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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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CAS No. : | 6298-19-7 |
Formula : | C5H5ClN2 |
M.W : | 128.56 |
SMILES Code : | ClC1=NC=CC=C1N |
MDL No. : | MFCD00006238 |
InChI Key : | MEQBJJUWDCYIAB-UHFFFAOYSA-N |
Pubchem ID : | 80528 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501 |
* 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 |
---|---|---|
97% | With sodium carbonate; benzaldehyde; triphenylphosphine;palladium diacetate; In water; toluene; | A solution of palladium acetate (224.5 mg, 1.00 mmol) and triphenylphosphine (1.05 g, 4.00 mmol) in toluene (1000 mL) was stirred at room temperature for 15 minutes. Phenylboronic acid (114 g, 935 mmol), 2-chloro-3-aminopyridine (100 g, 778 mmol), benzaldehyde (83.4 g, 786 mmol), and toluene (500 mL) were then added followed by a solution of sodium carbonate (200 g, 1.89 mol) in water (1500 mL). The mixture was heated to reflux for 18 hours, cooled to room temperature, and the layers were separated. The organic layer was washed with water (500 mL) and 2.5M aqueous hydrochloric acid was added (630 mL). The aqueous layer was separated and washed with toluene (300 mL). The pH was adjusted to 12-13 using 50% aqueous sodium hydroxide and the mixture was extracted with methyl-tert-butyl ether (500 mL). The organic layer was concentrated and the product was crystallized from diisopropyl ether to afford 2-phenyl-3-aminopyridine (128 g, 97% yield). M. p.=67-68 C. 1H NMR (300 MHz, CDCl3) δ3.88 (bs, 2), 7.02-7.11 (m, 2). 7.28-7.53 (m, 3), 7.67-7.71 (m, 2), 8.,13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ122.57, 122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93, 144.93. |
88% | With potassium phosphate; tetrabutylammomium bromide; In water; at 90℃; for 6h;Green chemistry; | General procedure: To a 10-mL reaction vial, heteroaryl halide (1.0 mmol), boronic acid (1.2 mmol), K3PO4 (2.0 mmol), tetra-butylammonium bromide (TBAB) (0.5 mmol), and 4 (0.1 mol %) in water (3.5 mL) were added. The reaction mixture was stirred at 85 C and the reaction progress was monitored by GC-MS analysis. After completion of the reaction, it was diluted with H2O and CH2Cl2. The organic layer was separated from mixture, the dried organic layer over MgSO4, and evaporated under reduced pressure. The crude reaction product was purified using column chromatography on silica-gel to afford the corresponding product with isolated yield up to 98%. |
71% | General procedure: 3-Amino-2-chloropyridine (0.5g, 3.9mmol), phenylboronic acid (0.47 g, 3.9 mmol), and bis(triphenylphosphine)palladium dichloride (0.137 g, 0.195 mmol) were added to 1,4-dioxane (20ml). Under nitrogen atmosphere the mixture was stirred at room temperature for 30 minutes. 1M aqueous sodium carbonate (8 ml) was poured in, and the temperature was raised to 80C. After the reaction at 80C for 8 hours, the mixture was distilled off under reduced pressure. The residue was extracted with addition of ethyl acetate and water. The impurities were filtered off from the organic layer, and the solvent was distilled off under reduced pressure. The purification by column chromatography gave the title compound (0.47 g, 71.0% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;palladium diacetate; triphenylphosphine; In water; toluene; for 4h;Heating / reflux; | 1.05 g (4 mmols) of triphenyl phosphine, 0.224 g (1 mmol) of palladium acetate and 750 ml of toluene were fed into a 3000-ml reactor equipped with a thermometer, a condenser and a stirrer, and stirred at 20 C. for 15 minutes. Next, 96.8 g (0.933 mols) of triphenylboroxine, 100.0 g (0.778 mols) of 3-amino-2-chloropyridine, and 950.0g (1.9 mols) of aqueous 21% sodium carbonate solution were fed into the reactor. The mixed slurry was heated and stirred at its boiling point for 4 hours. The reaction liquid was cooled to room temperature, and subjected to liquid-liquid separation to remove the aqueous layer. The toluene layer was washed with 200 g of water and then concentrated under reduced pressure to obtain 3-amino-2-phenylpyridine (purity 97.0%). [0036] 20 g of the thus-obtained 3-amino-2-phenylpyridine, 100 ml of 35% hydrochloric acid, 300 ml of water, and 20 g of 5% Pt/C (50% hydrate) were put into a 1000-ml glass autoclave, and stirred in a hydrogen atmosphere at about 30 C. under a pressure of 0.3 to 0.4 MPa for 13 hours. After the reaction, this was filtered to remove the catalyst. The filtrate was adjusted to have a pH of 12 with aqueous 48% sodium hydroxide solution added thereto, and then extracted with 300 ml of chloroform. The aqueous layer was removed through liquid-liquid separation, and the chloroform layer was concentrated to obtain 19.4 g of oily, racemic cis-3-amino-2-phenylpiperidine. Its chemical purity was 82.4%. [0037] 5.71 g (26.7 mmols) of the thus-obtained racemic cis-3-amino-2-phenylpiperidine, 8.16 g (26.7 mmols) of N-benzenesulfonyl-L-phenylalanine, and 22.6 g of methanol were fed into a 100-ml flask equipped with a stirrer, a thermometer and a condenser. This was heated at 50 to 55 C., and stirred for 1 hour at the temperature, and then cooled to 20 C. over a period of about 2 hours. The precipitated crystal was taken out through filtration, and dried to obtain 5.36 g of a salt. In the salt, the content of 3-amino-2-phenylpiperidine was 33.9%, and the optical purity of the (2R,3R) isomer was 93% d.e. Next, 0.5 g of aqueous 48% sodium hydroxide solution, 1 ml of water and 5 ml of chloroform were added to 0.3 g of the salt, and stirred at room temperature to extract out 3-amino-2-phenylpiperidine. After liquid-liquid separation, the chloroform layer was analyzed through gas chromatography, which confirmed that the purity of 3-amino-2-phenylpiperidine was 99.4% except the solvent peak. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydroxide; sodium carbonate; benzaldehyde;tetrakis(triphenylphosphine)palladium (0); In water; toluene; | To 2-chloro-3-aminopyridine (1.06 g, 8.24 mmol) in toluene (25 mL) was added benzaldehyde (0.878 g, 8.27 mmol). The reaction mixture was stirred at reflux in a Dean-Stark apparatus until GC/MS analysis of the reaction mixture no longer showed starting material. The reaction mixture was cooled to room temperature and the toluene solution containing benzylidene-(2-chloro-pyridin-3-yl)-amine was added to a mixture of phenylboronic acid (1.30 g, 10.7 mmol), sodium carbonate (2.66 g, 25.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.38mol %) in water (10 mL). The reaction mixture was heated to 100 C. for 30 minutes, cooled to room temperature and poured into 1N aqueous sodium hydroxide (10 mL). The aqueous layer was removed and the toluene layer was extracted with 1N aqueous hydrochloric acid (twice with 15 mL). The aqueous layer was neutralized to pH 12 with 6N aqueous sodium hydroxide and extracted with MTBE (twice with 20 mL). The MTBE extracts were dried over magnesium sulfate, filtered and concentrated to afford 2-phenyl-3-aminopyridine as a solid which crystallized from diisopropyl ether (1.26 g, 90% yield). M. p.=87-68 C. 1H NMR (300 MHz, CDCl3) δ3.88 (bs, 2), 7.02-7.11 (m, 2), 7.28-7.53 (m, 3), 7.6714 7.71 (m, 2), 8.13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ122.57, 122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93, 144.93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | Example 186 N-(2-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide 3-Amino-2-chloropyridine (0.206 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate: hexane = 1:1) to obtain the titled compound (0.140 g, 0.289 mmol, 54percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In hexane; dichloromethane; ethyl acetate; | Example 236 N-(2-Chloropyridin-3-yl)-5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide 3-Amino-2-chloropyridine (0.141 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (2:1) to obtain the titled compound (0.149 g, 0.329 mmol, 45percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a mixture of 3-methyl-2-oxobutanoic acid sodium salt (0.84 g, 6.0 mmol) in CHCl3 (5 mL) at rt was added 4 M HCl in dioxane (1.5 mL, 6.0 mmol). The mixture was stirred for 0.5 h at rt then cooled to -5 C and was added 3-amino-2-chloropyridine (0.77 g, 6.0 mmol), followed by DCC (1.24 g, 6.0 mmol) under N2 protection. The mixture was stirred at -5 C for 2 h, then concentrated. To the residue was added AcOEt (20 mL) and the white precipitate was removed by filtration. The filtrate was concentrated. The crude material was loaded on a 40 g silica gel column and purified on a Teledyne Isco instrument, eluting with 0-30% ethyl acetate in heptane to provide 4g (0.93 g, 68%) as an oil. 1H NMR (400 MHz, CDCl3) delta 1.17 (dt, J = 7.0, 1.4 Hz, 6H), 3.53-3.71 (m, 1H), 7.24-7.29 (m, 1H), 8.13 (dq, J = 4.7, 1.6 Hz, 1H), 8.67-8.80 (m, 1H), 9.34 (br s, 1H); 13C NMR (100 MHz, CDCl3) delta 18.0, 34.1, 123.4, 128.5, 130.9, 141.0, 144.9, 157.8, 201.2. MS (ESI) m/z 227.1 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
190 mg | 3-Amino-2-chloro-pyridine 4f (150 mg, 1.17 mmol), ethyl pyruvate 8 (0.25 ml, 2.00 mmol), pyridinium p-toluenesulfonate, (73 mg, 0.29 mmol) and tetraethoxy-silane (0.26 ml, 1.18 mmol) were suspended in 0.4 ml pyridine and stirred for 24 h at 20 °C. Afterwards Pd[P(C6H6)3]4 (70 mg, 0.06 mmol) and N,N-dicyclohexylmethylamine (0.35 ml, 2.06 mmol) were added and the reaction mixture was heated in a microwave oven to 160 °C for 20 min. The reaction mixture is diluted with 100 ml dichloromethan and extracted two times with 50 ml of a half saturated aqueous sodium hydrogencarbonat solution. The organic layer was dried with sodium sulfate, the solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P3, yielding 190 mg (1.00 mmol) of 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester. The ester was dissolved in 17 ml ethanol and 5 ml water. To this solution lithium hydroxide (120 mg, 5.00 mmol) was added. After 16 h the pH value of the reaction mixture was adjusted to pH 4 and the solvent is evaporated in vacuum. The crude product was purified using an acid ion exchanger (Strata-X-C, Phenomenex), yielding of 155 mg (82percent) of the title compound. Purity by method A1: >95percent; MS (ESI) m/z 163 (M + H)+; 1H NMR (DMSO) delta (ppm) 13.34 (br, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 5.4 Hz, J = 8.3 Hz, 1H), 7.33 (br, 1H); 13C NMR (500 MHz, DMSO) delta (ppm) 161.4 (s), 138.0 (s), 136.1 (s), 135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s). |
Tags: 2-Chloropyridin-3-amine | Pyridines | Chlorides | Amines | Organic Building Blocks | Heterocyclic Building Blocks | 6298-19-7
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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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