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Jang, Mingyeong ; Lim, Taeho ; Park, Byoung Yong ; Han, Min Su ;
Abstract: In this study, we developed a metal-free and highly chemoselective method for the reduction of aromatic nitro compounds. This reduction was performed using tetrahydroxydiboron [B2(OH)4] as the reductant and 4,4'-bipyridine as the organocatalyst and could be completed within 5 min at room temperature. Under optimal conditions, nitroarenes with sensitive functional groups, such as vinyl, ethynyl, carbonyl, and halogen, were converted into the corresponding anilines with excellent selectivity while avoiding the undesirable reduction of the sensitive functional groups.
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Purchased from AmBeed: 607-35-2 ; 578-66-5 ; 613-50-3 ; 100-19-6 ; 579-71-5 ; 3034-94-4 ; 5683-43-2 ; 99-92-3 ; 13534-97-9 ; 5676-60-8 ; 5470-18-8 ; 619-45-4 ; 553-26-4 ; 580-15-4 ; 611-34-7 ; 619-72-7 ; 100-13-0 ; 540-37-4 ; 1849-25-8 ; 4487-59-6 ; 555-16-8 ; 6298-19-7 ; 556-08-1 ; 953-26-4 ; 54060-30-9 ; 62-23-7 ; 607-34-1 ; 3867-18-3 ; 873-74-5 ; 3544-24-9 ; 94-52-0 ; 1520-21-4 ; 5470-34-8 ; 619-50-1 ; 586-39-0 ; 934-22-5 ; 402-54-0 ; 15411-43-5 ; 455-14-1 ; 17763-80-3 ; 3085-54-9 ; 1942-30-9 ; 1694-20-8 ; 6305-66-4 ; 41656-75-1 ; 6393-17-5 ; 4309-66-4
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CAS No. : | 4487-59-6 |
Formula : | C5H3BrN2O2 |
M.W : | 202.99 |
SMILES Code : | C1=CC(=NC=C1[N+](=O)[O-])Br |
MDL No. : | MFCD00006222 |
InChI Key : | HUUFTVUBFFESEN-UHFFFAOYSA-N |
Pubchem ID : | 78240 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319 |
Precautionary Statements: | P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330 |
* 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 |
---|---|---|
70% | The reported procedure from Oehlke, J.; Schroetter, E.; Dove, S.; Schick, H.; Niedrich, H. Pharmazie 1983, 38, 591-596, was slightly modified. When N,N-dimethylformamide (DMF) was used as the solvent instead of dimethylsulfoxide (DMSO) in the substitution of 2-bromo-5-nitropyridine by copper(I) cyanide, subsequent hydrolysis provided the described acid in an improved 70percent yield, typically used without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of ethyl-3-pyrazole carboxylate (3.53 g, 25.2 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60percent, 1.21 g, 30.2 mmol). The resulting mixture was stirred at room temperature for 40 min followed by the addition of 5-nitro-2-bromopyridine (5.1 g, 25.2 mmol). After being stirred for 20 min, the reaction mixture was partitioned between dichloromethane (1000 mL) and water (500 mL), the organic phase was washed with water (3.x.500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using 80percent DCM/hexane to give the desired product. To this nitro intermediate (6.77 g, 25.8 mmol) in acetic acid (220 mL) was added zinc powder (16.77 g, 258 mmol). The resulting mixture was heated at 60° C. for 30 min before it was filtered. The filtrate was concentrated in vacuum. To the residue was added DCM (1000 mL) and saturated sodium bicarbonate (1000 mL), and the resulting mixture was stirred at room temperature overnight. The organic phase was then washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using 5percent methanol in DCM (containing 0.1percent triethylamine) to give the desired product as a yellow solid. To this amine intermediate (5.96 g, 25.7 mmol) in tetrafluoroboric acid (48percent, 130 mL) at 0° C. was added a solution of sodium nitrite (1.95 g, 28.3 mmol) in water (20 mL) dropwise. The resulting solution was stirred at 0° C. for 1 h before filtration. The solid was washed with water and diethyl ether to give the desired product as a yellow solid. A mixture of this diazo intermediate (6.66 g) in acetic anhydride (250 mL) was heated at 70° C. overnight before it was concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM to give the desired product as a white solid. A solution of this acetate intermediate (3.5 g, 12.7 mmol) in ethanol (400 mL) in the presence of 4 drops of sulfuric acid was heated under reflux overnight. After being concentrated in vacuo, the residue was partitioned between DCM (300 mL) and water (200 mL). The pH of the resulting mixture was adjusted to pH=5 by saturated sodium bicarbonate solution. The DCM phase was dried with sodium sulfate and concentrated in vacuo to give the product as a solid. To a solution of this hydroxyl intermediate (2.86 g, 12.3 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60percent, 589 mg, 14.73 mmol). The resulting mixture was stirred at room temperature for 40 min followed by adding 4-methoxybenzyl alcohol (2.31 g, 14.73 mmol) and sodium iodide (10 mg). The resulting mixture was heated at 80° C. for 0.5 h. After being cooled to room temperature, the reaction mixture was partitioned between DCM (500 mL) and brine (500 mL). The DCM phase was washed with brine (3.x.500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was treated with 20percent EtOAc/hexane (50 mL) and the mixture was filtered to give the desired product. The filtrate was concentrated and the resulting residue was purified by flash chromatography using 20percent EtOAc/hexane to give additional product as a white solid. A suspension of this ethyl ester intermediate (4.13 g, 11.9 mmol) and lithium borohydride (384 mg, 17.6 mmol) in THF (300 mL) was heated under reflux overnight before it was cooled to 0° C. and quenched by 1N HCl until pH=6. The resulting mixture was diluted in EtOAc (400 mL) and washed with saturated sodium bicarbonate (2.x.400 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product as a white solid. To a solution of this alcohol (3.7 g, 11.88 mmol) in DCM (200 mL) at 0° C. was added pyridine (1.13 g, 14.27 mmol), triphenylphosphine (8.73 g, 33.29 mmol) and NBS (6.34 g, 35.66 mmol). The resulting solution was stirred at 0° C. for 1.5 h. The DCM phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with DCM to give the product as a white solid. To a solution of dimethylmalonate (6.0 g, 45.6 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (2.0 g, 50.15 mmol, 60percent). The mixture was stirred at 0° C. for 40 min before addition of the bromide intermediate (3.41 g, 9.12 mmol) as one portion. The resulting mixture was stirred at room temperature for 40 min before it was partitioned between ethyl acetate (500 mL) and saturated ammonium chloride (300 mL). The EtOAc phase was washed with brine (3.x.500 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with 20percent EtOAc/hexane to give the product as a white solid. To a solution of this diester (3.8 g, 8.9 mmol) in a mixture solvents of THF/MeOH/H2O (3:1:1, 300 mL) was added lithium hydroxide (1N, 150 mL) dropwise at room temperature. The solution was stirred for 40 min before it was concentrated in vacuo to remove ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | The reported procedure from Oehlke, J.; Schroetter, E.; Dove, S.; Schick, H.; Niedrich, H. Phannazie 1983, 38, 591-596, was slightly modified. When N, [N-DIMETHYLFORMAMIDE] (DMF) was used as the solvent instead of dimethylsulfoxide (DMSO) in the substitution of 2-bromo- 5-nitropyridine by copper [(I)] cyanide, subsequent hydrolysis provided the described acid in an improved 70percent yield, typically used without any further purification. | |
With copper(l) cyanide; In N,N-dimethyl-formamide; for 0.25h;Reflux; Inert atmosphere; | A mixture of 2-bromo-5-nitro-pyridine (5.8 g, 28.6 mmol) and CuCN (3.3 g, 37.1 mmol, 1.3 equiv) in DMF (50 ml.) was stirred at reflux for 15 min, under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with Et2O and H2O. The aqueous layer was separated and extracted with Et2O. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was treated with 6N HCI (50 ml.) for 1.5 h at reflux. The mixture was poured onto H2O (200 ml_). The resulting white solid was collected by vacuum filtration and dried to provide 3.1 g of the title compound: ESI-MS: 167.0 [M-H]"; tR= 1.59 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate;tetra-(n-butyl)ammonium iodide; In dimethyl sulfoxide; at 50℃; for 3h; | 2-Bromo-5-nitro-pyridine (11.39 g, 56.1 mmol), tetrabutylammonium iodide (TBAI) (1.04 g, 0.05 mmol), potassium carbonate (8.53 g, 61.7 mmol) and piperazine-1-carboxylic acid tert-butyl ester (11.5 g, 61.7 mmol) were mixed together in DMSO (100 mL) and gently warmed to 50 C. for 3 hours and cooled to room temperature overnight. The reaction was diluted with EtOAc (200 mL), the salts were filtered and then the EtOAc was evaporated to leave the DMSO solution. This was diluted with water and a precipitate formed. This precipitate was filtered, washed with water, and then dried in an oven vacuum to give 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.1 g, 93%) as a light orange solid. 1H NMR (400 MHz, CDCl3) ppm 1.47 (s, 9H), 3.55 (m, 4H), 3.75 (m, 4H), 6.55 (d, J=9.3 Hz, 1H), 8.21 (dd, J=9.5, 2.7 Hz, 1H), 9.03 (d, J=2.7 Hz, 1H). 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (16.0 g, 51.9 mmol) was dissolved in THF (400 mL), RaNi (4 g) added and placed under a H2 atmosphere at 50 psi for 5 h. The catalyst was removed by filtration through celite and the solvent evaporated in vacuo to give 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (14.5 g, 100%). 1H NMR (400 MHz, CDCl3) ppm 1.46 (s, 9H), 3.31 (m, 6H), 3.53 (m, 4H), 6.56 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 2.9 Hz, 1H), 7.78 (dd, J=2.9, 0.7 Hz, 1H). m/z 279.1 (M+1). |
84.18% | With potassium carbonate; at 150℃; for 0.25h;Microwave irradiation; | To a stirred solution of 367 2-bromo-5-nitropyridine (1.0 g, 4.926 mmol, 1 eq) and 63 tert-butyl piperazine-1-carboxylate (0.917 g, 4.926 mmol, 1.0 eq) in 4 mL of 368 H2O was added 64 K2CO3 (1.02 g, 7.389 mmol, 1.5 eq). The reaction mixture was heated at 150 C. for 15 min in microwave. The progress of reaction was monitored by LCMS. Upon the consumption of starting material, the precipitated compound was filtered off and dried to obtain the desired product, 369 tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (1.283 g, 84.18%) as a yellow solid. (0461) LCMS: 309 [M+1]+ |
71% | With potassium carbonate; In water; at 150℃; for 0.25h;Microwave irradiation; | In a 5 mL glass microwave tube were placed 2-bromo-5-nitro pyridine 1 (1015 mg, 5 mmol), 1-Boc-piperazine 2a (930 mg, 5 mmol), K2CO3 (690 mg, 5 mmol), H2O (3 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 300 W initial was used, the temperature being ramped from rt to 150 C. Once 150 C was reached, the reaction mixture was held at this temperature for 15 min. Thereafter the mixture was allowed to cool to rt, extracted with ethyl acetate (15 mL) and washed with water (10 mL) then dried over MgSO4. After filtration, the solvent was evaporated to afford a yellow solid 1100 mg (71%) yield. 1H NMR CDCl3 delta = 9.03 (1H, s), 8.18 (1H, d, J = 9.1 Hz), 6.53 (1H, d, J = 9.5 Hz), 3.77-3.52 (8H, m), 1.44 (9H, s). 13C NMR CDCl3 delta = 164.2, 154.7, 145.3, 135.0, 133.2, 105.0, 79.8, 52.9 (2C), 46.0 (2C), 28.4 (3C). |
70% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; at 20 - 80℃; for 1.25 - 2.25h; | BINAP [[ (R)-2,] 2'-Bis [(DIPHENYLPHOSPHINO)-1,] [1'-BINAPHTHYL]] (2.5 g, 3.94088 mmoles) and tris (dibenzylidene acetone) dipalladium (o) (7.2 g, 7.88177 mmoles) were taken in dry toluene (400 ml) and stirred under argon atmosphere at room temperature for 15 minutes. 2-Bromo-5-nitro-pyridine (40 g, 197.044 mmoles) was dissolved in toluene (200 ml) and added to the reaction mixture followed by N-t-butoxycarbonyl piperazine (44 g, 236.45 mmoles). To this cesium carbonate (90 g, [275,] 862 mmoles) was added at room temperature under argon atmosphere. The reaction mixture was heated to [80 C] for 1-2 hours under argon atmosphere and was cooled to RT and filtered through celite. Washed the residue thoroughly with ethylacetate. The combined filtrates were washed with water and brine solution. Dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel column using dichloromethane and methanol as eluent to yield the title compound (42.4 g, yield 70%). |
60.3% | With potassium carbonate; In tetrahydrofuran; for 4h;Reflux; | 2-Bromo-5-nitropyridine (20.0 g, 98.0 mmol) was dissolved in 300 mL of tetrahydrofuran, and potassium carbonate (27.0 g, 197.0 mmol) and tert-butyl piperazine-1-carboxylate (27.5 g, 148.0 mmol) were added and heated. Reflux for 4 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE: EA=3:1, v/v) to give solid 29a, yield: 60.3%; |
54% | In acetonitrile; for 2.5h;Reflux; | Example 197a tert-Butyl 4-(5-Nitropyridin-2-yl)piperazine-1-carboxylate 197a A mixture of 2-bromo-5-nitropyridine (5.0 g, 24.6 mmol), tert-butyl piperazine-1-carboxylate (13.8 g, 74.2 mmol), acetonitrile (150 mL) was stirred at reflux for 2.5 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197a as a yellow solid (4.1 g, 54%). MS-ESI: [M+H]+ 309. |
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 1h; | To a stirred solution of 2-bromo-5-nitro-pyridine (2.9 g) and N-terbutyloxycarbonyl-piperazine (3.2 g) in DMF (100 mL) was added potassium carbonate (1.98 g). The mixture was heated at 80 C. during 1 hour and then concentrated. The residue was taken in CH2Cl2 and the organic phase was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The titled compound was obtained as a yellow solid (4.4 g). [0253] m.p.: 169 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; at 50℃; | A solution of 2-bromo-5-nitro-pyridine (4 g, 19.7 mmol) and methylamine (2 M in THF, 15 mL, 30 mmol) in methylene chloride (40 mL) was heated at 50 degrees overnight. After cooling to room temperature, the reaction mixture was concentrated to give methyl-(5-nitro-pyridin-2-yl)-amine that was used in the following step without purification. Acetic anhydride (9.3 mL, 98.5 mmol) was added to the solution of methyl-(5-nitro-pyridin-2-yl)-amine (3.01 g, 19.7 mmol), pyridine (24 mL, 197 mmol), and a catalytic amount of 4-dimethylamino-pyridine (DMAP) in methylene chloride (40 mL). The resulted mixture was heated at 90 degrees for overnight. After the reaction was complete, solvent was removed, and then ethyl acetate was added. The ethyl acetate solution was extracted three times with water. Organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 50% ethyl acetate in hexane for 20 min) gave N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide. |
Tags: 2-Bromo-5-nitropyridine | Pyridines | Bromides | Nitroes | Organic Building Blocks | Heterocyclic Building Blocks | 4487-59-6
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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 |
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