* 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.
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 182,190
7
[ 16879-02-0 ]
[ 74-88-4 ]
[ 17228-64-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 1423 - 1428
8
[ 16879-02-0 ]
[ 74-88-4 ]
[ 17228-63-6 ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium carbonate In acetone at 20℃; for 16 h; Heating / reflux
To a solution of 6- chloropyridin-2-ol (10.00 g, 77.19 mmol) in acetone (350 mL) was added K2CO3 (37.34 g, 270.2 mmol) and iodomethane (17.37 ml, 270.2 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at reflux for 16 hours. The reaction mixture was cooled to room temperature and the K2CO3 was filtered off and washed with acetone. The filtrate was then concentrated and the residue was partitioned between H2O and CH2Cl2. The phases were separated, and the aqueous phase was re-extracted with CH2Cl2 (Ix). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to yield a yellow oil. The crude product <n="128"/>111-03-PCT - P2338R1 - 02120.004WO1127 was purified by silica gel flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc. The desired product (7.38 g, 67percent) was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.23 (dd, IH), 6.50 (dd, IH), 6.30 (m, IH), 3.69 (s, 3H). LRMS (ESI pos) m/e 144 (M+l).
59%
With potassium carbonate In acetoneReflux
[00179] To a mixture of 6-chloropyridin-2-ol (10.0 g, 77.5 mmol) and K2C03 (37.4 g, 271.3 mmol) in acetone (100 mL) was added iodomethane (38.5 g, 271.3 mmol) and the reaction was heated to reflux overnight. The reaction mixture was cooled to RT and the insoluble materials filtered. The solvent was concentrated in vacuo and the residue was partitioned between H20 and DCM. The organic layer was dried and concentrated. The solids were slurried in diethyl ether at RT for 30 min, filtered, washed with ether and dried to give 6.5 g (59percent) of the title compound. 1H NMR (400 MHz, MeOD-d4): δ 3.73 (s, 3H), 6.51-6.59 (m, 2H), 7.45-7.49 (m, 1H). [M+H] Calc'd for C6H6C1N0, 144; Found, 144.
1.96 g
With potassium carbonate In acetone at 20℃; for 5 h;
96.1 6-Chloro-1-methyl-1H-pyridin-2-one To a suspension of 6-chloro-2-pyridinol (3 g) in acetone (116 mL) was added potassium carbonate (11.2 g) and methyl iodide (4.92 mL) and the mixture was stirred for 5 h at RT. It was filtered off and the filtrate was concentrated in vacuo. The crude was purified by CC (Hept/EtOAc 8/2 to 0/1) to give 1.96 g of the titled compound as a white solid. LC-MS (B): tR=0.39 min; [M+H]+: 144.14
With potassium carbonate In ethanol at 70℃; for 18 h;
[00404] Step a: A mixture of 6-chloropyridin-2(1H)-one (500 mg, 3.86 mmol), K2C03 (800 mg, 5.79 mmol), and methyl iodide (0.360 mL, 5.79 mmol) in EtOH (11.6 mL) was stirred for 18 h at 70 °C. The reaction mixture was allowed to cool to RT, the volatiles were removed under reduced pressure and the residue was suspended in water. The aq. layer was extracted with EtOAc (2 x). The combined organic layers were dried over Mg504, filtered, and the volatiles were removed under reduced pressure. The residue was purified by silica chromatography (0 to 10percent gradient of MeOH/DCM) to give 6-chloro- 1 -methylpyridin-2( 1H)-one (472 mg, 3.29 mmol). ‘H NMR (400 MHz, DMSO-d6) ö ppm 7.39 (dd, J=9.2, 7.3 Hz, 1 H), 6.49 (dd, J=7.3, 1.2 Hz, 1 H), 6.41 (dd, J=9.2, 1.1 Hz, 1 H), 3.55 (s, 3 H). MS m/z 144.0 (M+H).
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 16, p. 5802 - 5808
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 6, p. 2313 - 2322
[3] Patent: WO2016/203405, 2016, A1, . Location in patent: Paragraph 00404
10
[ 16879-02-0 ]
[ 1221171-70-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165
11
[ 16879-02-0 ]
[ 1221171-70-5 ]
Reference：
[1] Patent: WO2012/93174, 2012, A1,
12
[ 16879-02-0 ]
[ 1885-46-7 ]
[ 1214377-45-3 ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium hydroxide In water; acetonitrile at 20℃; for 0.5 h;
To a vigorously stirred solution of 2-chloro-6-hydroxypyridine(0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6 M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwiseto the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water(20 mL) and extracted with diethyl ether (2 ×10 mL) and ethyl acetate(3 ×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethylether (100:0 to 70:30) as eluent to afford the pure title compound(129 mg, 72percent yield); 1H NMR (400 MHz, CDCl3): δ 7.62 (t, 1H,J = 7.9 Hz), 7.37 (t, 1H, J = 72.2 Hz), 7.07 (d, 1H, J = 7.9 Hz), 6.76(d, 1H, J = 8.0 Hz) ppm. 13C NMR (101 MHz, CDCl3): δ 158.3, 148.5,142.1, 120.1, 113.8 (t, J= 259 Hz), 109.6 ppm 19F NMR (376 MHz,CDCl3): δ −89.3 (d, 2F, J = 71.4 Hz) ppm. HRMS (ESI) calcd forC6H5ClF2NO [M + H]+: 180.002. Found: 180.000.
Reference：
[1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165
13
[ 16879-02-0 ]
[ 75-46-7 ]
[ 1214377-45-3 ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: With potassium hydroxide In water for 0.5 h; Stage #2: at 20℃; for 3 h;
General procedure: Using an apparatus previously described for method B [21] , potassium hydroxide (2.52 g, 45 mmol, 15 equiv) and water (2.52 g) were added to the reaction vessel and the mixture was allowed to stir until the potassium hydroxide was almost completely dissolved. Then, 2-bromo-3-pyridinol (0.354 g, 3 mmol) was added and the mixture stirred for 30 min, after which acetonitrile (10 mL) was added via syringe and the mixture stirred at room temperature. Fluoroform was then bubbled slowly into the mixture for 2 h, after which the resulting mixture was stirred for one additional hour. After being quenched with water and extracted with ethyl acetate, the ethyl acetate layer was washed with a saturated solution on sodium hydroxide, separated and concentrated. Additional impurities were removed via column chromatography on silica gel using an 80:20 mixture of hexanes/methylene chloride to give a 53percent yield of the liquid product, 2-bromo-3-difluoromethoxypyridine (3d): 1H NMR: δ 8.27 (d, J = 5 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.26 (m, 1H) 6.59 (t, 2JHF = 72 Hz, 1H); 19F NMR: δ -82.1 (d, 2JFH = 72 Hz, 2F); 13C NMR: δ 146.5, 134.5, 128.3, 124.3, 116.33 (t, 1JCF = 260 Hz).
Reference：
[1] Journal of Fluorine Chemistry, 2014, vol. 168, p. 34 - 39
14
[ 16879-02-0 ]
[ 1895-39-2 ]
[ 1214377-45-3 ]
Yield
Reaction Conditions
Operation in experiment
53%
With sodium hydroxide In N,N-dimethyl-formamide at 55℃; for 18 h;
solution of 6-chloropyridin-2-ol (1.0 equiv.), sodium 2-chloro-2,2-difluoroacetate (2.0 equiv.) and sodium hydroxide (1.1 equiv.) in DMF (0.77 M) was heated at 55° C. for 18 hrs, the reaction mixture was then partitioned between EtOAc and sat. NaHCO3 solution, the aqueous was extracted by EtOAc for 3 more times, combined organic was washed by water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The crude product was purified via silica gel to yield 2-chloro-6-(difluoromethoxy)pyridine in 53percent yield: LCMS (m/z): 180.0 (MH+), Rt=0.87 min. 1H NMR (400 M Hz, CHLOROFORM-d) δ ppm 7.69 (t, J=8.0 Hz, 1H), 7.44 (t, J=72 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H).
With potassium carbonate; In ethanol; at 70℃; for 18h;
[00404] Step a: A mixture of 6-chloropyridin-2(1H)-one (500 mg, 3.86 mmol), K2C03 (800 mg, 5.79 mmol), and methyl iodide (0.360 mL, 5.79 mmol) in EtOH (11.6 mL) was stirred for 18 h at 70 C. The reaction mixture was allowed to cool to RT, the volatiles were removed under reduced pressure and the residue was suspended in water. The aq. layer was extracted with EtOAc (2 x). The combined organic layers were dried over Mg504, filtered, and the volatiles were removed under reduced pressure. The residue was purified by silica chromatography (0 to 10% gradient of MeOH/DCM) to give 6-chloro- 1 -methylpyridin-2( 1H)-one (472 mg, 3.29 mmol). ?H NMR (400 MHz, DMSO-d6) oe ppm 7.39 (dd, J=9.2, 7.3 Hz, 1 H), 6.49 (dd, J=7.3, 1.2 Hz, 1 H), 6.41 (dd, J=9.2, 1.1 Hz, 1 H), 3.55 (s, 3 H). MS m/z 144.0 (M+H).
4.35 g
With potassium carbonate; In ethanol; at 70℃; for 17h;Sealed tube;
A mixture of 6-chloropyridin-2(1H)-one (5.03 g, 38.83 mmol) , CH 3I (8.49 g, 66.86 mmol) , K 2CO 3 (8.99 g, 65.05 mmol) and EtOH (25 mL) in a sealed tube was stirred for 17 h at 70 . After cooling to RT, the reaction mixture was poured into water (200 mL) and extracted with EA (2 A 100 mL) . The combined organic layers were dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure to give compound B2-1 (4.35 g) as a yellow solid. MS: 144 [M+1] +.
With potassium carbonate; In acetone; at 20℃; for 16h;Heating / reflux;
To a solution of 6- chloropyridin-2-ol (10.00 g, 77.19 mmol) in acetone (350 mL) was added K2CO3 (37.34 g, 270.2 mmol) and iodomethane (17.37 ml, 270.2 mmol). The reaction mixture was stirred at room temperature for 1 hour and then at reflux for 16 hours. The reaction mixture was cooled to room temperature and the K2CO3 was filtered off and washed with acetone. The filtrate was then concentrated and the residue was partitioned between H2O and CH2Cl2. The phases were separated, and the aqueous phase was re-extracted with CH2Cl2 (Ix). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to yield a yellow oil. The crude product <n="128"/>111-03-PCT - P2338R1 - 02120.004WO1127 was purified by silica gel flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc. The desired product (7.38 g, 67%) was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) delta 7.23 (dd, IH), 6.50 (dd, IH), 6.30 (m, IH), 3.69 (s, 3H). LRMS (ESI pos) m/e 144 (M+l).
59%
With potassium carbonate; In acetone;Reflux;
[00179] To a mixture of 6-chloropyridin-2-ol (10.0 g, 77.5 mmol) and K2C03 (37.4 g, 271.3 mmol) in acetone (100 mL) was added iodomethane (38.5 g, 271.3 mmol) and the reaction was heated to reflux overnight. The reaction mixture was cooled to RT and the insoluble materials filtered. The solvent was concentrated in vacuo and the residue was partitioned between H20 and DCM. The organic layer was dried and concentrated. The solids were slurried in diethyl ether at RT for 30 min, filtered, washed with ether and dried to give 6.5 g (59%) of the title compound. 1H NMR (400 MHz, MeOD-d4): delta 3.73 (s, 3H), 6.51-6.59 (m, 2H), 7.45-7.49 (m, 1H). [M+H] Calc'd for C6H6C1N0, 144; Found, 144.
With potassium carbonate; In acetone; at 20℃; for 5h;
Example 96 2-Chloro-N-(1 -hydroxy-cyclohexylmethyl)-5-(1 -methyl -6-oxo-1 ,6- dihydro-pyridin-2-ylamino)-benzamide96.1 6-Chloro- 1-meth yl- 1 H-p yridin-2-oneTo a suspension of 6-chloro-2-pyridinol (3 g) in acetone (1 16 mL) was added potassium carbonate (1 1.2 g) and methyl iodide (4.92 mL) and the mixture was stirred for 5h at RT. It was filtered off and the filtrate was concentrated in vacuo. The crude was purified by CC (Hept/EtOAc 8/2 to 0/1 ) to give 1 .96 g of the titled compound as a white solid.LC-MS (B): tR = 0.39 min; [M+H]+: 144.14
1.96 g
With potassium carbonate; In acetone; at 20℃; for 5h;
96.1 6-Chloro-1-methyl-1H-pyridin-2-one To a suspension of 6-chloro-2-pyridinol (3 g) in acetone (116 mL) was added potassium carbonate (11.2 g) and methyl iodide (4.92 mL) and the mixture was stirred for 5 h at RT. It was filtered off and the filtrate was concentrated in vacuo. The crude was purified by CC (Hept/EtOAc 8/2 to 0/1) to give 1.96 g of the titled compound as a white solid. LC-MS (B): tR=0.39 min; [M+H]+: 144.14
With N-Bromosuccinimide; In chloroform; for 2.0h;Heating / reflux;
A mixture of 2-chloro-6-hydroxypyridine (2 g, 15.4 mmol) and NBS (2.8 g, 16 mmol) in 20 mL of chloroform was refluxed for 2 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography. 2.1 g of a mixture of mono-bromination products was obtained. This material was used directly in the next step.
With potassium carbonate;copper(I) chloride; In N,N-dimethyl-formamide;
EXAMPLE 2 This example illustrates the preparation of (E)-methyl 2-[2-(6-(6-chloropyrid-2-yloxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (compound No. 18 of Table IV). A stirred mixture containing (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (0.75g, 2.34 mmol, prepared as described in Example 1), anhydrous potassium carbonate (0.35g, 2.57 mmol), 6-chloropyrid-2-one (0.33g, 2.57 mmol) and a catalytic amount of copper(I) chloride in DMF (25ml) was heated at 95 C. for 90 minutes and then overnight at 100 C. Work up as in Example 1 gave a pale yellow oil (0.70g), which was chromatographed (eluent diethyl ether-hexane, 7:1) to afford a thick colourless oil (0.34g). Crystallisation from ether/hexane then gave the title compound as a white solid (0.25g, 26%); mp 75-6 C.; infrared max 1712, 1643 cm-1; mass spectrum m/e 413(M+); 1 H NMR (270MHz): delta 3.63(3H,s), 3.75(3H,s); 6.47(1H,s); 7.05(1H,d); 7.17-7.47(5H,m); 7.48(1H,s); 7.78(1H,t); 8.47(1H,s) ppm.
[Co10(OH)2(6-chloro-2-hydroxypyridine(1-))14(O3PCH2CH2PO3)][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With triethylamine In acetonitrile to soln. Co salt in MeCN 6-chloro-2-hydroxypyridine, H2O3PCH2CH2PO3H2 and Et3N were added and stirred for 6 h; soln. was filtered and evapd., residue was extd. with CH2Cl2 and layeredwith hexane; elem. anal.;
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 1h;
7
Reference Example 7; 2-Chloro-6-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine; A tetrahydrofuran (30 mL) solution of 6-chloropyridin-2-ol (1.0 g, 7.72 mmol), 2-(3,4-dimethoxyphenyl)ethanol (1.55 g, 8.44 mmol), triphenylphosphine (2.23 g, 8.44 mmol), and diethyl azodicarboxylate (1.61 g, 8.44 mmol) was stirred for 1 hour at room temperature. The reaction mixture was concentrated at reduced pressure, and the residue was chromatographed on a silica gel column (hexane-ethyl acetate 80:20) to give 1.76 g of the titled compound (yield: 78%). Oily substance. 1H-NMR (CDCl3 ) δ : 3.01 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 3.88 (3H, s), 4.49 (2H, t, J = 6.9 Hz), 6.60 - 6.89 (5H, m), 7.45- 7.92 (1H, m).
78%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 1h;
121 2-chloro-6-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine
Reference Example 121 2-chloro-6-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine A solution of 6-chloropyridin-2-ol (1.0 g, 7.72 mmol), 2-(3,4-dimethoxyphenyl)ethanol (1.55 g, 8.44 mmol), triphenylphosphine (2.23 g, 8.44 mmol) and diethyl azodicarboxylate (1.61 g, 8.44 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80:20) to give the title compound (1.76 g, yield 78%) as an oil. 1H-NMR (CDCl3) δ : 3.01 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 3.88 (3H, s), 4.49 (2H, t, J = 6.9 Hz), 6.60-6.89 (5H, m), 7.45-7.92 (1H, m).
With sodium hydroxide; In N,N-dimethyl-formamide; at 55℃; for 18h;
solution of 6-chloropyridin-2-ol (1.0 equiv.), sodium 2-chloro-2,2-difluoroacetate (2.0 equiv.) and sodium hydroxide (1.1 equiv.) in DMF (0.77 M) was heated at 55 C. for 18 hrs, the reaction mixture was then partitioned between EtOAc and sat. NaHCO3 solution, the aqueous was extracted by EtOAc for 3 more times, combined organic was washed by water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The crude product was purified via silica gel to yield 2-chloro-6-(difluoromethoxy)pyridine in 53% yield: LCMS (m/z): 180.0 (MH+), Rt=0.87 min. 1H NMR (400 M Hz, CHLOROFORM-d) delta ppm 7.69 (t, J=8.0 Hz, 1H), 7.44 (t, J=72 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 85 - 1100℃; for 5h;
At room temperature, 6-chloro-2-hydroxypyridine (148.8g, 1.15mol),DMF (1500ml), K2CO3 (317g, 1.15mol), slowly add sodium difluorochloroacetate (210g, 1.38mol),The temperature was raised to 85 C. for 1 h, and then 100 C. for 4 h. The reaction was terminated.The solvent was evaporated under reduced pressure at 30 C, water (20 ml) was added, and EA (20 ml) was added for extraction twice.The organic phases were combined, washed with water (10 ml), the organic phase was concentrated, and the crude product was subjected to column chromatography.133.60 g of a pale yellow solid was obtained with a yield of 65%.
2-((5-bromopyridin-3-yl)methoxy)-6-chloropyridine[ No CAS ]
1-(5-bromo-pyridin-3-ylmethyl)-6-chloro-1H-pyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%; 15%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
To a solution of <strong>[120277-69-2]3-bromo-5-chloromethyl-pyridine</strong> (0.05 g, 0.242 mmol) in DMF (1 mL) were added 6-chloro-lH-pyridin-2-one (0.031 g, 0.242 mmol) and K2C03 (0.067 g, 0.484 mmol) and the reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with EtOAc, poured into H20 (3 mL) and the aqueous layer was extracted with EtOAc (2 x 10 mL). Combined organics were dried over Na2S04, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtO Ac-heptane gradient to give 2- ((5-bromopyridin-3-yl)methoxy)-6-chloropyridine (0.05 g, 69 %) as a colorless liquid, MS: 301.3 (M+H+); and l-(5-bromo-pyridin-3-ylmethyl)-6-chloro-lH-pyridin-2-one (0.011 g, 15 %) as a yellow solid. MS: 301.3 (M+H+).
General procedure: Using an apparatus previously described for method B [21] , potassium hydroxide (2.52 g, 45 mmol, 15 equiv) and water (2.52 g) were added to the reaction vessel and the mixture was allowed to stir until the potassium hydroxide was almost completely dissolved. Then, 2-bromo-3-pyridinol (0.354 g, 3 mmol) was added and the mixture stirred for 30 min, after which acetonitrile (10 mL) was added via syringe and the mixture stirred at room temperature. Fluoroform was then bubbled slowly into the mixture for 2 h, after which the resulting mixture was stirred for one additional hour. After being quenched with water and extracted with ethyl acetate, the ethyl acetate layer was washed with a saturated solution on sodium hydroxide, separated and concentrated. Additional impurities were removed via column chromatography on silica gel using an 80:20 mixture of hexanes/methylene chloride to give a 53% yield of the liquid product, 2-bromo-3-difluoromethoxypyridine (3d): 1H NMR: delta 8.27 (d, J = 5 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.26 (m, 1H) 6.59 (t, 2JHF = 72 Hz, 1H); 19F NMR: delta -82.1 (d, 2JFH = 72 Hz, 2F); 13C NMR: delta 146.5, 134.5, 128.3, 124.3, 116.33 (t, 1JCF = 260 Hz).
The 40 ml dichloromethane to join flask R 1 in, N 2 protection, stirring cooling to -50 C. Adding dichloroborane phosphoric acid phenyl ester (2.31g, 11 . 0mmol, 1 . 1equiv.), stirring 10-20min; disposable adding L-c amino acid isopropyl ester (1.85g, 11 . 0mmol, 1 . 1equiv.), slowly dropping N, N-diisopropyl ethylamine (2.8g, 22 . 0mmol, 2 . 2equiv.); the drop finishes, 3-4h to the temperature in the -10 - - 5C. The other flask R 2, by adding 2-hydroxy-6-chloro-pyridine (1.29g, 10 . 0mmol, 1 . 0equiv.) and 20 ml dichloromethane, N 2 protection, stirring cooling to -10 C; slowly dropping N, N-diisopropyl ethylamine (1.4g, 11 . 0mmol, 1 . 1equiv.); the drop finishes, 1-2h to the temperature in the-5-0C. To be R 1 temperature to -10 - - 5C mixed in, will R 2instillment to in slowly mixed solution of R 1 in, temperature control 0 C left and right; the drop finishes, to room temperature, stirring 6h. After the reaction, the organic phase washed 2 times, saturated salt water to wash 1 time, drying by anhydrous sodium sulfate, removal of solvent to obtain colorless oily turns on lathe does 3.88g, molar yield 97.5%.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
5 mL of DMF was added to 6-chloro-2-pyridone (0.2 g, 1.5 mmol), bromocyclobutane (0.26 g, 1.8 mmol) andK2CO3 (0.43 g. 3 mmol), and the mixtue was stirred at 80C for 16 hours. The reaction solution was concentrated underreduced pressure and purified by column chromatography to obtain the title compound (0.28 g, 98 %).1H NMR (CDCl3) delta 7.49 (1H, t), 6.86 (1H, d), 6.59 (1H, d), 5.16 (1H, m), 2.46 (2H, m), 2.13 (2H, m), 1.83 (1H, m), 1.66 (1H, m)
With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.5h;
To a vigorously stirred solution of 2-chloro-6-hydroxypyridine(0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6 M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwiseto the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water(20 mL) and extracted with diethyl ether (2 ×10 mL) and ethyl acetate(3 ×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethylether (100:0 to 70:30) as eluent to afford the pure title compound(129 mg, 72% yield); 1H NMR (400 MHz, CDCl3): delta 7.62 (t, 1H,J = 7.9 Hz), 7.37 (t, 1H, J = 72.2 Hz), 7.07 (d, 1H, J = 7.9 Hz), 6.76(d, 1H, J = 8.0 Hz) ppm. 13C NMR (101 MHz, CDCl3): delta 158.3, 148.5,142.1, 120.1, 113.8 (t, J= 259 Hz), 109.6 ppm 19F NMR (376 MHz,CDCl3): delta -89.3 (d, 2F, J = 71.4 Hz) ppm. HRMS (ESI) calcd forC6H5ClF2NO [M + H]+: 180.002. Found: 180.000.
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2.08333h; Reflux;
2-Chloro-6-(4-Jluorophenethoxy)pyridine:
To a 50 mL round bottom flask equipped with a stir bar was added 6- chloropyridin-2-ol (250 mg, 1.930 mmol), 2-(4-fluorophenyl)ethan-1-ol (0.242 mL, 1.930 mmol), triphenylphosphine (607 mg, 2.316 mmol) and THF (10 mL). To the stirredsolution was added DIAD (0.450 mL, 2.3 16 mmol). The solution warmed to a mild reflux, then cooled within 5 minutes. The solution was stirred at r.t. for 2 hrs. The reaction solution was concentrated in vacuo and the resulting oil was diluted with a mm of acetone, then concentrated onto Celite in vacuo. The resulting powder was subjected to silica gel chromatography(40 g column, 5-40% EtOAc:Hex) to afford the product 2- chloro-6-(4-fluorophenethoxy)pyridine (443 mg, 1.760 mmol, 91 % yield) as a white solid. ‘H NMR (500 MHz, chloroform-d) 7.52 (dd, J=8.2, 7.6 Hz, 1H), 7.26 (dd, J=8.7, 5.4 Hz, 2H), 7.04 - 6.99 (m, 2H), 6.91 (dd, J=7.6, 0.6 Hz, 1H), 6.65 (dd, J=8.2, 0.6 Hz,1H), 4.51 (t, J=6.9 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H). ESI-MS(+) m/z = 252.1 (M+1).
Fresh 8 1 (0.203g, 2.176mmol), chp (0.281g, 2.176mmol) and tBuSALOH2 (181.7mg, 0.726mmol) are mixed in the microwave reactor cavity. A microwave pulse of 150W is applied and the reaction kept at 170C for 10 minutes. The solid is extracted with 10mL of MeOH/MeCN (1:1 volume) while heating is applied. The suspension is filtered while hot and the solid discarded. Slow evaporation of the liquor results in green 13 crystals of complex 4 after circa. 3days. (0013) Yield: 44% (0.214g). Calculated elemental analyses for C55H74Cl4N4Ni3O15: C, 49.0%; N, 4.2%; H, 5.6%. Experimental elemental analyses: C, 49.1%; N, 4.2%; H, 5.6%. IR (KBr, cm-1): 3339 (m, broad), 2956 (s), 2522 (m, broad), 1596 (s), 1539 (s), 1435 (s), 1386 (s), 1331 (s), 1292 (s), 1244 (s), 1219 (m), 1202 (m), 1170 (s), 1151 (m), 1023 (s), 998 (s), 923 (s), 814 (m), 784 (s), 748 (m), 727 (m), 704 (m).
Stage #1: 6-chloro-2-hydroxypyridine; nickel hydroxide hydrate; 3,5-diisopropylsalicylic acid at 150℃; for 0.166667h; Microwave irradiation;
Stage #2: methanol In acetonitrile
2.4 [Ni3(chp)4(iPrSALOH)2(MeOH)6] (5) (Ni3iPr)
Fresh 8 1 (0.203g, 2.176mmol), chp (0.281g, 2.176mmol) and iPrSALOH2 (161.38mg, 0.726mmol) are mixed in the microwave reactor cavity. A microwave pulse of 150W is applied and the reaction kept at 150°C for 10 minutes. The solid is extracted with 10mL of MeOH/MeCN (1:1 volume) while heating is applied. The suspension is filtered while hot and the solid discarded. Slow evaporation of the liquor results in green 15 crystals of complex 5 after circa. 4days. (0015) Yield: 27% (0.130g). Calculated elemental analyses for C52H70Cl4N4Ni3O16: C, 47.1%; N, 4.2%; H, 5.3%. Experimental elemental analyses: C, 47.1%; N, 4.2%; H, 5.0%. IR (KBr, cm-1): 3332 (m, broad), 2956 (s), 2522 (m, broad), 1596 (s), 1538 (s), 1437 (s), 1392 (s), 1330 (s), 1243 (s), 1169 (s), 1072 (m), 1022 (s), 998 (s), 923 (s), 872 (w), 813 (s), 785 (s), 753 (m), 704 (m), 638 (w), 617 (m), 478 (m), 424 (m).
Co<SUB>4</SUB>Dy(OH)<SUB>2</SUB>(6-chloro-2-hydroxopyridine)<SUB>4</SUB>(3,5-ditert-butylsalicylato)<SUB>5</SUB>(H<SUB>2</SUB>O)(MeCN)(H<SUB>2</SUB>O)[ No CAS ]
Co<SUB>2</SUB>Dy<SUB>2</SUB>(6-chloro-2-hydroxopyridine)<SUB>2</SUB>(3,5-ditert-butylsalicylato)<SUB>8</SUB>(MeOH)<SUB>4</SUB>[ No CAS ]
Co<SUB>4</SUB>Tb(OH)<SUB>2</SUB>(6-chloro-2-hydroxopyridine)<SUB>4</SUB>(3,5-ditert-butylsalicylato )<SUB>5</SUB>(H<SUB>2</SUB>O)(MeCN)(MeOH)[ No CAS ]
Co<SUB>4</SUB>Dy(OH)<SUB>2</SUB>(6-chloro-2-hydroxopyridine)<SUB>4</SUB>(3,5-ditert-butylsalicylato)<SUB>5</SUB>(H<SUB>2</SUB>O)(MeCN)(H<SUB>2</SUB>O)[ No CAS ]
Ni<SUB>4</SUB>Dy(OH)<SUB>2</SUB>(6-chloro-2-hydroxopyridine)<SUB>4</SUB>(3,5-ditert-butylsalicylato)<SUB>5</SUB>(H<SUB>2</SUB>O)(MeCN)<SUB>2</SUB>[ No CAS ]
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