There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 2402-78-0 | MDL No. : | MFCD00006244 |
Formula : | C5H3Cl2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FILKGCRCWDMBKA-UHFFFAOYSA-N |
M.W : | 147.99 | Pubchem ID : | 16989 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 34.26 |
TPSA : | 12.89 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.68 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | 2.15 |
Log Po/w (WLOGP) : | 2.39 |
Log Po/w (MLOGP) : | 1.68 |
Log Po/w (SILICOS-IT) : | 2.73 |
Consensus Log Po/w : | 2.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.67 |
Solubility : | 0.319 mg/ml ; 0.00215 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.05 |
Solubility : | 1.31 mg/ml ; 0.00885 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.24 |
Solubility : | 0.0859 mg/ml ; 0.000581 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.43 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P280-P301+P310+P330-P302+P352-P305+P351+P338-P332+P313-P337+P313-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H315-H319 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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% | With ammonia In water at 150℃; for 6 h; | In a 600 mL autoclave equipped with a gas entrapment stirrer 240 g aqueous ammonia (28percent NH3 by weight) was added and mixed with 120 g of 2, 6-dichloropyridine. After purging with nitrogen, 48 g of liquid ammonia were added, and the reaction mixture was heated to 150°C for 6 h under stirring. The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure . The product was isolated by filtration, washed with water and MeOH and dried. The yield for 2-chloro-6-amino pyridine was about 70percent, and the purity as determined by GC chromatography was 98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91 %Chromat. | With ammonium acetate; ammonia In water at 150℃; for 8 h; | In a 600 mL autoclave equipped with a gas entrapment stirrer, a solution of 5 g CuI in 120 g aqueous ammonia (30percent NH3 by weight) was added and mixed with 77 g ammonium acetate and 60 g of 2, 6-dichloropyridine. After purging with nitrogen, 24 g of liquid ammonia were added resulting in a pressure of about 150 psi (1.03 MPa). Subsequently, the reaction mixture was heated to 150°C for 8 h under stirring. Over the course of the reaction, the pressure decreased from an initial pressure of 680 psi (4.69 MPa) to 450 psi (3.10 MPa). The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure. The reaction mixture was analyzed using a quantitative GC analytical method. The conversion of 2, 6-dichloropyridine was greater than 99.5percent. The reaction mixture contained 0.37 mol 2,6- diaminopyridine and 0.03 mol 2-chloro-6-amino pyridine. The yields for 2, 6-diaminopyridine and 2-chloro-6-amino pyridine were 91percent and 7percent, respectively. |
72 %Chromat. | With ammonia In water at 150℃; for 8 h; | This reaction was conducted in the same manner as described in Example 1, but no ammonium acetate was added to the reaction mixture, demonstrating that lower selectivity is obtained in an unbuffered solution. The conversion of 2, 6-dichloropyridine was greater than 99.5percent. The reaction mixture contained 0.29 mol 2, 6-diaminopyridine and less than 0.005 mol 2-chloro-6-amino pyridine. The yield for 2, 6-diaminopyridine was 72percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | at 0 - 20℃; Heating / reflux | A mixture of NaOH (14.7 g, 0.37 mol), hydrazine monohydrate (15 ml) and 2,6-diacetylpyridine (6g, 36.8 mmol) suspended in diethylene glycol (27 ml_) was cautiously heated to 120 °C for 16 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were washed with 1 N NaOH, dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0percent to 15percent EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58percent). 1H NMR (400 MHz, CDCI3): 5 1.29 (t, J=7.8 Hz, 3 H), 2.80 (d, J=7.8 Hz, 2 H), 6.97 (d, J=2.0 Hz, 2 H), 7.51 (t, J=7.6 Hz, 1 H). 2,6-Diethyl-pyridine has also been prepared as follows:A solution of ethylmagnesium bromide in ethyl ether [prepared from Mg (16.5 g, 0.68 mol) and ethyl bromide (50 mL, 0.68 mol) in 500 ml_ of ether] was added dropwise to a mixture of 2,6-dichloropyridine (50 g, 0.34 mol) and NiCI2(dppp) (1.0 g, 2 mol) in anhydrous ethyl ether(500 mL).at 0 °C unde(r N3 atmosphere. After addition, the resulting mixture was stirred,. , ' >.,"?, '['A V ' "' > 'ambient temperature oveifngh'tj was then heated to reflux for about 3 hours. The suspensiatonwas poured into cushed ice (200 g) and the mixture was saturated with NH4CI. The organic layer was separated and the aqueous phase was extracted with ether (200 mL x 3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give the product (41 .1 g, 89percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | at 100 - 200℃; Large scale | 1480.0g 2,6-dichloropyridine and 89.2g anhydrousFeCl3 are weighed, mixed and added into a 2000mL four-necked flask. When the mixture was heatedto 100∼120°C, chlorine gas is introduced until the reactionis carried out adequately, then cooled to 100°C, rectifiedunder reduced pressure. The product fraction is collectedat the top temperature of 118∼124°C under thepressure of -0.1 MPa. The distillate with low concentrationgained during the process of rectifying can be recycledfor the next batch of reaction and rectification. Finally,1715.0g 2,3,6-trichloropyridine is gained when thedistillate is recycled, and the total yield is 94.0percent, the purity |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 20 - 100℃; | Reference example 67: 2-(6-chloro-pyridin-2-ylaminoVethanol. 2-Arnino-ethanol (0.82 g, 13.5 mmol) was added to a solution of 2,6- dichloropyridine (2.0 g, 13.5 mmol) in pyridine (10 mL) at room temperature and then heated at 100 °C overnight The reaction mixture was concentrated in vacuo to obtain a residue which was dissolved in ethyl acetate. The solution was washed with water, brine, dried over anhydrous sodium sulfate and evaporated in vacuo to afford 2-(6- chloro-pyridin-2-ylamino)-ethanol (2.3 g, 99percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With hydrazine hydrate In ethanol at 100℃; for 4 h; | Compound 35 (50.0 g, 0.34 mol) in a mixture of 80percent of hydrazine monohydrate solution (120 mL, 1.92 mol) and ethanol (200 mL) was heated at 100 °C for 4 hours. TLC showed compound 35 was consumed completely. The solution was allowed to cool to room temperature, and evaporated to dryness. The residue was purified by recrystallization from petroleum ether to yield compound 36 as a white solid (31.0 g, 64 percent). ‘H NMR (400 MHz, CDC13) ö 7.42 (dd, J= 7.2 Hz, 0.4 Hz, 1H), 6.65 (t, J= 7.2 Hz, 2H), 6.14 (s, 1H), 3.63 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | for 11 h; Reflux | Step 1 [Show Image] 2,6-dichloropyridine 11 (8.88 g, 60.0 mmol) and 2-(tributylstannyl)pyridine (7.36 g, 20.0mmol) were dissolved in toluene (74 ml). To the solution was added tetrakis triphenyl phosphinepalladium (2.31 g, 2.0 mmol) and the mixture was stirred under heat refluxing for 11 hours. The reactant was condensed under reduced pressure and the residue was purified by silica gel chromatography to give quantitatively the desired Compound 12 (3.9 g). 1H-NMR (DMSO-d6) δpppm: 7.50-7.53 (m, 1H), 7.59 (d, 1H, J = 8.0 Hz), 7.93-8.05 (m, 2H), 8.30 (d, 1H, J = 8.0 Hz), 8.38 (d, 1H, J = 8.0 Hz), 8.72 (d, 1H, J = 4.4 Hz). |
100% | for 11 h; Reflux | 2,6-dichloropyridine 11 (8.88 g, 60.0 mmol) and 2-(tributylstannyl)pyridine (7.36 g, 20.0 mmol) were dissolved in toluene (74 ml). To the solution was added tetrakis triphenyl phosphinepalladium (2.31 g, 2.0 mmol) and the mixture was stirred under heat refluxing for 11 hours. The reactant was condensed under reduced pressure and the residue was purified by silica gel chromatography to give quantitatively the desired Compound 12 (3.9 g) 1H-NMR (DMSO-d6) ? ppm: 7.50-7.53 (m, 1H), 7.59 (d, 1H, J=8.0 Hz), 7.93-8.05 (m, 2H), 8.30 (d, 1H, J=8.0 Hz), 8.38 (d, 1H, J=8.0 Hz), 8.72 (d, 1H, J=4.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With [Ni(2,2'-bipyridine)2Br2]; sodium iodide In N,N-dimethyl-formamide at 20℃; for 8 h; Electrochemical reaction; Inert atmosphere | General procedure: To an undivided electrochemical cell, fitted by a zinc rod as the anode and surrounded by a nickel foam as the cathode, were added DMF (50 mL), 0.1 M NaI, and 1,2-dibromoethane (2.5 mmol, 215 μL). The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at room temperature for 20 min. Then the current was stopped, and [Ni(bpy)]Br2 complex21 (2.6 mmol, 562 mg), 2,6-dichloropyridine (5 mmol, 0.74 g), and 2-bromo-6-methylpyridine (10 mmol, 1.72 g) were sequentially added. The solution was electrolyzed at 0.1 A and room temperature until the starting material was totally consumed (8 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With nickel(II) bromide hydrate; sodium iodide In N,N-dimethyl-formamide at 20℃; for 8 h; Electrochemical reaction; Inert atmosphere | General procedure: To an undivided electrochemical cell, fitted by a zinc rod as the anode and surrounded by a nickel foam as the cathode, were added DMF (50 mL), 0.1 M NaI, and 1,2-dibromoethane (2.5 mmol, 215 μL). The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at room temperature for 20 min. Then the current was stopped, and [Ni(bpy)]Br2 complex21 (2.6 mmol, 562 mg), 2,6-dichloropyridine (5 mmol, 0.74 g), and 2-bromo-6-methylpyridine (10 mmol, 1.72 g) were sequentially added. The solution was electrolyzed at 0.1 A and room temperature until the starting material was totally consumed (8 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With [Ni(2,2'-bipyridine)2Br2]; sodium iodide In N,N-dimethyl-formamide at 20℃; for 8 h; Electrochemical reaction; Inert atmosphere | General procedure: To an undivided electrochemical cell, fitted by a zinc rod as the anode and surrounded by a nickel foam as the cathode, were added DMF (50 mL), 0.1 M NaI, and 1,2-dibromoethane (2.5 mmol, 215 μL). The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at room temperature for 20 min. Then the current was stopped, and [Ni(bpy)]Br2 complex21 (2.6 mmol, 562 mg), 2,6-dichloropyridine (5 mmol, 0.74 g), and 2-bromo-6-methylpyridine (10 mmol, 1.72 g) were sequentially added. The solution was electrolyzed at 0.1 A and room temperature until the starting material was totally consumed (8 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With bis(bipyridine)nickel(II) bromide; sodium iodide In N,N-dimethyl-formamide at 20℃; for 3.3 h; Electrochemical reaction; Inert atmosphere | General procedure: To an undivided electrochemical cell, fitted by a zinc rod as the anode and surrounded by a nickel foam as the cathode, were added DMF (50 mL), 0.1 M NaI, and 1,2-dibromoethane (2.5 mmol, 215 μL). The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at room temperature for 15-20 min. Then the current was stopped, and [Ni(bpy)]Br2 complex21 (1 mmol, 375 mg), 2,6-dichloropyridine (10 mmol, 1.48 g) or 2,6-dibromopyridine (10 mmol, 2.38 g) were sequentially added. The solution was electrolyzed at 0.1 A and room temperature until the starting material was totally consumed (3.3 h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 %Chromat. | With bis(bipyridine)nickel(II) bromide; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere | General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure. |
40 %Chromat. | With bis(bipyridine)nickel(II) bromide; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere | General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20 - 60℃; for 24 h; | To a stirred solution of 2,6-dichloropyridine (8) (68.9 g, 466 mmol) in MeOH (500 mL) was added NaOMe (100 g, 1.86 mol) at room temperature. The resulting mixture was stirred at 60°C for 24 h. After cooling, the mixture was quenched with 2 Maqueous HCl, and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford 9(66.9 g, quant) as a colorless oil.9: IR (film, cm−1): 1599, 1585, 1560, 1468, 1410, 1302, 1265, 1152, 1024, 876, 789; 1H-NMR (CDCl3, 500 MHz) δ: 7.51 (t, J=7.37 Hz, 1H), 6.90 (d, J=7.37 Hz, 1H), 6.65 (d, J=7.37 Hz, 1H), 3.94 (s, 3H); 13C-NMR (CDCl3, 125 MHz) δ: 163.9, 148.4, 140.5, 116.2, 109.1, 54.0; HR-MS (ESI-time-of-flight (TOF)): Calcd for C6H7ClNO [(M+H)+] 144.0211. Found 144.0211. |
97.5% | at 70 - 75℃; | Add 2,6-dichloropyridine, methanol, and sodium hydroxide in the corresponding proportions in Table 1 to a 250 ml or 500 ml three-necked flask equipped with a reflux condenser, stirrer, and thermometer, and heat to 70-75°C with stirring. While maintaining reflux, the reaction was sampled separately for 1 hour, 3 hours, and 5 hours. The conversion of 2,6-dichloropyridine was measured and the reaction product was 6-chloro-2-methoxypyridine.Table 1 Composition of 2,6-dichloropyridine, Methanol, and NaOH in Examples 1-20 |
88% | for 8 h; Reflux | In a 500 ml reaction flask, 29.6 g of 2,6-dichloropyridine was added,8 g of solid sodium hydroxide and 200 ml of methanol,Stirring began to heat up to reflux, the reaction time was 8 hours,Stop the reaction, steamed most of the methanol, cooled, add 100 ml of water,Extract once with dichloromethane, remove methylene chloride to give the crude product,The crude product was distilled under reduced pressure to give 2-methoxy-6-chloropyridine,The yield is 88percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 %Spectr. | With tetramethylammonium fluoride In N,N-dimethyl-formamide at 20℃; for 24 h; | General procedure: General Procedure E: General Experimental Details for NMR Yields Reported in Figure 3. In a drybox, anhydrous NMe4F (18.6 mg, 0.2 jumol, 2 equiv) and the appropriate aryi chloride or nitroarene substrate (0.1 nimol, 1 equiv) were weighed into a 4 mL vial equipped with a micro stirbar. DMF (0.5 mL) was added, and the viai was removed from the drybox and stirred at room temperature unless otherwise noted for 24 hours. The reaction was cooled to room temperature and an internal standard (1, 3, 5-trifluorobenzene, 100 iL of a 0.5 M solution in toluene) was added. An aliquot was removed for analysis by 59F NMR spectroscopy and GCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.15% | at 80℃; for 2 h; | Weighed 2.0 g of the catalyst silicate tungstate heteropoly acid,150 g of crushed 2,6-dichloropyridine was added to 95 g of TFA,Stirring and heating to 80 ° C dissolved slowly after the concentration of 50percent of the concentration of H2O2115g, about 1h drops finished.And then heated to reflux state, stirring and holding 2h. After the end of the insulation, the first filter out the catalyst,Cooled to room temperature, slowly poured into 300 mL of ice water, and the unreacted 2,6-dichloropyridine residue was filtered off.The filtrate was dewatered to remove water and excess TFA, and the mother liquor was added with the appropriate amount of CHCl3 to extract,De-dissolving pale yellow loose 2,6-dichloropyridine-N-oxide, HPLC analysis content of 98.9percentYield 90.15percent. |
87.6% | With dihydrogen peroxide; trifluoroacetic acid In water at 0℃; for 6.5 h; Reflux | (1) 2,6-dichloropyridine-N-oxide After the reaction solution of trifluoroacetic acid (485 mL, 6.3 mol), 2,6-dichloropyridine (48 g, 324 mmol) and 35percent hydrogen peroxide (85.0 mL, 971 mmol) was stirred for 6.5 h under the condition of reflux, it was cooled to room temperature. The reaction solution was poured into beaker contained 2.4 L water, and cooled overnight at 0° C. The solid (unreacted 2,6-dichloropyridine) was removed through a suction filtration. The filtrate was concentrated, to which 500 mL chloroform was added, and potassium carbonate was added until no gas was produced. It was filtrated. The filtrate was concentrated under vacuum to afford 46.6 g light yellow solid, 87.6percent. |
87.6% | With dihydrogen peroxide; trifluoroacetic acid In water for 6.5 h; Reflux | (1) 2,6-dichloropyridine-N-oxide After the reaction solution of trifluoroacetic acid (485 5 mL, 6.3 mol), 2,6-dichloropyridine (48 g, 324 mmol) and 35percent hydrogen peroxide (85.0 mL, 971 mmol) was stirred for 6.5 h under the condition of reflux, it was cooled to room temperature. The reaction solution was poured into beaker contained 2.4 L water, and cooled overnight at 0 °C. The solid (unreacted 2,6-dichloropyridine) was removed through a suction filtration. The filtrate was concentrated, to which 500 mL chloroform was added, and potassium carbonate was added until no gas was produced. It was filtrated. The filtrate was concentrated under vacuum to afford 46.6 g light yellow solid, 87.6percent. |
67% | With sodium percarbonate; trifluoromethylsulfonic anhydride In acetonitrile at 0℃; for 3.5 h; | General Procedure: To an oven-dried 4-dram vial is added the pyridine (1.0 mmol), sodium percarbonate (157 mg, 1.0 eq.) and anhydrous CH3CN (5.0 mL). To the suspension, cooled in an ice water bath, is dropwise added triflic anhydride (339 μL, 2.0 eq.). Bubbles form during addition of triflic anhydride. The mixture continues stirring for 3.5 hr at 0° C. Most solid sodium percarbonate disappears after 3 hr. The reaction may be monitored using TLC (or NMR spectrum) of a worked-up aliquot to monitor consumption of starting material, and the reaction may be quenched when the TLC or NMR spectrum indicates that no further reaction is occurring. The reaction mixture is then poured onto a mixture of crushed ice (10 g) and saturated sodium bicarbonate (40 mL). After stirring for 30 min, the mixture is extracted with DCM (3.x.20 mL). The combined DCM solution is washed with brine (20 mL) and dried over sodium sulfate. The aqueous solution is treated with 10percent Na2S2O5 solution. After concentration, the DCM solution is loaded onto a 20 g ISOLUTE.(R). silica cartridge and eluted with Hexane/EtOAc. Table 1 shows representative oxidations of electron deficient pyridines |
55% | With dihydrogen peroxide; trifluoroacetic acid In water for 3 h; Reflux | General procedure for synthesis of 2,6-dichloropyridine-1-oxide (Y-2) A solution of 2,6-dichloropyridine (Y-1) (10.0 g, 0.067 mol) in a mixture of CF3COOH (80 mL) and 30percent aq H2O2 (25 mL) was heated at reflux for 3 h. Then, saturated Na2S2O4 solution was added to the mixture until hydrogen peroxide was consumed completely via an inspection with potassium iodide-starch test paper. Thereafter, the reaction mixture was concentrated under reduced pressure to about 10 mL and then poured on 50 mL water. The unreacted 2,6-dichloropyridine (Y-1) was formed as a precipitate, filtered, the filtrate was basified to pH = 8-9 using solid Na2CO3. The obtained precipitation was filtered and dried, giving the crude 2,6-dichloropyridine-1-oxide (Y-2) as a white solid, yield 55percent, mp: 137-138 °C. |
54% | With dihydrogen peroxide; trifluoroacetic acid In water for 3 h; | 2,6-Dichloropyridine (E-1) (10.0 g, 0.067 mol) was dissolved in a mixture of CF3COOH (80 mL) and 30percent aq H2O2 (25 mL), which was heated at reflux for 3 h. Then, saturated Na2S2O4 solution was added to the above solution until hydrogen peroxide was depleted completely via an inspection with potassium iodide-starch test paper. Afterwards, the reaction mixture was concentrated in vacuo to about 10 mL and then added 50 mL water, filtered, basified the filtrate to pH = 8-9 with solid Na2CO3. The obtained precipitation was filtered and dried, affording the crude 2,6-dichloropyridine-1-oxide (E-2) as a white solid, yield 54percent, mp: 137-138 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 2 h; |
Lithium diisopropylamide (2 M, 20.5 mL, 40.53 mmol, 1.2 eq.) was added into anhydrous tetrahydrofuran (20 mL) at -78 °C. Compound 1-1 (5.0 g, 33.78 mmol, 1.0 eq.) in tetrahydrofuran (20 mL) was added dropwise over 1 h at -78 °C. NN-Dimethylformamide (7.5 g, 101.35 mmol, 3.0 eq.) was added into the solution, and the mixture was stirred for another 2 hat -78 °C. Saturated ammonium chloride (60 mL) was added to the mixture to quench the reaction. The solution was evaporated to remove tetrahydrofuran and extracted with ethyl acetate (3 x 50 mL). The organic layer was collected, dried over sodium sulfate, and evaporated to give the crude product, which was purified by silica gel column chromatography (100percent petroleum ether to ethyl acetate : petroleum ether = 1:10) to give compound 1-2 as a white solid (3.5 g, yield: 59percent). MS (ESI) m/z 176.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.333333 h; |
Under N2, to a solution of 2,6-dichloroyridine (6.00 g, 40.5 mmol) in anhydrous THF (75 mL) cooled at -78 0C was added LDA (2.0 M in heptane/THF/ethylbenzene, 20.5 mL, 41.0 mmol). After the mixture was stirred at -78 0C for 30 min, 1-formylpiperidine (4.64 g, 41.0 mmol) was added. The mixture was stirred at -78 0C for 20 min, and at -780C aqueous EPO <DP n="63"/>HCl (1 N, 60 mL) and Et2O (50 mL) were added. The organic layer was collected and the aqueous layer was extracted with Et2O (3 X 100 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (CH2Cl2/hexanes, 1 :2 v/v) to afford 2,6-dichloro-pyridine- 3-carbaldehyde as a white solid (2.85 g, 40percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | for 8 h; Reflux | (1) In a 500 ml reaction flask, 29.6 g was added2,6-dichloropyridine, 16 g of solid sodium hydroxide and 200 ml of methanol,Stirring began to heat up to reflux, the reaction time was 8 hours,Stop the reaction, steamed most of the methanol, cooled, add 100 ml of water,Extract once with dichloromethane, remove methylene chloride to give the crude product,The crude product was distilled under reduced pressure to give 2,6-dimethoxypyridine in 94percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 20 - 120℃; for 10.5 h; | The 80mL of concentrated sulfuric acid was added to a 150mL three-neck flask, stirring at room temperature, was slowly added 7.4g (0.05mol) 2,6- dichloropyridine (IV), followed by slow addition of 10.1g (0.1mol) potassium nitrate. After the addition stirring was continued for 30min, warmed slowly to 120 , the reaction incubated 10h. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into crushed ice with stirring, the precipitate was washed with a large amount of white solid was immediately filtered off with suction, ice water until neutral, and dried to give a white solid of 2,6-dichloro-3-nitropyridine (V) 7.75g, yield 80percent .mp61-63 |
75.38% | With sulfuric acid; nitric acid In water at 20 - 105℃; for 5 h; | 2,6-Dichloropyridine, 25.0 gm (0.168 mole) was added slowly under constant stirring to concentrated sulfuric acid at 20°-25 ° C. To this solution, 75.0 gm of concentrated nitric acid (98.0percent) was added slowly, keeping the reaction temperature below 50° C. After the addition, the resulting mixture was heated to 100°-105 ° C. for 5.0 hrs. The progress of the reaction was monitored by TLC. After the reaction was over, the reaction mixture was cooled to 50° C. and poured in ice water. The resulting precipitate was filtered and washed with water. The wet cake thus obtained was dried to give 24.5 gm of 2,6-dichloro-3-nitropyridine. The yield of 2,6-dichloro-3-nitropyridine was 75.38percent and the GC purity was 99.5percent. |
70% | at 80℃; for 3 h; | Prior synthesis of pyrido[3,2-d]pyrimidines utilized ethoxyethanol and aniline for substitution on 3 (Scheme 1) whereas for substituted anilines, strong bases such as LDA were used to facilitate the reaction. Both methods suffer from long durations and stringent reaction conditions, respectively. A simpler and versatile synthetic route to obtain 4-18 from 3 was envisioned using appropriate anilines at reflux in isopropanol at 120 °C, a highly versatile reaction process that provided good yields (75-83percent). Reduction of the nitro group was performed using iron in cone. HCl (Bechamp reduction) or using H2/Pd to give quantitative yields. Cyclization of the resultant intermediate with chlorformamidine in dimethylsulfone at 140 °C provided the desired target compounds. |
28 g | at -15 - 150℃; | To a stirred solution of 2,6-dichloropyridine 25g (171.1mmol) in conc.H2S04 was added cone HN03 at -15°C dropwise. The reaction was then heated at 150 °C for 4h. Upon completion, the reaction was cooled to RT and poured into ice water. The obtained solids were filtered and dried under vacuum to afford the required compound as an off-white solid (28g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.91 g | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 35℃; for 2 h; Inert atmosphere |
To a solution of acetonitrile (2.77 mL) in tetrahydrofuran (80 mL) was added dropwise n-butyl lithium hexane solution (1.6 M, 29.6 mL) at -78°C, and the reaction mixture was stirred at -78°C for 1 hr under argon atmosphere. A solution of 2,6-dichloropyridine (2.0 g) in tetrahydrofuran (10 mL) was added dropwise thereto at -78°C, and the reaction mixture was stirred at -78°C for 2 hr under argon atmosphere, and allowed to be warmed to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.91 g). 1H NMR (300 MHz, CDCl3) δ 3.93 (2H, s), 7.33 (1H, dd, J = 8.1, 0.6 Hz), 7.43 (1H, dd, J = 7.5, 0.6 Hz), 7.73 (1H, t, J = 7.8 Hz)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 100℃; for 1 h; Inert atmosphere | Intermediate 24:-dichloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridineUnder an atmosphere of nitrogen, a mixture of 2,6-dichloropyridine (3g, 20.3mmol), 4,4,4,,4,,5,5,5,,5'-octamethyl-2,2,-bi-1 ,3,2-dioxaborolane (5.92g, 23.3mmol), 1 ,10- phenanthroline (145mg, 0.81 mmol) and chlorobis(1 ,5-cyclooctadiene)iridium(l) dimer (267mg, 0.30mmol) was treated with 1 ,2-dichloroethane (20ml_). Nitrogen was passed through the mixture for 5 minutes after which time the mixture was heated at 100°C for 1 hour. The cooled reaction mixture was poured into a mixture of diethyl ether (150ml_) and aqueous sodium hydroxide solution (4M, 200ml_) and the phases were separated. The aqueous phase was ice-cooled and acidified with aqueous hydrochloric acid (5M) and the resulting precipitate was filtered, washed with water and dried to afford the title compound (4.9g, 17.9mmol, 88percent yield). LCMS (Method A): Rt 0.74 minutes; m/z 192,194 (ionised as the boronic acid) (MH+). NMR (400MHz, dmso-d6) δ 1.28 (12H, s), 7.57 (2H, s). |
58% | With 1,10-Phenanthroline In 1,2-dichloro-ethane at 100℃; for 15 h; | To a mixture of 2, 6-dichloropyridine (3.28 g, 22.2 mmol) and bis (pinacolato) diboron (6.2 g, 24.4 mmol) was added 1,10-phenanthroline (0.24 g, 1.3 mmol) and CHLORO-1, 5-cyclooctadiene iridium (I) dimer (0.44 g, 0.66 mmol) under nitrogen followed by anhydrous 1,2- dichloroethane. Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100 °C for 15 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature, poured onto DIETHYLETHER/4N sodium hydroxide (50 ml/200 ml) and the phases separated. The aqueous phase was acidified with 6N hydrochloric acid and the resulting solid was filtered, washed with water and dried on the sinter to yield the pinacol ester of 2, 6-dichloropyridin-4-ylboronic acid (3.5 g, 58 percent) as a grey solid. |
58% | With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine In tetrahydrofuran at 80℃; for 19 h; Inert atmosphere; Glovebox | Example 4 Borylation of Pyridines Borylation of 2,6-Dichloropyridine An oven-dried 3 mL screw-cap Wheaton® vial was charged inside a nitrogen-filled glovebox with [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol) and dtbpy (2.7 mg, 0.01 mmol). THF (1.5 mL) was added, followed by B2pin2 (127 mg, 0.5 mmol) and 2,6-dichloropyridine (147 mg, 1.0 mmol). The vial was capped and heated outside of the glovebox at 80° C. for 19 h. The reaction solvent was removed on a rotary evaporator, and the residue was purified by flash column chromatography using hexanes-EtOAc mixtures as eluent providing 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a white solid (160 mg, 58percent): 1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 1.33 (s, 12H) |
4.8 g | With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 1,10-Phenanthroline In 1,2-dichloro-ethane at 100℃; for 15 h; Inert atmosphere; Sealed tube | 2,6-Dichloropyridine (20.3 mmol, 3.0 g), bis-(pinacolato)diboron (22.3 mmol, 5.66 g) and 1,10-phenantroline (1.2 mmol, 0.212 g) were dissolved in dry 1,2- dichloroethane (100 ml) , degassed and purged with Ar for 5 minutes. Chloro-1,5- cyclooctadiene iridium(I) dimer (0.445 g, 0.7 mmol) was added and the resulting reaction mixture was stirred at 100°C for 15 hours in sealed tube conditions. Aftercompletion of the reaction the contents were cooled, filtered through Celite and 1,2- dichloroethane was evaporated with vacuum. The crude residue was dissolved in diethyl ether and washed with sodium hydroxide (4N solution in water). The aqueous layer was acidified to pH=1 with HC1 (6N solution in water) and resulting solid was filtered off and washed with water. 4.8 g of the title compound was obtained as a grey solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | at 100℃; for 15 h; | Description 6 2*6-DICHLORO-4-(3-METHVL-2-PYRIDYL) PERIDINE To a mixture of 2, 6-dichloropyridine (3.28 g, 22.2 mmol) and bis (PINACOLATO) diboron (6.2 g, 24.4 mmol) was added 1, 10-phenanthroline (0.24 g, 1. 3 mmol) and CHLORO-1, 5-CYCLOOCTADIENE iridium (I) dimer (0.44 g, 0.66 mmol) under nitrogen followed by anhydrous 1, 2-dichloroethane. Nitrogen was bubbled through the mixture for 5 min and the reaction was then heated with stirring at 100 C for 15 h under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature, poured onto DIETHYLETHER/4N sodium hydroxide (50 ML/200 ML) and the phases separated. The aqueous phase was acidified with 6N hydrochloric acid and the resulting solid was filtered, washed with water and dried on the sinter to yield pinacol 2,6-dichloropyridine-4-boronate (3.5 g, 58 percent) as a grey solid, MS: (ES (M+1)) 274/276. LH NMR (360 MHz, DMSO) 8 1.30 (12H, s), 7.57 (2H, s) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With copper(l) iodide In water at 180℃; for 2 h; Sealed tube; Microwave irradiation | General procedure: Compounds I–VII (4.22 mmol), catalytic amounts of CuI (10 mg, 0.052 mmol) and water (100 μL) were treated with 6equiv of the respective amine and sealed in a 5 mL microwave vial. Pd(PPh3)4 (10 mg, 0.008 mmol) was added in the case of anilines. After the reaction was completed (see Table 1), 2 equiv of solid K2CO3 were added. The resulting product was obtained after filtration and washing with water as an analytically pure crystalline solid. Otherwise all volatiles were then evaporated and purified by flash column chromatography (A) or bulb-to-bulb distillation (B). In the case of methylamine and ethylamine the corresponding aqueous solution was used without extra water addition. |