuran; hexanes; at -78 - 20℃; for 0.5h;
To a suspension of methyltriphenylphosphonium bromide (1.76 g, 4.93 mmol) in THF (30 ml), cooled to -78 C., was added n-BuLi (1.88 ml of 2.5M soln. in hexanes; 4.68 mmol), and the mixture was stirred at -78 C. for 30 min and then at 0 C. for 45 min. It was cooled back to -78 C., and a solution of aldehyde 6 (0.50 g, 2.34 mmol) in THF (5 ml) was added. The reaction mixture was stirred at -78 C. for 30 min and warmed up to rt. It was quenched with water, and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and purified by flash chromatography (0.5% MeOH/CH2Cl2) to provide 0.24 g of 20 as a clear oil. Step 2: BOC-deprotection and amide coupling steps as described in Example 2 were used to obtain the title compound MS (M+H): 347.
With palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 130℃; for 2.0h;
Step B: tert-Butyl 4-[(E)-2-(4-Fluoro-l-oxo-13-dihydro-2-benzofuran-5-yl)ethenyllpiperidine- 1-carboxylate To a flask added 5-bromo-4-fluoro-2-benzofuran-l (3H)-one (0.10 g, 0.43 mmol) palladium(II)acetate (0.097 g, 0.043 mmol), triethylamine (0.12 mL, 0.88 mmol) and tert-butyl 4-ethyenylpiperidine-l-carboxylate (0.27 g, 1.2 mmol); the resulting mixture was then dissolved in DMF (15 mL) and heated in an oil bath at 130 C for 2 h. The flask was cooled to room temperature, diluted with EtOAc and washed with saturated sodium bicarbonate and water, then dried (Na2SC>4), filtered and adsorbed into silica gel. MPLC (hexanes/EtOAc = 1/1) purification provided tert-butyl 4-[(E)-2-(4-fluoro- 1 -oxo- 1 ,3-dihydro-2-benzofuran-5-yl)ethenyl]piperidine- 1-carboxylate. LC/MS: [(M+2)]+ =233.
With palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 130℃; for 2.0h;
[0171] To a flask added 5-bromo-4-fluoro-2-benzofuran-1(3H)-one (0.10 g, 0.43 mmol) palladium(II)acetate (0.097 g,0.043 mmol), triethylamine (0.12 mL, 0.88 mmol) and tent-butyl 4-ethyenylpiperidine-1-carboxylate (0.27 g, 1.2 mmol);the resulting mixture was then dissolved in DMF (15 mL) and heated in an oil bath at 130 C for 2 h. The flask was cooledto room temperature, diluted with EtOAc and washed with saturated sodium bicarbonate and water, then dried (Na2SO4),filtered and adsorbed into silica gel. MPLC (hexanes/EtOAc = 1/1) purification provided tert-butyl 4-[(E)-2-(4-fluoro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethenyl]piperidine-1-carboxylate. LC/MS: [(M+2)]+ =233.
tert-butyl 4-[(E)-2-(4-nitrophenyl)ethenyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichlorobis(tri-O-tolylphosphine)palladium; triethylamine; In N,N-dimethyl-formamide; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation;
4- r(E)-2-(4-nitrophenyl)ethenyl1piperidinium Chloride Step A: fert-Butyl 4-r(E)-2-(4-nitrophenyl)ethenyl1piperidine-l-carboxylate tert-Butyl 4-ethenylpiperidine- 1 -carboxylate (0.50 g, 2.4 mmol), tra/?s-dichlorobis(tri-o- tolylphosphine) palladium (II) (0.050 g, 0.064 mmol), l-bromo-4-nitrobenzene (0.57 g, 2.8 mmol), and triethylamine (1.6 mL, 12 mmol) were added to a microwave tube, diluted with DMF (2 mL) and degassed under a stream of nitrogen. The tube was sealed and heated in the microwave to 130 C for 30 min. The resulting mixture was diluted with diethyl ether and washed successively with saturated sodium bicarbonate, water (2x), 1 N hydrochloric acid, and brine, then dried (MgS04), filtered and concentrated. The resulting tert-butyl 4-[(E)-2-(4- nitrophenyl)ethenyl]piperidine-l -carboxylate was used directly in the next step. LC/MS: [(M+l)]+ = 333.
With dichlorobis(tri-O-tolylphosphine)palladium; triethylamine; In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Inert atmosphere; Sealed tube;
[0070] tert-Butyl4-ethenylpiperidine-1-carboxylate (0.50 g, 2.4 mmol), trans-dichlorobis(tri-o-tolylphosphine) palladium(II) (0.050 g, 0.064 mmol), 1-bromo-4-nitrobenzene (0.57 g, 2.8 mmol), and triethylamine (1.6 mL, 12 mmol) were addedto a microwave tube, diluted with DMF (2 mL) and degassed under a stream of nitrogen. The tube was sealed andheated in the microwave to 130C for 30 min. The resulting mixture was diluted with diethyl ether and washed successivelywith saturated sodium bicarbonate, water (2x), 1 N hydrochloric acid, and brine, then dried (MgSO4) filtered and concentrated.The resulting tert-butyl4-[(E)-2-(4-nitrophenyl)ethenyl]piperidine-1-carboxylate was used directly in the nextstep.LC/MS: [(M+1)]+ = 333.
tert-butyl 4-[(E)-2-(2,1,3-benzoxadiazol-5-yl)ethenyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;
[0077] In a 15 mL microwave tube was added <strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.94 g, 4.7 mmol), tert-butyl 4-ethenylpiperidine-1-carboxylate (1.0 g, 4.7 mmol), triethylamine (0.66 ml, 4.7 mmol), palladium (II) acetate (0.11 mg, 0.47 mmol)and DMF (5 mL). The solution was degassed and filled with nitrogen (3x), then heated to 100 C for 2 hr. The reactionwas diluted with ethyl acetate, washed with water, filtered through a pad of diatomaceous earth and a plug of silica gel.The organic phase was dried over MgSO4, concentrated and purified by MPLC (eluted with gradient 0->30% EtOAc/Hexane)to provide tert-butyl 4-[(E)-2-(2,1,3-benzoxadiazol-5-yl)ethenyl]piperidine-1-carboxylate as a mixture with the Zolefin.LC-MS (IE, m/z): 352 [M+Na]+.
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