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CAS No. : | 3510-66-5 |
Formula : | C6H6BrN |
M.W : | 172.02 |
SMILES Code : | C1=C(Br)N=CC(=C1)C |
MDL No. : | MFCD00209553 |
InChI Key : | YWNJQQNBJQUKME-UHFFFAOYSA-N |
Pubchem ID : | 564216 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
80% | With n-butyllithium In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; acetonitrile | Step 3-Preparation of 2-(5-methylpyridin-2-yl)acetonitrile To a solution of anhydrous acetonitrile (10.1 mL, 191.83 mmol, 3.3 equiv.) in dry THF (500 mL) was added dropwise n-butyl lithium (2.5 M in hexane, 69.8 mL, 174.39 mmol, 3 equiv.) at minus 78° C. under nitrogen atmosphere. The resulting white suspension was stirred at minus 78° C. for 1 hour, and then a solution of 2-bromo-5-methylpyridine (10.0 g, 58.13 mmol, 1 equiv.) in dry THF (30 mL) was added. The reaction mixture was kept at minus 78° C. for 1 hour and then warmed up slowly to room temperature and stirred for another hour. Ice water was added and the layer was separated. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated to give 18 g of crude product. The crude product was purified by silica-gel column chromatography (eluent, PE/EtOAc=15:1) to give 2-(5-methylpyridin-2-yl)acetonitrile (6.2 g, yield 80percent). 1H NMR (300 MHz, CDCl3): δ 8.40 (d, J=3.0 Hz, 1H), 7.54 (dd, J1=3.0 Hz, J2=6.0 Hz, 1H), 7.32 (d, J=6.0 Hz, 1H), 3.90 (s, 2H), 2.40 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 20℃; for 2 h; |
To a solution of anhydrous acetonitrile (10.1 mL, 191.83 mmol, 3.3 equiv.) in dry THF (500 mL) was added dropwise n-butyl lithium (2.5 M in hexane, 69.8 mL, 174.39 mmol, 3 equiv.) at minus 78° C. under nitrogen atmosphere. The resulting white suspension was stirred at minus 78° C. for 1 hour, and then a solution of 2-bromo-5-methylpyridine (10.0 g, 58.13 mmol, 1 equiv.) in dry THF (30 mL) was added. The reaction mixture was kept at minus 78° C. for 1 hour and then warmed up slowly to room temperature and stirred for another hour. Ice water was added and the layer was separated. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated to give 18 g of crude product. The crude product was purified by silica-gel column chromatography (eluent, PE/EtOAc=15:1) to give 2-(5-methylpyridin-2-yl)acetonitrile (6.2 g, yield 80percent). 1H NMR (300 MHz, CDCl3): δ 8.40 (d, J=3.0 Hz, 1H), 7.54 (dd, J1=3.0 Hz, J2=6.0 Hz, 1H), 7.32 (d, J=6.0 Hz, 1H), 3.90 (s, 2H), 2.40 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; In dichloromethane; water; for 0.5h;Heating / reflux; | Generally, to a refluxing mixture of 2-bromo-methyl-pyridine (5 g, 29 mmol) in a biphasic medium of DCM (500 ml) and water (500 ml) was added Br2 (1.65 ml, 31.9 mmol). The mixture was illuminated using a halogen lamp (500 W, distance: 5-10 cm) under reflux for 30 min. The solution was cooled to room temperature and neutralized with a 10% Na2CO3 aqueous solution and solid NaCl was added. The aqueous layer was extracted three times with DCM, the combined organic extracts were dried over MgSO4 and evaporated in vacuo. HPLC analysis of the crude product showed the relative ratio of 13.6:76.5:9.9 (Retention time: 8.1, 10.6 and 13.4 min, respectively) for starting material 2-bromo-methyl-pyridine:2-bromo-5-(bromomethyl)pyridine: 2-bromo-5-(dibromomethyl)pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 85℃; for 0.5h; | (Referential Example 8) Synthesis of 2-bromo-5-(bromomethyl)pyridine (referential compound 8) N-Bromosuccinimide (16 g, 91 mmol) and 0.40 g (2.4 mmol) of 2,2'-azobis(isobutyronitrile) were added to a solution of 12 g (70 mmol) of 2-bromo-5-methylpyridine in 100 ml of 1,2-dichloroethane and the mixture was stirred at 85C. After 15 minutes, 0.40 g (2.4 mmol) of 2,2'-azobis(isobutyronitrile) was added thereto and the mixture was stirred for 15 minutes. After the reaction was finished, water was added to the reaction solution and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 10:1 to 9:1 (v/v)) and the fraction containing the aimed substance was concentrated in vacuo to give 15 g of the title compound as white powder (yield: 89%). Rf value: 0.63 (n-hexane: ethyl acetate = 9:1 (v/v)) Mass spectrum (CI, m/z): 250, 252, 254 (M+ + 1) 1H-NMR spectrum (CDCl3, δ ppm): 4.42 (s, 2H), 7.49 (d, J = 8.3Hz, 1H), 7.61 (dd, J1 = 8.3Hz, J2 = 2.7Hz, 1H), 8.39 (d, J = 2.7Hz, 1H) |
82.2% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; at 80℃; | 2-Bromo-5-methylpyridine 19a (10.0g, 58.13mmol) was dissolved in carbon tetrachloride (100mL),Add N-bromosuccinimide (10.9g, 61.24mmol) at room temperatureAnd dibenzoyl peroxide (200mg, 0.83mmol),The temperature was raised to 80C and reacted overnight.The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated.The crude product was purified by silica gel column chromatography to obtain the title compound 19b (12 g, yield 82.2%). |
61% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; at 90℃; for 2.5h; | 37A (5g, 29.07 mmol) was dissolved in carbon tetrachloride (50 mL) and N-bromosuccinimide (5.43 g, 30.52 mmol) and azodiisobutyronitrile (1.19 g, 7.27 mmol) were added to the reaction at 90 C for 2.5 h. Cooled to room temperature, concentrated reaction solution, residue separated and purified with silica gel column chromatography (PE: EA (v/v) = 10:1) to give title compound 37B (4.42g, 61%). |
59% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride;Reflux; | Synthesized from 2-bromo-5-methylpyridine (3.00 g, 17.40 mmol), NBS (3.41 g, 19.20 mmol) and DBPO (230 mg, 0.80 mmol) in carbon tetrachloride according to Method A. Yield: 2.56 g (59 %); lachrymatory yellow needles; 1 H NMR (CDCIs, 500 MHz): δΗ (ppm) = 4.14 (s, 2H), 7.47 (d, J = 8.2 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 8.38 (s, 1 H); MS (ESI): m/z = 252.37 [M+H]+.Methylpyridine was dissolved in 40 ml_ of dry carbon tetrachloride. To this solution was added /V-bromsuccinimide (NBS) (1.1 eq) and benzoyl peroxide (5 mol%) and the mixture was refluxed over night. After cooling, the succinimide was removed by filtration and the filtrate was concentrated under vacuum. The crude product was further purified by flash column chromatography on silica gel using a mixture of petroleum ether / ethyl acetate (95:5) as eluent. |
52.6% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; at 80℃; for 2h;Inert atmosphere; | To a solution of 169-51 (5.0 g, 29.1 mmol) in Cd4 (40 mL) was added NBS (5.22 g, 29.1 mmol) and BPO (350 mg, 1.4 mmol). The reaction mixture was stirred at 80 C under an atmosphere of nitrogen for 2 hours. The mixturewas diluted with DCM, washed with water and brine, dried, and concentrated to dryness. The remaining residue was purified by column chromatography on silica gel (eluted with PE/EtOAc = 120:1) to afford 169-S2 (3.81g, 52.6% yield) as a yellow oil. LC/MS (ESI) m/z: 250 (M+H)t |
50% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; at 75℃; for 2h;Inert atmosphere; | Step 1) 2-bromo-5-(bromomethyl) pyridine To a solution of 2-bromo-5-methylpyridine (17 g, 100 mmol) in carbon tetrabromide (250 mL) was added AIBN (164 mg, 1mmol) and the mixture was heated to 75 C, and then NBS (26.7 g, 150 mmol) was added, and the mixture was stirred for 2 h. TLC showed that the reaction was complete, water (150 mL) was added and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3.0g of the residue, which was purified by column chromatography (silica gel 200-300 mesh, PE/EA= 1000:1 to 10:1) to give intermediate 2-bromo -5-(bromomethyl) pyridine (13 g, 50% yield). MS (ESI), m/z, 250.9 [M+1]+. |
49% | With N-Bromosuccinimide;dibenzoyl peroxide; In Carbon tetrachloride; for 4h;Heating / reflux; | 2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1.4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHCO3/H2O. The mixture was adsorbed onto silica gel and then chromatographed. eluting with a gradient of hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49%). LC/MS (M+H)+ m/z=249.8, 251.8, 253.8. |
49% | Step A2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1 .4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHC03/H2O.The mixture was adsorbed onto silica gel and thenchromatographed. eluting with a gradient of hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49%). LC/MS (M+H)+ m/z = 249.8, 251.8, 253.8. | |
46% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane; at 55℃; for 6h;Heating; Irradiation; | Example 16 Step 1: A mixture of 2-bromo-5-methylpyridine (10 g, 58 MMOL), N-bromosuccinimide (15.5 g, 87.2 MMOL), and AZOBISISOBUTYRONITRILE (0.25 g) in anhydrous CH2CI2 (100 ml) was heated at 55 C under irradiation (200W lamp) for 6 h. The mixture was cooled down to RT, diluted with CH2CI2 (200 ML), washed with saturated NaHCO3 solution, dried (MGS04), filtered and concentrated. The residue was subjected to silica gel flash chromatography (5<7% EtOAc/hexanes) to afford the product (6.75 g, 46%). |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | Synthesis Example 18 N-[1-((6-bromopyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound 231) An amount of 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 mL of carbon tetrachloride, following which 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added and the mixture was refluxed under heating for 19 hours. Following reaction completion, the reaction mixture was returned to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 143 mg of 2-bromo-5-bromomethylpyridine (yield, 20%). 1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 ml of carbon tetrachloride, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 19 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 143 mg (yield 20%) of 2-bromo-5-bromomethylpyridine. [0250] 1H-NMR (CDCl3, δ, ppm): 4.42(2H, s), 7.47(1H, d), 7.59(1H, dd), 8.38(1H, d) |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 ml of carbon tetrachloride, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 19 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 143 mg (yield 20%) of 2-bromo-5-bromomethylpyridine. [0240] 1H-NMR (CDCl3, δ, ppm) : 4.42(2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) |
20% | With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; for 19h;Reflux; | In 15 ml of carbon tetrachloride, 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved. To this solution, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added, followed by heating under reflux for 19 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1). Thus, 143 mg of 2-bromo-5-bromomethylpyridine was obtained (Percentage Yield: 20%). 1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) |
With N-Bromosuccinimide; azobisisobutyronitrile; In Carbon tetrachloride; ethyl acetate; | Step A 2-Bromo-5-bromomethyl-pyridine 2-Bromo-5-methylpyridine (4.01 g, 23.31 mmol), NBS (5.19 g, 29.14 mmol), and AIBN (0.19 g, 1.17 mmol) were dissolved in CCl4 (46.6 mL, 23.31 mmol). The reaction mixture was heated to 75 C. for 4 h. The residue was quenched with water and extracted from EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo in vacuo. The crude mixture was purified by flash column chromatography on silica gel eluted with 7% EtOAc/hexane to give 2.65 g of the title compound. MS m/e 251.9 (M+). | |
With N-Bromosuccinimide; In Carbon tetrachloride; hexane; ethyl acetate; | Step D Preparation of 2-bromo-5-(bromomethyl)pyridine In a three neck flask equipped with a stir bar and a reflux condenser, a solution of 2-bromo-5-methylpyridine (40.0 g, 0.225 mol) and N-bromosuccinimide (45.0 g, 0.252 mol) in carbon tetrachloride (800 mL) was irradiated with a 300 watt lamp. After 3 h, the solution was cooled, and the solvent removed in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by flash chromatography on silica gel using 7% ethyl acetate in hexane. The title product was obtained as a white solid. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; | Step 4: Preparation of 2-bromo-5-bromomethylpyridine. A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g (173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 69% monobromomethyl product): NMR (CDCl3) δ 4.42 (s, 2H), 7.48 (d, J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride; | Step 2 2-bromo-5-bromomethyl pyridine To a flask was charged 2-bromo-5-methylpyridine (34.9 mmol, 6.0 g), N-bromosuccinimide (38.4 mmol, 6.83 g), benzoyl peroxide (3.49 mmol, 0.85 g) and carbon tetrachloride (60 mL). This solution was refluxed for 6 hr, cooled to ambient temperature and purified on a silica gel column. Eluted with ethyl acetate: hexane (1:9) to provide the title compound. FAB MS: calc: 250.9 found: 251.9. 1 H-NMR (CDCl3): 4.4 ppm (s, 2H); 7.5 ppm (d, 1H); 7.6 ppm (d, 1H); 8.4 ppm (s, 1H). | |
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; at 75℃; for 5h; | To a suspension of 2-bromo-5-methyl-pyridine 11 (5.0Og, 29 mmol) and NBS (5.162g, 29 mmol) in CCl4 (40 mL) is added AIBN (0.477g, 2.9 mmol). The reaction is stirred at 75 0C for 5 hours and filtered. The filter cake is washed with CCl4, and the filtrate is evaporated to give a light yellow residue. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In Carbon tetrachloride; for 1.5h;Heating / reflux; | a) (S)-tert-Buty{ 2-amino-3-(6-bromopyridin-3-yl)propanoatePrepared according to the procedures detailed in Patent WO2006/127948.To a slurry of 2-bromo-5-methylpyridine (10.29 g) and N-bromosuccinimide (5.32 g) in carbon tetrachloride (150 mL) was added AIBN (200 mg) and the reaction vessel was purged with nitrogen. The reaction mixture was heated, under reflux, for 1.5 h then allowed to cool <n="54"/>to room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-bromo-5-(bromomethyl)pyridine (4 g). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In Carbon tetrachloride;Reflux; | To a solution of 2-Bromo-5-methylpyridine (3.1 g, 17.4 mmol) in carbon tetrachloride (40 mL, 400 mmol) was added benzoyl peroxide (230 mg, 950 μmol) and NBS (3.4 g, 19.2 mmol). The resulting mixture was heated at reflux overnight. The mixture was cooled at 0 C. and the NBS was removed by filtration. The filtrate was concentrated to yield 2-bromo-5-bromomethylpyridine (4.6 g), which was used directly in the next step. | |
With N-Bromosuccinimide;dibenzoyl peroxide; In Carbon tetrachloride;Inert atmosphere; Reflux; | To a solution of 2-bromo-5-methylpyridine ((3.1 g, 17.4 mmol, 1 eq.) in carbon tetrachloride (40 mL, 400 mmol) was added benzoyl peroxide (230 mg, 950 μmol) and NBS (3.4 g, 19.2 mmol, 1.1 eq.). The resulting mixture was heated at reflux overnight. The mixture was cooled at 0 C. and filtered. The filtrate was concentrated to yield 2-bromo-5-bromomethylpyridine (4.6 g), which was used without further purification. | |
With N-Bromosuccinimide; [2-(1,1'-biphenyl)-4-yl]-5-phenyloxazole; In Carbon tetrachloride; at 80℃; for 16h;Inert atmosphere; | To a solution of 2-bromo-5-methyl-pyridine (20 g, 1 16.96 mmol) in CCL, (200 mL) was added NBS (21 .56 g, 122.80 mmol) and BPO (0.4 g, 1 %) under N2. The mixture was stirred at 80 C for 16 hr, then cooled to r.t., filtered and concentrated to afford the desired crude compound which was used directly in the next step. LCMS: m/z 252 (M+l )+. | |
With N-Bromosuccinimide; In 1,2-dichloro-ethane; at 85℃; for 0.5h; | 2-bromo-5-methyl-pyridine (70.0 mmol) and N-bromosuccinimide (80.0 mmol) were dissolved in 1,2- dichioroethane (150 ml) and to this mixture 2,2’-azobis(2- ethylpropionitrile) (1.50 mmol) was added. The reaction mixture was heated under reflux at 85 C. for 15 minutes and next portion of 2,2’-azobis(2-methylpropionitrile) (1.50 mmol) was added and reaction mixture was heated at 85 C. for further 15 minutes. After cooling to room temperature was the reaction mixture kept at 5 C. for 2 hours and the precipitate was filtered off and washed with small amount of 1 ,2-dichlo- roethane. The filtrate was evaporated under reduced pressure and the crude product was used for further reaction step without purification. The crude 2-bromo-5-bromomethyl-py- ridine was dissolved in chloroform (100 ml) and urotropine (70.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off, washed with small amount of chloroform and dried on air. The crude urotropine salt was refluxed in a mixture of conc. ammonium hydroxide (12 ml) and water (80 ml) for 90 minutes and afier cooling to room temperature, 40% formaldehyde (5.0 ml) was added with stirring. The precipitate was filtered off, washed with ice-cold water and dried in vacuum dessicator. The crude product was crystallized from ethanol. Yield: 40% m.p. 105-106 C. Elemental analysis: Calcd. for C5H7HrN2 (187.04): C, 38.53; H, 3.77; N, 14.98. Found: C, 38.22; H, 3.72; N, 14.71. HPLC-MS (ESI+): 188.02(97.2%). ‘H NMR (DMSO, d5): 4.04 (t, J=5.67, 2H, CH2), 7.71 (d, J=8.19, 1H,ArH), 7.95 (dd, J=8.19, J’=i.95, 1H,ArH), 8.51 (d, J=i .95, 1H, ArH), 8.74 (s(br), 2H, NH2). | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 90℃; for 12h;Inert atmosphere; | To a solution of 2-bromo-5-methyl-pyridine (20.0 g, 116 mmol) in acetonitrile (300 mL) was added 2,2-azobisisobutyronitrile (1.91 g, 11.63 mmol) and N-bromosuccinimide (24.8 g, 139 mmol), and the mixture was stirred at 90 C for 12 hrs under nitrogen atmosphere. On completion, the reaction was concentrated to give a residue. The residue was purified by chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give the title compound. MR (400MHz, CDC13) δ = 8.40 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 2.6, 8.2 Hz, 1H), 7.51 (d, J= 8.3 Hz, 1H), 4.42 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,1-dimethoxyethylene; water; at 130.0℃; for 0.5h;Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester To a solution of 3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (100 mg, 0.326 mmol), 2-bromo-5 methyl-pyridine (56 mg, 0.326 mmol), K3PO4 (138 mg, 0.652 mmol) in dimethoxy ethylene (3 mL) and water (1 mL) was added Pd(Pph3)4 (11.3 mg, 0.001 mmol). The mixture was flushed with N2 and heated under microwave at 130 C. for 30 minutes. The reaction mixture was cooled, solvent was removed under reduced pressure, and the residue was purified by column chromatography (EtOAc/hexane=1:3) to afford 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (50 mg, 56%). MS (M+H)=273. |
56% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic Acid Methyl Ester; To a solution of 3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (100 mg, 0.326 mmol), 2-bromo-5 methyl-pyridine (56 mg, 0.326 mmol), K3PO4 (138 mg, 0.652 mmol) in dimethoxy ethylene (3 mL) and water (1 mL) was added Pd(Pph3)4 (11.3 mg, 0.001 mmol). The mixture was flushed with N2 and heated under microwave at 130 C. for 30 minutes. The reaction mixture was cooled, solvent was removed under reduced pressure, and the residue was purified by column chromatography (EtOAc/hexane=1:3) to afford 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (50 mg, 56%). MS (M+H)=273. |
56% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester To a solution of 3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (100 mg, 0.326 mmol), 2-bromo-5 methyl-pyridine (56 mg, 0.326 mmol), K3PO4 (138 mg, 0.652 mmol) in dimethoxy ethylene (3 mL) and water (1 mL) was added Pd(Pph3)4 (11.3 mg, 0.001 mmol). The mixture was flushed with N2 and heated under microwave at 130 C. for 30 minutes. The reaction mixture was cooled, solvent was removed under reduced pressure, and the residue was purified by column chromatography (EtOAc/hexane=1:3) to afford 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (50 mg, 56%). MS (M+H)=273. |
40% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester; EPO <DP n="58"/>To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4(226 mg, 0.2 mmol) and K3PO4(2.76 g, 13 mmol) in DME/H2O (5ml/ ImI) was added 3-nitro-5- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 1300C for 0.5 h. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2ZMeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
40% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic Acid Methyl Ester; To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
40% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Microwave heating; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
40% | With potassium phosphate; In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4(226 mg, 0.2 mmol) and K3PO4(2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
40% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
40% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Inert atmosphere; Microwave radiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Step 3 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl esterTo a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4(226 mg, 0.2 mmol) and K3PO4(2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). | |
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130.0℃; for 0.5h;Inert atmosphere; Microwave irradiation; | To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130 C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dibenzoyl peroxide; In chloroform; for 6h;Heating / reflux; | Step 2: 2-Bromo-5-bromomethylpyridine To a suspension of 2-bromo-5-methylpyridine (170g, 0. [95MO1)] in [CC14] (2L) was added NBS (193g, [1.] [08MOL)] and benzoylperoxide (15g) and the mixture was refluxed for 6h. The reaction mixture was cooled down to rt and the solid formed was filtered off. The filtrate was concentrated affording 275g of crude 2-bromo-5-bromomethylpyridine which was used without further purification in the next step (mixture of mono-bromo and di-bromo). [TLC, [RF=] 0.7, pet. ether/ethylacetate 9: 1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 120℃; for 18.0h; | Step 1: Preparation of 5-methyl-2-vinylpyridine To a solution of 3 g (17.4 mmol) of 2-bromo-5-methylpyridine in 30 ml of dimethylformamide was successively added 2 g (1.7 mmol) of tetrakis (triphenylphosphine)palladium and 5.52 g (17.4 mmol) of tributyl(vinyl)tin. The reaction mixture was stirred at 120C for 18 hours. After cooling, the reaction mixture was poured into 50 ml of water saturated with potassium fluoride and stirred for 1 hour. The mixture was filtered on supersel and the aqueous phase was extracted with ethyl ether. The organic phase was washed twice with water saturated with potassium fluoride, once with water and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 3.5 g of a crude mixture as a yellow oil. The mixture was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 4/1) to give 5-methyl-2-vinylpyridine as a yellow oil: 0.9 g (43%); mass spectrum: 120 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 90℃; for 48h; | To a stirred solution of 2-bromo-5-methyl- pyridine (1.00 g, 5.81 mmol) and 2,3-dichloro phen- ylboronic acid (1.33 g, 6. 98 mmol) in DME (5.8 ML) was added potassium carbonate (1.21 g, 8.7 mmol). The mixture was degassed by bubbling nitrogen with a syringe for 5 min through the mixture, followed by addition of Pd (PPH3) 4 (0.672 g, 0.58 MMOL). A reflux condenser was attached to the flask and the mixture heated to 90C FOR 48 h. The mixture was cooled to ambient temperature and partitioned between. ethyl acetate and brine. The organic phase was washed with brine (3X20 mL) and dried over sodium sulfate, filtered, and concentrated IN VACUO. The resulting oil was purified by flash chromatography on silica gel ELUTING WITH 1 : 1 ethyl acetate: hexane to provide the title compound' (0. 380 g, 5. 81. MMOL, 27% yield) as A light yellow oil which ch solidified upon standing to an off with solid. 1H NMR (CDCl3, 400 MHz) 5 8. 54 (M, 1H), 7. 58 (m, 1H), 7.5 (s, 2H), 7.44 (DD, J=1.56, 7.42 Hz, 1H), 7.43 (m, 1H), 7. 27 (t, J=7.81 Hz, 1H), 2. 40 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With K2CO3; copper; In dichloromethane; | Step 1 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.37 (s, 1H), 7.96(d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.65(dd, J=2.4 and 8.2 Hz, 1H), 7.32(dd, J=2.9 and 9.7 Hz, 1H), 6.61(d, J=9.7 Hz, 1H) and 2.39(s,3H)ppm. | |
With copper; potassium carbonate; In dichloromethane; | Step A Preparation of 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.37 (s, 1H), 7.96(d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.65 (dd, J=2.4 and 8.2 Hz, 1H), 7.32 (dd, J=2.9 and 9.7 Hz, 1H), 6.61 (d, J=9.7 Hz, 1H) and 2.39 (s, 3H)ppm. | |
With copper; potassium carbonate; at 180℃; for 16h; | Step 1: 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.37 (s, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.65 (dd, J=2.4 and 8.2 Hz, 1H), 7.32 (dd, J=2.9 and 9.7 Hz, 1H), 6.61 (d, J=9.7 Hz, 1H) and 2.39 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper; | Step 1 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one <strong>[4214-79-3]5-Chloro-2-pyridinol</strong> (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2 CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2*) and the combined organic extracts were washed with brine, dried (Na2 SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2 Cl2 20:80 to 50:50 gradient elution) to afford the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) delta 8.37 (s, 1H), 7.96(d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.65(dd, J=2.4 and 8.2 Hz, 1H), 7.32(dd, J=2.9 and 9.7 Hz, 1H), 6.61(d, J=9.7 Hz, 1H) and 2.39(s,3H)ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In tetrachloromethane; | Step 4: Preparation of 2-bromo-S-bromomethylpyridine A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) δ 4.42 (s, 2H), 7.48 (d, J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In tetrachloromethane; | Step 4: Preparation of 2-bromo-5-romomethylpyridine. A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3)δ4.42 (s, 2 H), 7.48 (d, J=9 Hz, 1 H), 7.60 (dd, J=9 and 3 Hz, 1 H), 8.37 (d, J=3 Hz, 1 H). | |
With N-Bromosuccinimide; In tetrachloromethane; | Step 4: Preparation of 2-bromo-5-romomethylpyridine A solution of 296.3 g (1.72 mol) of 2-bromo-5picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) δ4.42 (s, 2H), 7.48 (d, J=9Hz, 1H), 7.60 (dd, J=9 and 3Hz, 1H), 8.37 (d, J=3Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sec.-butyllithium; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; cyclohexane; water; | PREPARATION 4 5-Methyl-2-pyridinesulfonamide STR142 Sec-butyllithium (9.8 ml of 1.3 M in cyclohexane) and N,N,N'N'-tetramethylethylenediamine (1.8 ml, 12.2 mmol) were added to a stirred solution of 2-bromo-5-methylpyridine (2 g, 11.6 mmol) at -78 C. under a nitrogen atmosphere. After 90 min sulphur dioxide (approximately 30 ml) was condensed into the reaction mixture using a cold finger and the reaction mixture was slowly warmed to room temperature over 12 h. The reaction mixture was concentrated to dryness and the residue dissolved in ice-water. To this was added a mixture of sodium hydroxide (1.39 g, 35 mmol) and hydroxylamine sulphonic acid (3.9 g, 35 mmol) in water (20 ml). After 24 h the solution was extracted with ethyl acetate, dried (MgSO4) and concentrated. Flash column chromatography (95% dichloromethane/5% methanol) gave the product (250 mg) as a clear oil which crystallized on standing. 1 H NMR (400 MHz, CDCl3): delta=2.40 (s, 3 H), 5.20 (brs, 2 H), 7.80 (d, 1 H), 7.90 (d, 1 H), 8.50 (s, 1 H). LRMS (Thermospray): 172.8 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃;Inert atmosphere; | Step 1; To a stirred mixture of 2-bromo-5-methyl-pyridine (1.7 g, 10 mmol), 2,4,6- trivinyl-cyclotriboroxanein (1.20 g, 5 mmol) and Na2CO3 (3.73 g, 35.2 mmol) in toluene (15 mL) / EtOH (10 mL) / H2O (5 mL) was added Pd(PPh3)4 (300 mg, 0.25 mmol) under N2. The mixture was stirred at 100 0C overnight. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3).The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography column (PE:EA=50:1 ) to afford 5-methyl-2-vinyl-pyridine (900 mg, 75.6%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; at 100℃; for 2.0h;Inert atmosphere; | To a stirred solution of 2-bromo-5-methylpyridine (23.8 g, 138.0 mmol) and potassium vinyl trifluoroborate (20.39 g, 152.0 mmol) in dioxane (235 mL) under nitrogen was added Pd(dppf)2Cl2 (11.30 g, 13.8 mmol), cesium carbonate (135.0 g, 415.0 mmol), and water (41.5 mL). The resulting mixture heated to 100C for 2 hours. The reaction was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was concentrated and flash column separation using a 0-30% ethyl acetate/ hexane gradient gave E-1 as a volatile oil, which was carried on directly to next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | A mixture of 2-bromo-5-methylpyridine [purchased from TCI] (0.827 g, 4.81 mmol), <strong>[128733-85-7](5-(tert-butyl)-2-methoxyphenyl)boronic acid</strong> [Intermediate 5] (1.2 g, 5.77 mmol) and potassium carbonate (0.997 g, 7.21 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (277.8 mg, 0.24 mmol) was added and the reaction mixture heated to 80 C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 35% ethyl acetate in hexanes to give 2-(5-(tert-butyl)-2-methoxyphenyl)-5-methylpyridine (1.216 g, 99% yield) as a colorless oil. HPLC/MS Rt=2.58 min, m/z 256.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; at 120℃; | General procedure: A mixture of methyl anthranilate (50 mg, 1 equiv.), 2-bromopyridine (2 equiv.),Pd(OAc)2 (0.03 equiv.), Xantphos (0.04 equiv.), and Cs2CO3 (2.5 equiv.) in eucalyptol(1.5 mL) was stirred at 120 C for 18-24 h. The reaction was followed by TLC. After completion,the reaction was then cooled to room temperature, and the mixture was concentratedunder vacuum. The solid obtained was purified by flash chromatography using a mixtureof ethyl acetate/petroleum ether. |
Tags: 2-Bromo-5-methylpyridine | Pyridines | Bromides | Organic Building Blocks | Heterocyclic Building Blocks | 3510-66-5
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P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
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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