* 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] European Journal of Organic Chemistry, 2009, # 9, p. 1327 - 1334
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, p. 737 - 744
Reference：
[1] Chemical Communications, 2018, vol. 54, # 73, p. 10324 - 10327
8
[ 620-08-6 ]
[ 1815-99-2 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 21, p. 6711 - 6714
9
[ 620-08-6 ]
[ 17217-57-1 ]
Yield
Reaction Conditions
Operation in experiment
32 %Spectr.
at 140℃; for 18 h; Inert atmosphere
Under a nitrogen atmosphere, palladium acetate (11.2 mg, 0.05mmol), 1, 10 - phenanthroline (49.6 mg, 0.25mmol), silver acetate (250 mg, 1.5mmol), (1 ml) was suspended in pyridine (51.1 mg, 0.5mmol) pivalic acid, stirred at 140 °C 26 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration over celite, methylene chloride (10 ml) was washed. The filtrate was concentrated under reduced pressure, 1, 1, 2, 2 - tetrachloroethane (15.8 μl, 0.15mmol) was added as an internal standard substance was obtained residue,1H NMR (88percent) yield was calculated based oxidizing agent. (Methylene chloride/hexane=5/95) to give a residue for a thin layer chromatography analysis, the subject compound (quantitative value NMR 89percent, 80percent isolated yield) was obtained as a white powder 93.1 mg.
Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14830 - 14835
[2] Journal of the American Chemical Society, 2007, vol. 129, # 36, p. 11006 - 11007
[3] Organometallics, 2012, vol. 31, # 13, p. 4817 - 4831
[4] Organometallics, 2016, vol. 35, # 14, p. 2348 - 2360
[5] Patent: JP2017/132738, 2017, A, . Location in patent: Paragraph 0083; 0090; 0091; 0100-0102
10
[ 620-08-6 ]
[ 31872-62-5 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: at 70℃; for 60 h;
To cone. H2SO4 (5 mL) chilled in an ice bathm is added 4-methoxypyridine (0.5 mL, 4.9 mmol) dropwise over a 20 s period. Cone. Fuming nitric acid (5 mL) is added, and the reaction mixture is heated at 70 °C for 2.5 days. This mixture is cooled to rt, and then is poured into ice. Soild K2CO3 is added until the pH of the mixture is basic. The mixture is partitioned between H20 and EtOAc. The two layers is separated, and the aqueous layer is extracted with EtOAc once. The combined organic layers are washed with H2O and brine, dried over MgS04, filtered, and concentrated in vacuo to yield 0.7 g (92percent) of the product a yellow powder. 1H NMR (CDC13, 300 MHz) δ 9.02 (s, 1H), 8.65 (d, J= 5.8, 1 H), 7.04 (d, J = 5.9, 1H), 4.05 (s, 3H). LC Rt: 0.5 min; LCMS m/z 155 (M+l, 100percent).
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; zinc dichloro(N,N,N′,N′-tetramethylethylenediamine) In tetrahydrofuran; hexane at 20℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; hexane at 20℃; Inert atmosphere
General procedure: To a stirred, cooled (0 C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2-3 mL) were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min later, ZnCl2TMEDA[51] (0.13 g, 0.50 mmol). The mixture was stirred for 15 min at 0 C before introduction of the substrate (1.0 mmol) at 0-10 C. After 2 h at room temperature, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was stirred overnight before addition of an aqueous saturated solutionof Na2S2O3 (4 mL) and extraction with AcOEt (320 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatographyon silica gel (the eluent is given in the product description) led to the compounds described below.
70%
Stage #1: With (THF)Li(TMP)Zn(tBu)2 In tetrahydrofuran at 25℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere
General procedure: [Li(TMP)Zn(tBu)2] 1 was made according to the literature procedure2 on a 0.4 mmol scale in THF solution. To this solution 2-methoxypyridine (0.042 mL, 0.4 mmol) was added and the resultant light orange reaction allowed to stir at room temperature for 2 hours. Next the solution was cooled to 0°C and quenched with I2 (508 mg, in 1 mL THF) and allowed to stir for 1 hour. Next a 10percent solution of Na2S2O3 was added until bleaching and the product extracted with DCM (3 x 1 mL). The combined organic extracts were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by SiO2 chromatography using Heptane:DCM as eluent (20:80-->40:60) to give 3-iodo2-methoxypyridine 2a as a colourless oil (87.1 mg, 92percent yield).
Reference：
[1] Tetrahedron, 2016, vol. 72, # 17, p. 2196 - 2205
[2] Tetrahedron, 1993, vol. 49, # 37, p. 8373 - 8380
[3] Tetrahedron Letters, 2011, vol. 52, # 36, p. 4590 - 4594
[4] Chemical Communications, 2014, vol. 50, # 85, p. 12859 - 12862
[5] Chemistry - A European Journal, 2013, vol. 19, # 24, p. 7944 - 7960
[6] Tetrahedron Letters, 1991, vol. 32, # 42, p. 5919 - 5922
Stage #1: With n-butyllithium; 2,4,6-trimethylphenyl bromide In tetrahydrofuran; pentane at -78 - 20℃; for 1 h; Stage #2: at -78 - 23℃; for 3 h; Stage #3: at -78℃; for 1 h;
Example 2 Preparation of 4-Methoxypyridine-3-carboxaldehyde tert-Butyllithium (90.6 mL, 154 mmol ; 1.7 M in pentane) was added via cannula to a stirred solution of tetrahydrofuran (380 mL) under an atmosphere of nitrogen at room temperature. The reaction mixture was cooled to-78 °C before adding 2-bromomesitylene (11.3 mL, 74.1 mmol) dropwise. The reaction mixture was allowed to stir for 1 hour at-78 °C. To the reaction mixture at-78 °C was added 4- methoxypyridine (5.79 mL, 57 mmol) dropwise, and the resulting mixture was stirred at- 23 °C for 3 hours. The reaction mixture was then re-cooled to-78 °C and dimethylformamide (6.62 mL, 85.5 mmol) was added and stirring was continued for 1 hour at-78 °C. The reaction mixture was quenched slowly at-78 °C with saturated aqueous sodium chloride solution (100 mL) and allowed to warm to room temperature slowly. To the reaction mixture was added diethyl ether (200 rnL) and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150 mL) and the combined organic layers were dried over potassium carbonate (20 g). The potassium carbonate was removed by filtration and washed with diethyl ether (100 mL) and the solvent removed under reduced pressure. The resulting crude 4-methoxy-3- pyridinecarboxaldehyde was purified by column chromatography (SiO2, 5: 95 ethanol: ethyl acetate) to give 4.79 g of the title intermediate as a yellow solid (61 percent yield; >98percent purity by'H NMR).
47.6%
Stage #1: With 2,4,6-trimethylphenyl bromide; tert.-butyl lithium In tetrahydrofuran at -78 - 20℃; for 3 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere
To a solution of t-butyllithium in THF (1.7 M, 9.7 mL, 16.5 mmol, 2.1 eq) in THF (40 mL) maintained at -78 °C was added 2-bromomesitylene (1.6 g, 8.0 mmol, 1.3 eq) dropwise. The resulting solution was stirred for 1 h at -78 °C, then 4-methoxypyridine (681 mg, 0.63 mL, 6.2 mmol) was added and the mixture was warmed to -20 °C in an ice-salt bath. After stirring for 3 h at -20 °C, the mixture was cooled back to -78 °C and DMF (1.17 g, 16.0 mmol, 2.0 eq) was added. The reaction mixture was stirred for 1 h, quenched with brine at -78 °C and extracted with diethyl ether (3 × 100 mL). The combined organic extracts were dried over K2CO3, filtered and evaporated to yield a crude oil that was purified by silica gel chromatography using 1:1 EtOAc:hexanes to yield 405 mg (47.6percent) of product as a pale yellow oil: Rf 0.25 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3)δ 10.43 (s, 1H), 8.87 (s, 1H), 8.62 (d, 1H), 6.92 (d, 1H), 4.1 (s, 3H).
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 1, p. 39 - 41
[2] Tetrahedron Letters, 2000, vol. 41, # 24, p. 4777 - 4780
[3] Patent: WO2005/42514, 2005, A2, . Location in patent: Page/Page column 25
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 419 - 434
[5] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[6] Tetrahedron Letters, 1988, vol. 29, # 7, p. 773 - 776
[7] Patent: WO2009/156462, 2009, A2, . Location in patent: Page/Page column 126-127
[8] Biochemistry, 2010, vol. 49, # 49, p. 10421 - 10439
17
[ 620-08-6 ]
[ 576-83-0 ]
[ 594-19-4 ]
[ 68-12-2 ]
[ 82257-15-6 ]
Yield
Reaction Conditions
Operation in experiment
61%
Stage #1: at -78℃; for 1 h; Stage #2: at -78 - 23℃; for 4 h;
TERT-BUTYLLITHIUM (90.6 mL, 154 mmol; 1.7 M in pentane) was added via cannula to a stirred solution of tetrahydrofuran (380 mL) under an atmosphere of nitrogen at room temperature. The reaction mixture was cooled to-78°C before adding 2-bromomesitylene (11.3 mL, 74.1 mmol) dropwise. The reaction mixture was allowed to stir for 1 hour at- 78°C. To the reaction mixture at-78°C was added 4-methoxypyridine (5.79 ML, 57 mmol) dropwise, and the resulting mixture was stirred AT-23°C for 3 hours. The reaction mixture was then re-cooled to-78°C and DIMETHYLFORMAMIDE (6.62 mL, 85.5 mmol) was added and stirring was continued for 1 hour AT-78°C. The reaction mixture was quenched slowly AT-78°C with saturated aqueous sodium chloride solution (100 mL) and allowed to warm to room temperature slowly. To the reaction mixture was added diethyl ether (200 mL) and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150 mL) and the combined organic layers were dried over potassium carbonate (20 g). The potassium carbonate was removed by filtration and washed with diethyl ether (100 mL) and the solvent removed under reduced pressure. The resulting crude 4-methoxy-3- pyridinecarboxaldehyde was purified by column chromatography (SiO2, 5: 95 ethanol: ethyl acetate) to give 4.79 g of the title intermediate as a yellow solid (61percent yield; >98percent purity by'H NMR). Analytical Data : HNMR (300 MHz, CDCL) 8 10.43 (s, 1H, CHO), 8.87 (s, 1H, ArH), 8.63 (d, 1H, J= 6, ARH), 6.92 (d, 1H, J= 6, ART), 3.98 (s, 3H, CH30).
Stage #1: With phenyl chloroformate In tetrahydrofuran at -40℃; for 0.25 h; Stage #2: at -40 - 20℃; for 0.5 h;
A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40°C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40°C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40°C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20°C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47percent) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine in 20 mL tetrahydrofuran was cooled to -40°C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75percent) of the title compound. ISMS: m/e = 346 (M+H)
General procedure for methylation of compounds in solvent-free system
General procedure: To a round bottle flask containing 1 (2 mmol) was added methyl iodide (10 mmol; 5 equiv.) and the mixture was stirred at room temperature or refluxed overnight. The reaction was monitored by TLC. After completion, the resulting precipitate was separated by filtration and purified by recrystallization.
With ammonium formate; silica gel; zinc In methanol at 20℃; for 0.166667h; chemoselective reaction;
95%
With carbon dioxide; water; iron at 100℃; for 10h; Autoclave; Green chemistry; chemoselective reaction;
93%
With methyloxorhenium(V)(2-(mercaptomethyl)thiophenolate) triphenylphosphine; tetrabutylammomium bromide; triphenylphosphine In water; benzene at 20℃; for 3h;
91%
Stage #1: 4-methoxypyridine N-oxide With bis(pinacol)diborane In acetonitrile at 70℃; for 5h; Inert atmosphere;
Stage #2: With ethylenediamine In acetonitrile at 20℃; for 1h;
90%
With 1,1,2,2-tetrabutyl-1,2-dichloro distannane In tetrahydrofuran for 1h; Heating;
86%
With cerium(III) chloride heptahydrate; zinc In methanol at 20℃; for 3.5h;
85%
With phosphorus trichloride for 0.333333h;
81%
With ammonium chloride In methanol Heating;
80%
With Lawessons reagent In benzene at 20℃; for 1h;
79%
With N,N,N,N,N,N-hexamethylphosphoric triamide; 1,1,1,2,2,2-hexamethyldisilane; methyllithium In tetrahydrofuran 1.) -78 deg C, 20 min, 2.) room temperature, 12 h;
78%
With benzyl alcohol at 120℃; for 6h; Inert atmosphere; Schlenk technique; chemoselective reaction;
77%
With tetraethylammonium hexafluorophosphate In water; acetonitrile at 80℃; Inert atmosphere; Electrolysis;
3. General Procedure for the Electrochemical Deoxygenation Reactions
General procedure: A 10 mL three-necked round-bottomed flask was charged with the N-heteroaromatic N-oxide(0.30 mmol, 1.0 equiv) and Et4NPF6 (0.06 mmol, 0.2 equiv). The flask was then equipped with a condenser, a reticulated vitreous carbon (100 PPI, ~65 cm2 cm-3, 1.2 cm x 1.0 cm x 0.8cm) anode and a Pb plate (1.0 cm x 1.0 cm) cathode, and flushed with argon. MeCN and H2O (4:1, 10.0 mL) were added. The electrolysis was carried out at 80 °C using a constant current of 10 mA until complete consumption of the substrate (monitored by TLC or 1H NMR). The reaction mixture was concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with ethyl acetate/hexane to give the desired product.
76%
With iron; acetic acid at 100℃; for 4h;
69%
With lithium tetrafluoroborate In water; acetonitrile at 20℃; for 4h; Electrochemical reaction; Inert atmosphere;
45%
With sulfuric acid; zinc at 98℃; for 16h;
4-Methoxypyridine (3)
To a solution of 45.0 g (0.360 mol) of 4-methoxypyridine-Noxide(Olin) in 1.5 L of 2M H2SO4 was added over 135 min 90.0 g (1.38 mol) of zincdust. The solution was heated at 98 C for 16 h before it was cooled and basified withconcentrated NH4OH. Decanting and filtering the aqueous solution from unreacted zincand extraction with ether gave, after drying over anhydrous K2CO3 and concentrationin vacuo, a cloudy yellow oil. Distillation at H2O aspirator pressure gave 17.6 g (45%)of 3 as a colorless oil: bp 150-160 C with external heating from a heat gun (lit.17 bp185 C (712 Torr)).
44%
In water at 35℃; for 161h; baker's yeast;
With methanol; nickel Hydrogenation;
With palladium on activated charcoal; ethanol Hydrogenation;
With iron; acetic acid
With triphenylphosphine at 270℃;
With hydrogen In ethanol
With 5% Pd on active carbon; hydrogen In methanol
With sulfuric acid; zinc Yield given;
With hydrogen In ethanol
With hydrogen
99 % Spectr.
With triphenylphosphine In toluene at 80℃; for 3h;
With tetrahydroxydiboron In N,N-dimethyl-formamide at 25℃; for 0.2h; Sealed tube;
61 %Chromat.
With hydrogen In decane at 100℃; for 1h; Schlenk technique; Sealed tube;
With [Re(tert-Bu2-(2-phenyl pyridine))(CO)3Cl]; N-ethyl-N,N-diisopropylamine In [D3]acetonitrile at 20℃; UV-irradiation;
Stage #1: 4-methoxypyridine With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -25℃; for 0.5h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; n-heptane; ethylbenzene at -25 - 20℃; for 16.25h;
2.C 4-methoxy-3-triisopropylsilyl-pyridine
Preparation 2 4-methoxy-3-triisopropylsilyl-pyridine The synthetic procedure used in this preparation is outlined in Scheme C. To a solution of 4-methoxypyridine (14.0 g, 128.3 mmol) in THF (150 mL) was added at -25° C., 2.0M LDA in heptane/THF/ethyl benzene (76.9 mL, 153.9 mmol). The mixture was stirred at -25° C. for 30 minutes. Triisopropylsilyl chloride (35.3 mL, 166.8 mmol) was added and the mixture was stirred at -25° C. for 15 minutes and then at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The extract was washed with water, brine dried over MgSO4 and concentrated to dryness. Purification of the residue by flash chromatography (hexane/ethylacetate 8:2-1:1) gave 4-methoxy-3-triisopropylsilanyl-pyridine (7.56 g, 22%) as an orange solid.
22%
Stage #1: 4-methoxypyridine; triisopropylsilyl chloride With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -25℃; for 0.5h;
Stage #2: triisopropylsilyl chloride In tetrahydrofuran; n-heptane; ethylbenzene at -25 - 20℃; for 16.25h;
2.C 4-methoxy-3-triisopropylsilyl-pyridine
Preparation 2 4-methoxy-3-triisopropylsilyl-pyridine The synthetic procedure used in this preparation is outlined in Scheme C. Following the procedure reported in JACS 1994, 116, 4719-4728, to a solution of 4-methoxypyridine (14.0 g, 128.3 mmol) in THF (150 mL) was added at -25° C., 2.0M LDA in heptane/THF/ethyl benzene (76.9 mL, 153.9 mmol). The mixture was stirred at -25° C. for 30 minutes. Triisopropylsilyl chloride (35.3 mL, 166.8 mmol) was added and the mixture was stirred at -25° C. for 15 minutes and then at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The extract was washed with water, brine dried over MgSO4 and concentrated to dryness. Purification of the residue by flash chromatography (hexane/ethylacetate 8:2-1:1) gave 4-methoxy-3-triisopropylsilanyl-pyridine (7.56 g, 22%) as an orange solid.
Example 2 Preparation of 4-Methoxypyridine-3-carboxaldehyde tert-Butyllithium (90.6 mL, 154 mmol ; 1.7 M in pentane) was added via cannula to a stirred solution of tetrahydrofuran (380 mL) under an atmosphere of nitrogen at room temperature. The reaction mixture was cooled to-78 C before adding 2-bromomesitylene (11.3 mL, 74.1 mmol) dropwise. The reaction mixture was allowed to stir for 1 hour at-78 C. To the reaction mixture at-78 C was added 4- methoxypyridine (5.79 mL, 57 mmol) dropwise, and the resulting mixture was stirred at- 23 C for 3 hours. The reaction mixture was then re-cooled to-78 C and dimethylformamide (6.62 mL, 85.5 mmol) was added and stirring was continued for 1 hour at-78 C. The reaction mixture was quenched slowly at-78 C with saturated aqueous sodium chloride solution (100 mL) and allowed to warm to room temperature slowly. To the reaction mixture was added diethyl ether (200 rnL) and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150 mL) and the combined organic layers were dried over potassium carbonate (20 g). The potassium carbonate was removed by filtration and washed with diethyl ether (100 mL) and the solvent removed under reduced pressure. The resulting crude 4-methoxy-3- pyridinecarboxaldehyde was purified by column chromatography (SiO2, 5: 95 ethanol: ethyl acetate) to give 4.79 g of the title intermediate as a yellow solid (61 % yield; >98% purity by'H NMR).
47.6%
To a solution of t-butyllithium in THF (1.7 M, 9.7 mL, 16.5 mmol, 2.1 eq) in THF (40 mL) maintained at -78 C was added 2-bromomesitylene (1.6 g, 8.0 mmol, 1.3 eq) dropwise. The resulting solution was stirred for 1 h at -78 C, then 4-methoxypyridine (681 mg, 0.63 mL, 6.2 mmol) was added and the mixture was warmed to -20 C in an ice-salt bath. After stirring for 3 h at -20 C, the mixture was cooled back to -78 C and DMF (1.17 g, 16.0 mmol, 2.0 eq) was added. The reaction mixture was stirred for 1 h, quenched with brine at -78 C and extracted with diethyl ether (3 × 100 mL). The combined organic extracts were dried over K2CO3, filtered and evaporated to yield a crude oil that was purified by silica gel chromatography using 1:1 EtOAc:hexanes to yield 405 mg (47.6%) of product as a pale yellow oil: Rf 0.25 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) delta 10.43 (s, 1H), 8.87 (s, 1H), 8.62 (d, 1H), 6.92 (d, 1H), 4.1 (s, 3H).
A flask is charged with 1.7M tert-butyllithium in pentane (47.1 ml_, 80.1 mmol) and THF (20 ml_), and cooled to -78 0C. 2-Bromomesitylene (6.0 ml_, 39 mmol) is added dropwise. The mixture is stirred for 1 h, and 4-methoxypyridine (3.0 ml_, 30 mmol) is added dropwise. The mixture is warmed to -23 C and stirred for 3 h. The mixture is <n="128"/>cooled again to -78 C and dimethylformamide (3.5 ml_, 45 mmol) is added. After 1 h, brine (50 ml.) is added to the mixture at -78 C and warmed to room temperature. The mixture is extracted with ether and the combined organic layer is dried over Na2SO4. Concentration followed by silica gel chromatography eluting with a O to 6% methanol- dichloromethane gradient gives 4-methoxy-pyridine-3-carbaldehyde. 1H NMR (400 MHz, CDCI3) delta ppm 4.01 (s, 3 H), 6.94 (d, J=5.8 Hz, 1 H), 8.65 (d, J=5.8 Hz, 1 H), 8.90 (s, 1 H), 10.46 (s, 1 H).
With hydrogenchloride Yield given. Multistep reaction;
Stage #1: 4-methoxypyridine; methylmagnesium chloride; phenyl chloroformate In tetrahydrofuran at -30℃; for 0.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
A solution of 4-methoxypyridine (3.57 mmol) in THF (5 mL) is cooled to -30° C. MeMgCl solution (3.93 mmol) is then added followed by dropwise addition of ClCO2Ph (3.93 mmol). The resulting reaction mixture is stirred for 30 min at -30° C., and acidified with 10% HCl solution. The mixture is allowed to warm up to room temperature and is extracted with ethyl acetate. Combined organic phase is successively washed with saturated bicarbonate and brine solution, and dried over anhydrous Na2SO4. The crude product obtained after evaporation of the solvent is purified by flash column chromatography. Resulting colorless oily product solidifies upon standing. LC/MS: m/z=232 (MH+) 1H NMR (CDCl3) δ: 1.38, 2.40, 2.97, 4.87, 5.44, 7.15-7.46, 7.87.
With L-Selectride; In tetrahydrofuran; for 2h;Reflux; Inert atmosphere;
General procedure: Toa solution of 1 (1.00 mmol) in THF (7.0 mL) was added L-selectride(1 M in THF, 3.0 mL, 3.00 mmol, 3 equiv) under an argonatmosphere. After being refluxed and monitored by TLC, thereaction mixture was quenched with MeOH and evaporated invacuo. The residue was purified by silica gel column chromatographyto give the desired compound 2.
With dihydrogen peroxide; acetic acid for 24h; Reflux;
88%
With dihydrogen peroxide; acetic acid In water for 24h; Reflux; Inert atmosphere;
14 Synthesis of 4-methoxypyridine 1-oxide
Synthesis of 4-methoxypyridine 1-oxide [0320] To a stirred solution of 4-methoxypyridine (5 g, 45.87 mmol) in acetic acid (25 mL) under argon atmosphere was added a 30%> hydrogen peroxide solution (4.2 mL) at RT. The reaction mixture was stirred at reflux for 24 h. After the consumption of the starting materials (monitored by TLC), the volatile components were removed in vacuo to afford 4- methoxypyridine 1-oxide (5 g, 88%>) as a yellow liquid. LC-MS: 125.9 (M+l); (column; Eclipse XDB C-18 (150 4.6 mm, 5.0 μιη); RT 5.02 min. 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 5% MeOH:CH2Cl2 (R 0.1).
88%
With dihydrogen peroxide In acetic acid for 24h; Reflux; Inert atmosphere;
129 Synthesis of 4-methoxypyridine 1-oxide
To a stirred solution of 4-methoxypyridine (5 g, 45.87 mmol) in acetic acid (25 mL) under an argon atmosphere was added a 30% hydrogen peroxide solution (4.2 mL) at room temperature. The reaction mixture was stirred at reflux for 24 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo to afford 4-methoxypyridine 1-oxide (5 g, 88%) as a yellow liquid. LCMS: 125.9 (M+1); (column; Eclipse XDB C-18 (150 × 4.6 mm, 5.0 µm); RT 5.02 min. 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 5% MeOH: CH2Cl2 (Rf: 0.1).
88%
With dihydrogen peroxide; acetic acid In water for 24h; Inert atmosphere; Reflux;
129 Synthesis of 4-methoxypyridine 1-oxide
Synthesis of 4-methoxypyridine 1-oxide To a stirred solution of 4-methoxypyridine (5 g, 45.87 mmol) in acetic acid (25 mL) under an argon atmosphere was added a 30% hydrogen peroxide solution (4.2 mL) at room temperature. The reaction mixture was stirred at reflux for 24 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo to afford 4-methoxypyridine 1-oxide (5 g, 88%) as a yellow liquid. LCMS: 125.9 (M+1); (column; Eclipse XDB C-18 (150*4.6 mm, 5.0 μm); RT 5.02 min. 0.05% Aq TFA: ACN; 1.0 mL/min); TLC: 5% MeOH: CH2Cl2 (Rf: 0.1).
87%
With dihydrogen peroxide; methyltrioxorhenium(VII) In dichloromethane; water at 24℃; for 15h;
65.4%
With fluorosulfonyl fluoride; dihydrogen peroxide; potassium carbonate In methanol at 23 - 32℃; Sealed tube;
10 Example 10: Synthesis of 4-methoxypyridine nitroxide
Add 4 mL of methanol to a 25 mL round-bottom two-neck flask, then add 4-methoxypyridine (0.5mmol, 54.6mg), then add 30% H2O2 (6.0eq., 0.3mL), potassium carbonate (4.0eq., 276.4 mg), using two straight piston straight-bending joints at the same time, while connecting the balloon with a hose, while injecting SO2F2 gas, stirring and reacting at room temperature of 2332 for 2040min under sealed conditions. After the reaction, the solid potassium carbonate was removed by filtration, dried with anhydrous sodium sulfate to remove water and filtered again. The solvent was concentrated to obtain a crude product, which was finally separated and purified by column chromatography to obtain 40.3 mg of 4-methoxypyridine nitroxide. The rate is 65.4%.
65%
With fluorosulfonyl fluoride; dihydrogen peroxide; potassium carbonate In methanol; water at 20℃;
General procedure: The optimal reaction conditions for tertiary aminesoxidation are as follows: 30% H2O2 (6.0 equiv), K2CO3 (4.0 equiv),SO2F2 (balloon), MeOH, room temperature for 20-40 min.
With dihydrogen peroxide In acetic acid for 24h; Heating;
With 3,3-dimethyldioxirane In acetone at 23℃;
With dihydrogen peroxide In acetic acid
2.2 2-2.
2-2. Preparation of 4-Methoxypyridine N-Oxide (17) 4-Methoxylpyridine (10.0 ml, 85.9 mmol) was dissolved in glacial acetic acid (50.0 ml), 30% hydrogen peroxide (8.4 ml, 85.9 mmol) was added, and the reaction mixture was refluxed for 24 h. The reaction mixture was concentrated in vacuo and the resulting red gummy liquid, 17 (9.6 g, 76.5 mmol, 89%), was used without further purification.
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃;
In dichloromethane
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃;
2. Synthesis of Substrates
General procedure: Compounds 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1o are synthesized by the following procedure. 3-Chloroperoxybenzoic acid (15.0 mmol, 1.5 equiv) was added to a solution of N-heteroaromatic compound (10.0 mmol, 1.0 equiv) in CH2Cl2 (40 mL) at 0 °C. The resulting reaction mixture was stirred at RT until complete consumption of the heterocycle (monitored by TLC). The solvent was evaporated under reduced pressure. The residue was further diluted with H2O (30 mL) and extracted with ethyl acetate (3 x 30 mL).The combined organic solution was washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the product.
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃;
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 24h;
Stage #1: 4-methoxypyridine With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 24h;
Stage #2: With potassium carbonate In dichloromethane; water at 20℃; for 0.5h;
With dihydrogen peroxide; acetic acid for 24h; Reflux;
32.1
Step 1: [0440] To a stirred solution of 4-methoxy pyridine (10.0 g, 9.17 mmol) in acetic acid (50 mL) was added H2O2 (30%, 25 mL) and the RM was heated to reflux for 24 h. Then the RM was cooled to RT and evaporated to afford 4-Methoxy-pyridine 1-oxide (9.0 g). This crude material was used in the next step with out any purification.
General procedure: To a stirred, cooled (0 C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2-3 mL) were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min later, ZnCl2TMEDA[51] (0.13 g, 0.50 mmol). The mixture was stirred for 15 min at 0 C before introduction of the substrate (1.0 mmol) at 0-10 C. After 2 h at room temperature, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was stirred overnight before addition of an aqueous saturated solutionof Na2S2O3 (4 mL) and extraction with AcOEt (320 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by chromatographyon silica gel (the eluent is given in the product description) led to the compounds described below.
70%
General procedure: [Li(TMP)Zn(tBu)2] 1 was made according to the literature procedure2 on a 0.4 mmol scale in THF solution. To this solution 2-methoxypyridine (0.042 mL, 0.4 mmol) was added and the resultant light orange reaction allowed to stir at room temperature for 2 hours. Next the solution was cooled to 0C and quenched with I2 (508 mg, in 1 mL THF) and allowed to stir for 1 hour. Next a 10% solution of Na2S2O3 was added until bleaching and the product extracted with DCM (3 x 1 mL). The combined organic extracts were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by SiO2 chromatography using Heptane:DCM as eluent (20:80-->40:60) to give 3-iodo2-methoxypyridine 2a as a colourless oil (87.1 mg, 92% yield).
4-methoxypyridine (1.1 g, 10.1 mmol) was dissolved in methanol (20 mL), sodium borohydride(410 mg, 10.8 mmol)was added at -78 C, stirred for 30 min, then benzyl chloroformate (1.9 g) , 11.1 mmol), reacted at -78 C for 1hour.After adding 60 mL of water at -60 C, the temperature was raised to 20 C, and extracted with ethyl acetate (50 mL × 3). The product was 2.16 g, yield: 92.3%.
60%
To a 2.0 L reactor, 4-methoxypyridine (C1, 45.0 g, 412.39 mmol, 1.0 eq) and methanol (900 ml.) were added. The mixture was cooled to -75 C with dry ice/acetone bath. A solution of benzyl chloroformate (73.86 g, 432.99 mmol, 1.05 eq) in THF (90 ml.) was charged dropwise while keeping IT < -70 C. The reaction was stirred for 1 hour to afford a white suspension at -70 C. Sodium borohydride (16.38 g, 432.99 mmol, 1.05 eq) was added in portions while keeping IT < -70 C. The reaction was stirred at -70 C for 2 hours. Water (200 g) was added and the cooling bath was removed. A solution of 36% hydrogen chloride (16.72 g, 164.95 mmol, 0.4 eq) in water (50 ml.) was added in 10 min at 0 - 5 C and stirred for 1 hour. Then 20% Na2CC>3 (85.5 g) was added to adjust pH = 7 while maintained IT < 5 C. Organic solvents were removed under vacuum. The resulting residue was extracted with dichloromethane (450 ml_). The dichloromethane phase was washed with 3wt% hydrogen chloride (151 ml.) and 3 wt% Na2C03 (151 ml_). After solvent exchange with MTBE, about 4 volume (180 ml) of the MTBE mixture was obtained. The mixture was heated to 50 C to afford a solution and then cooled to 45 C. Crystal seed of C6 was charged and the mixture was aged at 40 - 45 C for 7 hours. The mixture was cooled to 10 - 15 C in 3 hours. The white suspension was filtered and the wet cake was rinsed with cold MTBE (45 ml_). The cake was dried under vacuum at 40 - 50 C for 2 hours to afford C6 as a white powder (91.56 g, 60% yield). 1H NMR (400 MHz, CDCI3): d (ppm) = 7.85 (br. s, 1H), 7.37 - 7.43 (m, 5H), 5.43 (br. s, 1H), 5.26 (s, 2H), 4.05 (t, J=7.34 Hz, 2H), 2.54 - 2.58 (m, 2H).
Stage #1: 4-methoxypyridine; benzyl chloroformate With triethylamine In tetrahydrofuran at -40℃; for 0.333333h;
Stage #2: methylmagnesium bromide In tetrahydrofuran; diethyl ether at 20℃; for 2h; Inert atmosphere;
1.1
150 g of 4-methoxypyridine (1.375 mol) were dissolved in 1850 ml of tetrahydrofuran, 19 ml (1.375 mol) of triethylamine was added, and the temperature was reduced to minus 40 ° and then 235 g (1.375mmol) of Cbz-Cl after the completion of the drop, keep minus 40 °C 20 minutes, under nitrogen protection, A solution containing 3 mol / L methylmagnesium bromide in ether was added dropwise. After the reaction was complete, the reaction was allowed to proceed at room temperature for 2 hours. The reaction was complete by TLC. The reaction was quenched with 500 ml of IMol / L hydrochloric acid. Extracted three times with 300 ml of ethyl acetate, and the organic phases were combined, washed once with brine, dried over sodium sulfate and evaporatedto give 323.8 g of a reddish brown oil, l-Cbz-2-methyl-3,4-dihydro-4-piperidone in 96% yield, which was used in the next step without further purification.
94%
Stage #1: 4-methoxypyridine; methylmagnesium bromide; benzyl chloroformate In tetrahydrofuran at -25℃; for 4h;
Stage #2: With hydrogenchloride In tetrahydrofuran at 20℃; for 0.166667h; Further stages.;
94%
Stage #1: 4-methoxypyridine; methylmagnesium bromide; benzyl chloroformate In tetrahydrofuran at -25℃; for 4h;
Stage #2: With hydrogenchloride at 20℃; for 0.166667h; Further stages.;
58%
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: methylmagnesium bromide In tetrahydrofuran
I.1.9.1
To a solution of Compound 1 (10.9 g, 100 mmol) in THF (100 mL) was added CbzCI (17.6 g, 100 mmol), at 0 °C . The formed mixture was stirred for 10 minutes. Then C]MgBr (100 mL, 100 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was extracted with EtOAc (200 mL). The organic layer was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 4: 1) to give the desired product 2 (14.7 mg, 58 %).
50%
In tetrahydrofuran at -25℃; for 2h;
46%
Stage #1: 4-methoxypyridine; methylmagnesium bromide In tetrahydrofuran; toluene at -30℃; for 0.0833333h; Large scale;
Stage #2: benzyl chloroformate In tetrahydrofuran; toluene at -30 - 25℃; for 2.5h; Large scale;
4-methoxypyridine (796 g, 7.29 mole) was stirred in 8 L of anhydrous THF in a 20 L reactor. The reactor was cooled to -30 °C, then methyl magnesium bromide (5.1 L, 7.29 mole) was added as a 1.4 M solution in 3:1 toluene/THF was added via cannula one 800mL bottle at a time with 800 mls added over a 5 min time period. After the addition was complete and the reaction temperature was -30 °C, benzyl chloroformate (1244 g, 7.29 mole) was added dropwise over a 60 min period via addition funnel. The warmest temperature reached was 16 °C. After addition was complete the reaction was warmed to 25 °C and stirred for 1.5 hrs. The reaction was cooled to 0 °C and quenched with 4.0 L of 2 N HCl. 4 L of MTBE and brine was added and the layers separated. The temperature was now 25 °C. The aqueous phase was extracted with 2 x 2L of MTBE. The combined organics were washed with brine and dried over Na2SO4, filtered and concentrated to give the crude oil (1.67 kg). Chromatography using a Varian Metaflash 150 long (15 cm x 60 cm long 5 kilo silica) and eluting with10-35% EtOAc/Heptanes gave the product as an oil (823 g, 46%).
Stage #1: 4-methoxypyridine; benzyl chloroformate With triethylamine In tetrahydrofuran at -60 - -50℃;
Stage #2: methylmagnesium bromide In tetrahydrofuran; diethyl ether at -60 - 20℃;
1.1
Preparation 1; Racemic (5R7S),{5SJR)-1-{3-fluoroρhenyl}-7-methyl-1 ,8~diazasρiro[4,53dec- 3-eϖ-2-one (Pt )Step 1. SynthβsiiS of ....benzyl .....2-methyj^oxθr3,4rdjhydτQpyr|djϖe-1{2H)r carboxyJate^CCIJ, Benzyl chloroformate (235 g, 1.38 mol) was added drop-wise to a chilled solution of 4-methoxypyridine (150 g, 1.38 mol) and tnethylamine (19 mL, 0,137 mol) in anhydrous fetrahydrofuran (6 L), while keeping the temperature below -500C. A white precipitate formed After completion of the addition, the resulting suspension was stirred at -60CJC for 20 minutes. Methyl magnesium bromide (3,0 M in diethyl ether, 650 ml, 1.95 mol) was then added drop-wise at ~60"C - ~50"C. The reaction mixture was stirred at room temperature ohernight, at which time thin layer chromatography {petroleum ether/ethyl acetate = 1 :1) indicated that the reaction was complete. After quenching the reaction with 1 N aqueous hydrochloric acid (500 ml), the color of the reaction mixture became brown-black. The organic layer was separated and concentrated in vacuo, and the residue and the aqueous layer were extracted with ethyl acetate (2 x 2 L). The combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried oher sodium sulfate and ehaporated to dryness to gihe crude CI1 which was used in the next step without purification, YieSd: 1500 g, 4 batches.
Stage #1: 4-methoxypyridine; benzyl chloroformate With triethylamine In tetrahydrofuran at -78℃; for 0.183333h;
Stage #2: methylmagnesium bromide In tetrahydrofuran; toluene at -78 - 20℃; for 2h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; toluene at -10℃;
V
Intermediate V: (5S,7R)-(5S,7R)-l-(3-fluorophenyl)-4-imino-8-(3-isopropoxybenzyl)-7-methyl-l,3,5 triazaspiro[4.5]decan-2-one; 4-methoxypyridine (5.36 g, 49.1 mmol, 1.0 eq) was weighed into a 500 mL flask with a stir bar and septum. The flask was flushed with nitrogen, and THF (80 mL) was added, followed by triethylamine (0.70 mL, 5.0 mmol, 0.10 eq). The solution was stirred and cooled to -78 0C, at which point benzyl chloroformate (7.0 mL, 49.7 mmol, 1.01 eq) was added over 1 min, giving a large amount of white precipitate. An additional portion of THF (50 mL) was added to assist stirring. After stirring at - 78 0C for lOmin, a 1.4M solution of methyl magnesium bromide in toluene:THF (3:1) (50 mL, 70mmol, EPO 1.4equiv) was added over 1.5 min, causing most of the precipitate to go into solution. The cold bath was removed and the reaction was allowed to stir and warm to rt over 2h. The reaction was then cooled to - 10 0C in an ice salt bath, then quenched by addition of IH hydrochloric acid. The reaction was diluted with ether, and the aqueous layer removed. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to provide the desired enone, which was carried on directly to the next reaction.1H NMR (CDCW, 400 MHz) δ: 7.74(br s, IH), 7.38 (m, 5H), 5.31 (m, IH), 5.26 (s, 2H), 4.72 (br s, IH), 2.84 (dd, J=15.6, 7.3Hz, IH), 2.30 (d, J=15.6Hz, IH), 1.25 (br s, 3H). EI-MS m/z: 246 (M + H)+.
Stage #1: 4-methoxypyridine; methylmagnesium bromide In tetrahydrofuran; toluene at -30℃; for 0.0833333h;
Stage #2: benzyl chloroformate In tetrahydrofuran; toluene at -30 - 25℃; for 2.5h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; toluene at 0℃;
9.1
EXAMPLE 9; (5R,7S)-4-(cyclohexylamino)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8- triazaspiro[4.5]dec-3-en-2-one (R,S enantiomer of Example 4) 9-2; Step 1: Racemic Benzyl 2~methyl-4-oxo-3,4-dihydropyridme-l(2H)-carboxylate; 4-methoxypyridine (796g, 7.29 mole) was stirred in 8 L of anhydrous THF in a 20 L reactor. The reactor was cooled to -30° C, then methylmagnesium bromide (5.1 L, 7.29 mole) was added as a 1.4M solution in 3:1 toluene/THF was added via cannula one 80OmL bottle at a time with 80OmIs added over a 5 min time period. After the addition was complete and the reaction temperature was -30° C, benzyl chloroformate (1244g, 7.29 mole) was added dropwise over a 60 min period via addition funnel. The warmest temperature reached was 16° C. After addition was complete the reaction was warmed to 25° C and stirred for 1.5 hrs. The reaction was cooled to 0° C and quenched with 4.0L of 2 N HCl. 4L of MTBE and brine was added and the layers separated. The temperature was now 25° C. The aqueous phase was extracted with 2 x 2L of MTBE. The combined organics were washed with brine and dried over Na2SO4, filtered and concentrated to give the crude oil. Chromatography using a Varian Metaflash 150 long (15 cm x 60 cm long 5 kilo silica) and eluting with 10-35% EtOAc/Heptanes gave the product as an oil. lH NMR (400 MHz, CDC13) δ 7.85 (dd, J = 1.5, 8.2 Hz, IH), 7.38 (m, 6H), 5.31 (d, J = 12 Hz, IH), 5.27 (d, J = 12 Hz, IH), 4.74 (m, IH), 2.92(dd, J = 7, 17 Hz, IH), 2.26 (d, J = 17 Hz, IH), 1.21 (d, J = 7 Hz, 3H).LCMS observed mass = 202
Stage #1: 4-methoxypyridine; benzyl chloroformate With triethylamine In tetrahydrofuran at -50 - -10℃; for 1h;
Stage #2: methylmagnesium bromide In tetrahydrofuran; diethyl ether at -78 - 20℃; for 3h;
1.1
Step 1. Synthesis of benzyl 2-methyl-4-oxo-3,4-dihvdropyridine-1 (2/-/)- carboxylate (CD. Triethylamine (92.6 g, 0.915 mol) was added to a solution of 4- methoxypyridine (1 .00 kg, 9.16 mol) in tetrahydrofuran (12 L), and the solution was cooled to minus 50 °C. Benzyl chloroformate (1.58 kg, 9.26 mol) was added to the reaction mixture at minus 50 °C. A white precipitate formed; additional tetrahydrofuran (4 L) was added to the reaction mixture to assist in stirring. The reaction mixture was kept at minus 50 °C to minus 10 °C for 1 hour and cooled to minus 78 °C. A solution of methylmagnesium bromide in diethyl ether (3.0 M, 3.67 L, 1 1 mol) was added over 1 hour, while maintaining the reaction temperature at minus 78 °C. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. At this point, it was cooled to minus 10 °C and quenched with aqueous hydrochloric acid (2 N, 10 L). Ethyl acetate (15 L) was added, and the layers were separated. The organic layer was washed with aqueous sodium chloride solution (10 L), dried over sodium sulfate, filtered and concentrated to afford the crude product, which was used in the next step without purification. Yield: 1.90 kg, 7.75 mol, 85%. 1 H NMR (400 MHz, CDCI3) δ 7.75 (br d, J=7 Hz, 1 H), 7.30-7.45 (m, 5H), 5.34 (br d, J=8 Hz, 1 H), 5.28 (AB quartet, JAB=12.0 Hz, ΔγΑΒ=10.8 Hz, 2H), 4.69-4.70 (br m, 1 H), 2.86 (dd, J=16.5, 6.7 Hz, 1 H), 2.33 (br d, J=16.4 Hz, 1 H), 1.27 (d, J=6.8 Hz, 3H).
105 g
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -25℃; for 1h;
Stage #2: methylmagnesium bromide In tetrahydrofuran; diethyl ether at 20 - 40℃; for 0.5h;
11.4 Step 4: preparation of benzyl 2-methyl-4-oxo-2,3-dihydropyridine-1-carboxylate
To a stirred solution of 4-methoxypyridine (50.0 g, 458 mmol) in anhydrous THF (500 mL) was added a solution of benzyl chloroformate (50.0 g, 458 mmol) in anhydrous THF (400 mL) at -25 °C. After being stirred for 1 hr at the same temperature, the reaction mixture was cooled to - 40 °C, followed by drop- wise addition of methylmagnesium bromide (3.0 M in diethyl ether, 183 mL, 550 mmol). The cooling bath was removed and the resulting mixture was stirred at rt for 0.5 hr and then poured into 10 % aqueous HC1 (1 L). The resulting mixture was stirred at rt for 10 mins, and then extracted with EA (2 L) twice. The organic layers were combined and washed sequentially with saturated aqueous NaHC03 (1 L) and brine (1 L), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by column chromatography (eluting with PE/EA=10/1, v:v) to give benzyl 2-methyl-4-oxo-2,3-dihydropyridine-l-carboxylate (105 g) as a colorless oil.
420 g
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -25℃; for 1h;
Stage #2: methylmagnesium bromide In tetrahydrofuran; diethyl ether at -40 - 20℃; for 0.5h;
1.1; 2.1 Step 1: Preparation of benzyl 2-methyl-4-oxo-2,3-dihydropyridine-l-carboxylate
To a stirred solution of 4-methoxypyridine (50.0 g, 458 mmol) in anhydrous THF (500 mL) was added a solution of benzyl chloroformate (50.0 g, 458 mmol) in anhydrous THF (400 mL) at -25 °C. After being stirred for 1 hr at the same temperature, the reaction mixture was cooled to - 40 °C. Then to the cooled mixture was added drop-wise methylmagnesium bromide (3.0 M in diethyl ether, 183 mL, 550 mmol). After the addition, the cooling bath was removed. The resulting mixture was stirred at rt for 0.5 hr and then poured into 10 % aqueous HCl (1 L). The resulting mixture was stirred further at rt for 10 mins. The reaction was conducted at the same scale for 4 times. The resulting mixtures from 4 batched were combined, and then extracted with EA (2 L) twice. The organic layers were combined and washed sequentially with saturated aqueous NaHC03(1 L) and brine (1 L), dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by column chromatography (eluting with PE/EA=3/1, v:v) to give benzyl 2-methyl-4-oxo-2,3-dihydropyridine-l-carboxylate (420.0 g) as a colorless oil.
N-amino-4-methoxypyridin-1-ium 2,4-dinitrophenolate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
In dichloromethane; at 20℃; for 20h;
N-Amino-(4-methoxy)pyridinium-2,4-dinitrophenolate (C2a); A suspension of 11.4 ml (0.112 mol) 4-methoxypyridine and 24.6 g (0.124 mol) <strong>[17508-17-7]O-(2,4-dinitrophenyl)hydroxylamine</strong> in 371 ml dichloromethane was stirred for 20 hrs at room temperature. After addition of diethylether the precipitate was filtered off and dried in under reduced pressure. Yield: 34 g (99 %) yellow solid. Mp.: 140C. MS (EI): m/z 184 (M+1)+ C6H3N2O5; 124 (M-1)+ C6H9N2O. IR (KBr) v (cm-1): 3096; 1597; 1552; 1535; 1508; 1256; 739; 714. 1H NMR (DMSO-d6, 360 MHz) delta (ppm): 4.05 (s, 3H, OCH3); 6.36 (d, J = 9.8 Hz, 1 H, H-6 DNP); 7.52-7.54 (m, 2H, H-3/5 Pyr); 7.75 (br s, 2H, NH2); 7.81 (dd, J = 9.8 Hz, 3.2 Hz, 1H, H-5 DNP); 8.60 (d, J = 3.2 Hz, 1H, H-3 DNP); 8.65-8.67 (m, 2H, H-2/6 Pyr).
95%
In acetonitrile; at 40℃; for 24h;
4-Methoxy pyridine (3.8 ml, 0.037 mmol) and <strong>[17508-17-7]O-(2,4-dinitrophenyl)hydroxylamine</strong> (8.19 g, 0.041 mmol) were mixed in ACN. After sealing the reaction vessel, the reaction mixture was stirred at 400C for 24 hours, and then concentrated. The residue thus obtained was pulverized using Et2O, filtered, and dried in vacuo to give 2,4-dinitro-phenolate l-amino-4-methoxy-pyridinium as a bright orange solid (Hg, yield1H-NMR (300 MHz, DMSOd6): 4.04(s, 3H), 6.31(d, J=9.7 Hz, IH), 7.51(d, J=7.4 Hz, 2H), 7.75- 7.8 l(m, 3H), 8.58(d, J=3.2 Hz, IH), 8.65(d, /=7.5 Hz, 2H)
95%
In acetonitrile; at 40℃; for 24h;
4-Methoxy pyridine (3.8 ml, 0.037 mmol) and <strong>[17508-17-7]O-(2,4-dinitrophenyl)hydroxylamine</strong> (8.19 g, 0.041 mmol) were mixed in ACN. After sealing the reaction vessel, the reaction mixture was stirred at 40 C. for 24 hours, and then concentrated. The residue thus obtained was pulverized using Et2O, filtered, and dried in vacuo to give 2,4-dinitro-phenolate 1-amino-4-methoxy-pyridinium as a bright orange solid (11 g, yield 95%).1H-NMR (300 MHz, DMSO-d6): 4.04(s, 3H), 6.31(d, J=9.7 Hz, 1H), 7.51(d, J=7.4 Hz, 2H), 7.75-7.81(m, 3H), 8.58(d, J=3.2 Hz, 1H), 8.65(d, J=7.5 Hz, 2H)
Stage #1: p-trifluoromethylphenyl bromide With magnesium; ethylene dibromide In tetrahydrofuran
Stage #2: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -25 - -20℃; for 0.5h;
3.1
4-Trifluoromethyl bromobenzene (4.2ml, 30mmol) was added portionwise to magnesium turnings (0.729g, 30mmol) in dry THF (30ml), and two drops of 1 ,2-dibromoethane were added to initiate the reaction. The resulting brown solution was cooled to -25°C. 4-Methoxypyridine (3.0ml, 30mmol) was added followed by benzyl chloroformate (4.3ml, 30mmol). The reaction was stirred for 30 mins at -20°C then quenched with 2N HCl. After stirring for 10 mins the mixture was extracted with EtOAc (x3). The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-40% EtOAc/hexanes) to give the dihydropyridine (9.3Og, 83%). 1H NMR (500 MHz, CDCl3) δ: 2.77 (IH, d, J 16.6), 3.18 (IH, dd, J 7.7, 16.6), 5.20 (IH, d, J 12.0), 5.27 (IH, d, J 12.0), 5.42 (IH, d, J 8.3), 5.77 (IH, d, J 6.3), 7.24-7.37 (7H, m), 7.54 (2H, d, J 8.2), 8.00 (IH, m).
83%
Stage #1: p-trifluoromethylphenyl bromide With magnesium In tetrahydrofuran at -25℃;
Stage #2: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -20℃; for 0.5h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran for 0.166667h;
3.1
Intermediate 3: (+/-)-Methyl {(2R*,3S*)-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl} acetate ; Step 1: (+/-)-Benzyl 4-oxo-2-[4-(trifluoromethyl)phenyl]-3,4-dihydropyridine-l(2H)- carboxylate; 4-Trifluoromethyl bromobenzene (4.2ml, 30mmol) was added portionwise to magnesium turnings (0.729g, 30mmol) in dry TηF (30ml), and two drops of 1 ,2-dibromoethane were added to initiate the reaction. The resulting brown solution was cooled to -25°C. 4-Methoxypyridine (3.0ml, 30mmol) was added followed by benzyl chloroformate (4.3ml, 30mmol). The reaction was stirred for 30 mins at -20°C then quenched with 2N HCl. After stirring for 10 mins the mixture was extracted with EtOAc (x3). The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-40% EtOAc/hexanes) to give the dihydropyridine (9.3Og, 83%). 1H NMR (500 MHz, CDCl3) δ: 2.77 (IH, d, J 16.6), 3.18 (IH, dd, J 7.7, 16.6), 5.20 (IH, d, J 12.0), 5.27 (IH, d, J 12.0), 5.42 (IH, d, J 8.3), 5.77 (IH, d, J 6.3), 7.24-7.37 (7H, m), 7.54 (2H, d, J 8.2), 8.00 (IH, m).
Stage #1: 4-methoxypyridine; isopropylmagnesium bromide In tetrahydrofuran at -50 - -40℃; for 0.333333h;
Stage #2: isopropyl chloroformate In tetrahydrofuran at -50 - 20℃; for 2h;
Stage #3: With water In tetrahydrofuran
71.30
30). Synthesis of 4-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)- amino]-2,6-frans-diisopropyl-piperidine-1-carboxylic acid isopropyl ester (racemic); To a solution of 4-methoxypyridine (70 mmol, 7 ml) in THF (300 ml_) at -40 0C is added slowly 0.76 M THF solution of isopropyl magnesium bromide (76 mmol, 100 ml) via cannula under nitrogen. After stirred for 20 minutes at -50 0C, isopropyl chloroformate (73 mmol, 8.36 ml_) is added and resulted in slightly gray suspension. The mixture is allowed to warm to room temperature, and after stirring for additional 2 hrs, the reaction is quenched with 90 ml H2O and extracted with Et2O. The combined organic layer is washed three times with 50 ml of aq.1 N HCI. After washing with brine, the organic layer is dried over MgSO4, filtrated, and concentrated under reduced pressure to give 2-isopropyl-4-oxo-3,4-dihydro- 2H-pyridine-1-carboxylic acid isopropyl ester (15 g, 95%) which is used for next step without further purification. ESI-MS m/z: 226.04 [M+1]+, Retention time 1.84 min (condition A).
Stage #1: 4-methoxypyridine; benzyl chloroformate In toluene at -20℃; for 0.25h;
Stage #2: ethylmagnesium bromide In tetrahydrofuran; toluene for 1h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water; toluene
6
Synthesis of benzyl 2-ethyI-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (82). To a solution of 4-methoxylpyridine 81. (4.41 g, 40.5 mmol) in toluene (200 mL) at -20 °C was added CbzCI (5.7 mL, 40.5 mmol) in toluene (200 mL) dropwise. After 15 min, ethylmagnesium bromide (23 mL, 2M in THF, 46 mmol) was added dropwise. After 1 hr, 10% aqueous HCI (100 mL) was added and the mixture stirred overnight. The mixture was separated and the organic layer was washed with sat. NaHCO3 and brine. It was dried and concentrated to afford 82 (9 g, 36.4 mmol, 89.9%) that was used directly in the next reaction.
81%
Stage #1: 4-methoxypyridine; ethylmagnesium bromide; benzyl chloroformate In tetrahydrofuran
Stage #2: With hydrogenchloride at 20℃; for 0.166667h; Further stages.;
Stage #1: 4-methoxypyridine; benzyl chloroformate In toluene
Stage #2: ethylmagnesium bromide In tetrahydrofuran
Stage #3: With hydrogenchloride In water
24.8 g
Stage #1: 4-methoxypyridine; ethylmagnesium bromide; benzyl chloroformate In tetrahydrofuran at -23℃; for 0.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water at 15℃; for 0.333333h;
35.1 Step 1: preparation of benzyl 2-ethyl-4-oxo-2,3-dihydropyridine- 1-carboxylate
A mixture of 4-methoxypyridine (10 g, 91.7 mmol) and CbzCl (15.6 g, 91.7 mmol) in THF (100 mL) was cooled to -23°C. Then to the cooled mixture was added EtMgBr (30.6 mL, 91.7 mmol) dropwise. The resulting mixture was stirred at -23 °C for 30 mm, then poured into 10%HC1 and stirred further at 15 °C for 20 mm. The resulting mixture was extracted with MTBE (100 mL) for 3 times. The combined organic layer was washed with brine and concentrated in vacuo. The residue was further purified by flash column (eluting with PE/EA=1:1, v:v) to give benzyl 2-ethyl-4-oxo-2,3-dihydropyridine-1-carboxylate (24.8 g) as a green oil.
16.1; 19.1
Benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine-l(2H)-carboxylate was prepared according to the method in (Tetrahedron Lett., 1986, 27, 4549-4552) using 4-methoxypyridine (29.8 mL, 290 mmol), benzyl chloroformate (50.0 mL, 350 mmol) and 4-fluorophenyl magnesium bromide (0.8 M solution in TΗF), (450 mL, 0.36 mmol), to yield (81 g, 86% yield) of the title compound. MS (EI) for Ci9Hi6FNO3: 326 (MH+).
86%
In tetrahydrofuran
20.1
Benzyl 2-(4-fluorophenyl)-4-oxo-3 ,4-dihydropyridine- 1 (2H)-carboxylate was prepared according to the method in (Tetrahedron Lett., 1986, 27, 4549-4552) using A- methoxypyridine (29.8 mL, 290 mmol), benzyl chloroformate (50.0 mL, 350 mmol) and A- fluorophenyl magnesium bromide (0.8 M solution in THF), (450 mL, 0.36 mmol), to yield (81 g, 86% yield) of the title compound. MS (EI) for Ci9Hi6FNO3: 326 (MH+).
86%
In tetrahydrofuran
20.1
Benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine- 1 (2H)-carboxylate was prepared according to the method in (Tetrahedron Lett., 1986, 27, 4549-4552) using 4- methoxypyridine (29.8 mL, 290 mmol), benzyl chloroformate (50.0 mL, 350 mmol) and 4- fluorophenyl magnesium bromide (0.8 M solution in THF), (450 mL, 0.36 mmol), to yield (81 g, 86% yield) of the title compound. MS (EI) for C19Hi6FN03: 326 (MH+).
74%
Stage #1: 4-methoxypyridine; 4-flourophenylmagnesium bromide In tetrahydrofuran; diethyl ether at -30 - -20℃; for 0.5h;
Stage #2: benzyl chloroformate In tetrahydrofuran; diethyl ether at -50 - -15℃;
47%
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -20 - 20℃; for 1h; Inert atmosphere;
Stage #2: 4-flourophenylmagnesium bromide In tetrahydrofuran at -20℃; for 1h;
161.1 benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine-1 (2H)-carboxylate
To a solution of 4-methoxypyridine (10.0 g, 91.63 mmol) in anhydrous THF (250 mL) at -20 °C was slowly added benzyl carbonochloridate (17.01 mL, 119 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. (4-fluorophenyl)magnesium bromide in THF (1.0 M, 146.61 mL, 146.61 mmol) at -20 °C was added to the mixture and stirred at the same temperature for an additional 1 h. The mixture was quenched with 3% aq. hydrogen chloride (40 mL) and extracted with toluene (40 mL). The organic layer was washed with 4.5% aq. NaHCO3 (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Isopropyl alcohol (15 mL) was added to the mixture and stirred at room temperature for 1 h. The solid was isolated by filtered. The filter cake was washed with isopropyl alcohol (5 mL x 3) and dried in vacuo to give the title compound (14 g, 47%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.06 (d, J= 8.4 Hz, 1H), 7.42 - 7.30 (m, 5H), 7.27 - 7.22 (m, 2H),7.20 - 7.12 (m, 2H), 5.74 (d, J= 7.2 Hz, 1H), 5.36 - 5.17 (m, 3H), 3.32 - 3.20 (m, 1H), 2.62 (d, J16.8 Hz, lH). LCMS MJZ (M+H) 326.
47%
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -20 - 20℃; for 1h; Inert atmosphere;
Stage #2: 4-flourophenylmagnesium bromide In tetrahydrofuran at -20℃; for 1h; Inert atmosphere;
2.1 benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine- 1 (211)-carboxylate
To a solution of 4-methoxypyridine (10.0 g, 91.63 mmol) in anhydrous THF (250 mL) at -20 °C was slowly added benzyl carbonochloridate (17.01 mL, 119 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. (4-fluorophenyl)magnesium bromide in THF (1.0 M, 146.61 mL, 146.61 mmol) at -20 °C was added to the mixture and stirred at the same temperature for an additional 1 h. The mixture was quenched with 3% aq. hydrogen chloride (40 mL) and extractedwith toluene (40 mL). The organic layer was washed with 4.5% aq. NaHCO3 (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Isopropyl alcohol (15 mL) was added to the mixture and stirred at room temperature for 1 h. The solid was isolated by filtered. The filter cake was washed with isopropyl alcohol (5 mL x 3) and dried in vacuo to give the title compound (14 g, 47%) as a white solid. ‘HNMR (400 MI-Tz, DMSO-d6) 8.06 (d, J= 8.4 Hz, 1H), 7.42 - 7.30 (m, 5H), 7.27 - 7.22 (m, 2H), 7.20 -7.12 (m, 2H), 5.74 (d, J 7.2 Hz, 1H), 5.36-5.17 (m, 3H), 3.32-3.20 (m, 1H), 2.62 (d,J= 16.8 Hz, 1H).LCMS MIZ (M+H) 326.
In tetrahydrofuran at 0℃;
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -23℃; for 0.833333h;
Stage #2: 4-flourophenylmagnesium bromide In tetrahydrofuran at -20℃; for 1h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water at 20℃;
16
A solution of benzyl chloroformate (48.7 mL) in dry THF (60 mL) was added to a solution of 4-methoxypyridine (25 mL) in dry THF (900 mL) previously cooled at -23° C. under a nitrogen atmosphere. [0281] The mixture was stirred at -23° C. for 50 minutes, then p-fluorophenyl magnesium bromide (1M in THF-48.7 mL) was added. The solution was stirred at -20° C. for 1 hour, then it was warmed up to 20° C. and a 10% hydrochloric acid solution (560 mL) was added. The aqueous layer was extracted with AcOEt (1000 mL). [0282] The organic extract was washed with 5% sodium hydrogen carbonate solution (600 mL) and brine (600 mL) then partially concentrated in vacuo. CH (200 mL) was added drop-wise over 1 hour at 20° C. and the resulting mixture was stirred at r.t. for 10 minutes, then at 0° C. for 1.5 hours. The solid obtained was filtered off to give the title compound as a white solid (51.6 g). [0283] NMR (d6-DMSO): 8 (ppm) 8.05 (d, 1H); 7.4-7.3 (m, 5H); 7.24 (dd, 2H); 7.15 (t, 1H); 5.73 (d, 1H); 5.29 (d, 1H); 5.24 (dd, 2H); 3.25 (dd, 1H); 2.62 (d, 1H); 2.26 (s, 3H). [0284] MS (EI/+): m/z=325 [M]+.
With silver(I) acetate; palladium diacetate; Trimethylacetic acid; at 140℃; for 18h;Inert atmosphere;
Under a nitrogen atmosphere, palladium acetate (11.2 mg, 0.05mmol), 1, 10 - phenanthroline (49.6 mg, 0.25mmol), silver acetate (250 mg, 1.5mmol), (1 ml) was suspended in pyridine (51.1 mg, 0.5mmol) pivalic acid, stirred at 140 °C 26 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration over celite, methylene chloride (10 ml) was washed. The filtrate was concentrated under reduced pressure, 1, 1, 2, 2 - tetrachloroethane (15.8 mul, 0.15mmol) was added as an internal standard substance was obtained residue,1H NMR (88percent) yield was calculated based oxidizing agent. (Methylene chloride/hexane=5/95) to give a residue for a thin layer chromatography analysis, the subject compound (quantitative value NMR 89percent, 80percent isolated yield) was obtained as a white powder 93.1 mg.
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: phenylmagnesium bromide In tetrahydrofuran at -78 - 20℃; for 1h;
28.1 Benzyl 4-oxo-2-phenyl-3,4-dihydropyridine-1(2H)-carboxylate
To a solution of 4-methoxypyridine (10.0 g, 91.6 mmol) in THF (500 mL) was added dropwise benzyl chloroformate (15.6 g, 91.6 mmol) at -78 °C and stirred for 30 mm. Then phenylmagnesiumbromide in THF (110 mL, 2M, 110 mmol) was added slowly to the mixture at -78°C. The mixture was stirred at -78 °C for 30 mm, warmed up to room temperature and stirred for 30 mm. Then it was quenched by HCl (2M, 400 mL) and the organic solvent was removed under reduced pressure. The residue was filtered to afford the desired product (28 g, 99.4%) as a white solid. LCMS (ESI) mz: 330.1 [M+Na]+.
In tetrahydrofuran at -60℃;
30.1 Reference Example 30
Reference Example 30 (1) In 40 ml of tetrahydrofuran was dissolved 5.46 g of 4-methoxypyridine, and added dropwise thereto was 55 ml of a 1M phenylmagnesiumbromide-tetrahydrofuran solution under nitrogen atmosphere [AT-60°C] of below. Subsequently, added dropwise thereto was a solution of 10.24 g of benzyl chloroformate in 50 ml of tetrahydrofuran, and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 120 ml of a [5%] aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated. To the residue was added diisopropyl ether and the precipitates were collected by filtration, to give 8.51 g of 1-benzyloxycarbonyl-4-oxo-2- phenyl-3,4-dihydro-2H-pyridine. MS (m/z): 308 [[M++1]] (2) In 260 ml of acetic acid was dissolved 8.48 g of the compound of the above (1), added thereto was 3.61 g of zinc powder, and the mixture was stirred at room temperature for 18 hours. Subsequently, 1.8 g of zinc powder was added and after stirring the mixture at room temperature for 6 hours, 1.8 g of zinc powder was further added thereto and the mixture was stirred at [50°C] for 3 days. After insoluble matters were removed by filtration, the filtrate was concentrated under. reduced pressure. The residue was extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried and concentrated, to give 8.54 g of 1-benzyloxycarbonyl-4-oxo-2-phenylpiperidine. MS (m/z): 310 [[M++1]] (3) In 15 ml of tetrahydrofuran was dissolved 619 mg of the compound of the above (2), and added dropwise thereto was 4 ml of a 1M diisobutylalminiun hydride solution in toluene under nitrogen atmosphere [AT-60°C] or below. The mixture was stirred for 10 minutes. To the reaction mixture was added 667 pi of a 6M aqueous hydrochloric acid solution, and the mixture was concentrated. To the residue was added distilled water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2: [1-1] : 1), to give 553 mg of 1-benzyloxycarbonyl-4- hydroxy-2-phenylpiperidine. MS (m/z): 312 [[M++1]] (4) In a mixed solution of 14 ml of toluene and 1.6 ml of dichloromethane was added 511 mg of the compound of the above (3), and added thereto was 319 mg of 1, [1'-] carbonyldiimidazole, and the mixture was stirred at [60°C] for 2 hours. Added thereto was [396] pi of ethanolamine, and the mixture was stirred at [60°C] for 3 hours. To the reaction mixture was added distilled water and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone=9: [1~2] : 1), to give 462 mg of 1-benzyloxycarbonyl-4- (2-hydroxyethylaminocarbonyloxy)-2- phenylpiperidine. MS (m/z): 399 [[M++1]] (5) In 10 ml of methanol was dissolved 430 mg of the compound of the above (4), and added thereto was 30 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 5 days under hydrogen atmosphere. Insoluble matters were removed by filtration and the filtrate was concentrated, to give 348 mg of [4- (2-] hydroxyethylaminocarboxyoxy) -2-phenylpiperidine as shown in Table 134 below.
Step 1. To a cooled solution of THF (100 mL) containing 4-methoxypyridine (3.5 g, 32.5 mmol) (prepared according to Synthesis 1989, 645, at -15 C. was added 2,2,2-trichloroethyl chloroformate (4.5 mL, 32.7 mmol). After 30 min. at -15 C., 2M PhMgCl in THF (19.5 mL, 39 mmol) was added and the mixture was stirred at -15 C. for 30 min. followed by 30 min. at RT. The reaction mixture was quenched with 10% aq. HCl (100 mL), added to brine (200 mL) and partitioned. The aqueous layer was extracted with Et2 O (50 mL). The combined organic layers were dried with MgSO4 and concentrated to give 11.4 g of compound 3 shown above as a light tan solid.
Stage #1: 1-bromo-4-(trifluoromethyl)benzene With magnesium In tetrahydrofuran at -25℃;
Stage #2: 4-Methoxypyridine; benzyl carbonochloridate In tetrahydrofuran at -25 - -20℃; for 0.5h;
1
4-Trifluoromethyl bromobenzene (4.2ml, 30mmol) was added portionwise to magnesium turnings (0.729g, 30mmol) in dry THF (30ml), and two drops of 1 ,2-dibromoethane were added to initiate the reaction. The resulting brown solution was cooled to -250C. 4-Methoxypyridine (3.0ml, 30mmol) was added followed by benzyl chloroformate (4.3ml, 30mmol). The reaction was stirred for 30 mins at -20C then quenched with 2N HCl. After stirring for 10 mins the mixture was extracted with EtOAc (x3). The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-40% EtOAc/hexanes) to give the dihydropyridine (9.3Og, 83%). 1H NMR (500 MHz, CDCl3) d: 2.77 (IH, d, J 16.6), 3.18 (IH, dd, J 7.7, 16.6), 5.20 (IH, d, J 12.0), 5.27 (IH, d, J 12.0), 5.42 (IH, d, J 8.3), 5.77 (IH, d, J 6.3), 7.24-7.37 (7H, m), 7.54 (2H, d, J 8.2), 8.00 (IH, m).
83%
Stage #1: 4-Methoxypyridine; 1-bromo-4-(trifluoromethyl)benzene; benzyl carbonochloridate With magnesium In tetrahydrofuran at -25 - -20℃; for 0.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; lithium hydroxide monohydrate for 0.166667h;
78.1
4-Trifluoromethyl bromobenzene (4.2ml, 30mmol) was added portionwise to magnesium turnings (0.729g, 30mmol) in dry TΗF (30ml), a couple of drops of 1,2-dibromoethane was added to initiate the reaction. The resulting brown solution was cooled to -250C. 4-Methoxypyridine (3.0ml, 30mmol) was added followed by benzyl chloroformate (4.3ml, 30mmol). The reaction was stirred for 30 mins at -200C then quenched with 2N HCl. After stirring for 10 mins the mixture was extracted with EtOAc (x3). The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-40% EtOAc/hexanes) to give the dihydropyridine (9.3Og, 83%). 1H NMR (500 MHz, CDCl3) δ: 2.77 (IH, d, J 16.6), 3.18 (IH, dd, J 7.7, 16.6), 5.20 (IH, d, J 12.0), 5.27 (IH, d, J 12.0), 5.42 (IH, d, J 8.3), 5.77 (IH, d, J 6.3), 7.24-7.37 (7H, m), 7.54 (2H, d, J 8.2), 8.00 (IH, m).
83%
Stage #1: 4-Methoxypyridine; 1-bromo-4-(trifluoromethyl)benzene; benzyl carbonochloridate With magnesium In tetrahydrofuran at -25 - -20℃; for 0.5h;
Stage #2: With hydrogenchloride In tetrahydrofuran; lithium hydroxide monohydrate for 0.166667h;
78.1
4-Trifluoromethyl bromobenzene (4.2ml, 30mmol) was added portionwise to magnesium turnings (0.729g, 30mmol) in dry TΗF (30ml), a couple of drops of 1,2-dibromoethane was added to initiate the reaction. The resulting brown solution was cooled to -250C. 4-Methoxypyridine (3.0ml, 30mmol) was added followed by benzyl chloroformate (4.3ml, 30mmol). The reaction was stirred for 30 mins at -200C then quenched with 2N HCl. After stirring for 10 mins the mixture was extracted with EtOAc (x3). The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-40% EtOAc/hexanes) to give the dihydropyridine (9.3Og, 83%). 1H NMR (500 MHz, CDCl3) δ: 2.77 (IH, d, J 16.6), 3.18 (IH, dd, J 7.7, 16.6), 5.20 (IH, d, J 12.0), 5.27 (IH, d, J 12.0), 5.42 (IH, d, J 8.3), 5.77 (IH, d, J 6.3), 7.24-7.37 (7H, m), 7.54 (2H, d, J 8.2), 8.00 (IH, m).
Methyl magnesium bromide (3.0 M, ether solution, 7.6 ml) was dropped into the THF (25 ml) solution of 4-methoxypyridine (2.50 g) with maintaining a temperature between -30 C and -20C. After its mixture was stirred for 10 minutes, benzyl chloroformate (3.90 g) was dropped into it with maintaining a temperature between -30 C and -20C. After the mixture was stirred for 30 minutes, it was warmed to room temperature. The mixture was poured into 10 % hydrochloric acid, and was then subjected to extraction with ethyl acetate. Its organic layer was washed with a brine, and was then dried with magnesium sulfate. Its solvent was evaporated under reduced pressure to produce an oily matter (5.34 g), which was directly used for the next reaction.
A solution of 1.0 gm (9.16 mMol) 4-methoxypyridine in 15 mL tetrahydrofuran was cooled to -41°C. To this solution was added dropwise 12.6 mL (18.32 mMol) potassium tri(isopropoxy)borohydride (1.45 M in tetrahydrofuran). The resulting mixture was stirred for 15 minutes and then 1.58 gm (10.07 mMol) phenyl chloroformate were added and the resulting mixture stirred -41°C. After 2 hours, 7.19 gm (7.0 mMol) potassium tert-butoxide were added. After stirring at -41°C for 30 minutes, the reaction mixture was allowed to warm to room temperature. After 2 hours at room temperature, the reaction mixture was cooled again to -41°C and was then treated with saturated aqueous oxalic acid. The resulting mixture was extracted well with diethyl ether. The organic extracts were combined and washed sequentially with saturated aqueous oxalic acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 10-40percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 1.07 gm of the title compound as a white solid. MS(ES+): m/e = 198.2.
Reference Example 32 To 1.74 g of magnesium and 40 ml of tetrahydrofuran was added trace of iodine, and under nitrogen atmosphere and at room temperature, 10.4 g of 2-bromo-5-fluorotoluene was added dropwise spending 40 minutes. The reaction mixture was refluxed under heating for an hour, to prepare Grignard reagent solution. To the prepared Grignard reagent solution was added dropwise 5.46 g of 4-methoxypyridine spending 20 minutes, [AT-40C] under nitrogen atmosphere. After completion of dropwise addition, the mixture was stirred at a temperature [FROM-40C] to-30C for 30 minutes. Subsequently, the reaction mixture was cooled down [TO-40C,] and while keeping the temperature [AT-40C] or below, added dropwise thereto was a solution of 12 g of di-tert- butyldicarbonate in 20 ml of tetrahydrofuran. After completion of dropwise addition, the temperature of the reaction mixture was slowly raised. [AT-15C,] ice was added thereto and the mixture was stirred for 20 minutes. Further added thereto was an aqueous citric acid solution and the mixture was stirred at room temperature for 40 minutes. Tetrahydrofuran was removed by distillation and to the resultant residue was added ethyl acetate, and extracted twice. The combined organic layers were washed with saturated brine, dried and concentrated under reduced pressure. To the residue was added diisopropyl ether, and the obtained crystals were collected by filtration with diisopropyl ether, to give 11.9 g of 1-tert-butoxycarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxo-3,4-dihydro-2H-pyridine as shown in Table 134 below.
1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-oxo-3,4-dihydro-2H-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Reference Example 29 (1) In 15 ml of N, N-dimethylformamide were dissolved 3.94 g of [2-BROMO-5-FLUOROPHENOL] and 1.62 ml of methyl iodide, slowly added thereto was 5.08 g of potassium carbonate under ice-cooling. The mixture was stirred at room temperature for 3 hours. After insoluble matters were removed by filtration, distilled water was added to the filtrate, and the mixture was extracted with diethyl ether and washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography- (hexane : ethyl acetate=19: [1-9] : 1), to give 4.10 g of [1-BROMO4-FLUORO-2-] methoxybenzene. MS (m/z): 204/206 [(M++L) O] (2) To 7 ml of tetrahydrofuran were added 486 mg of magnesium and trace of iodine, and dropped thereto was a solution of 4.10 g of the compound of the above [(1)] in 16 ml of tetrahydrofuran, to prepare Grignard reagent. To the solution, a solution of 1.96 g of 4-methoxypyridine in 7 ml of tetrahydrofuran was added dropwise under nitrogen atmosphere [AT-60C] or below. Subsequently, a solution of 3.75 g of benzyl chloroformate in 18 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 40 ml of a 5% aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2: [1-1] : 2), to give 3.15 g of [1-BENZYLOXYCARBONYL-2- (4-FLUORO-2-METHOXYPHENYL)-4-OXO-] 3,4-dihydro-2H-pyridine. MS (m/z): 356 [[M++1]] (3) In a mixed solution of 79 ml of ethanol and 6 ml of tetrahydrofuran was dissolved 3.15 g of the compound of the above (2), and added thereto was 706 mg of sodium borohydride and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and distilled water was added to the residue. The mixture was extracted with chloroform, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone=19: [1-9] : 1), to give 1.62 g of [1-BENZYLOXYCARBONYL-2- (4-FLUORO-2-] methoxyphenyl)-4-hydroxypiperidine. MS (m/z): 360 [[M++1]] (4) In 20 ml of toluene was dissolved 1.62 g of the compound of the above (3), added thereto was 876 mg of 1, [1'-] carbonyldiimidazole and the mixture was stirred at [60C] for an hour. Added thereto was 1.09 ml of ethanolamine, and the mixture was stirred at [60C] for 6 hours. To the reaction mixture was added distilled water and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone=4: [1-1] : 1), to give 1.81 g of [1-BENZYLOXYCARBONYL-2- (4-FLUORO-2-METHOXYPHENYL)-4- (2-] hydroxyethylaminocarbonyloxy) piperidine. MS (m/z): 447 [[M++L]] [(5)] In 20 ml of methanol was dissolved 1.81 g of the compound of the above (4), and added thereto was 90 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for an hour under hydrogen atmosphere. After insoluble matters were removed by filtration, the filtrate was concentrated. To the residue was added diethyl ether and precipitates were collected by filtration, to give 1.30 g of [2- (4-FLUORO 2-METHOXYPHENYL)-4- (2-] hydroxyethylaminocarbonyloxy) piperidine as shown in Table 134 below.
A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 mL) was dropped over 30 minutes, into a mixture of magnesium (525 mg) and iodine (1 crystal) in dry THF (5 mL) previously heated to 70 C. under a nitrogen atmosphere. The mixture was stirred at 70 C. for 1.5 hours, then allowed to cool to r.t. [0196] A solution of (-)-mentyl chloroformate (3.53 mL) in dry THF (15 mL) was added to a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL) previously cooled to -78 C. under a nitrogen atmosphere. After 15 minutes, the solution containing the 4-fluoro-2-methyl-phenyl magnesium bromide was added drop-wise, and the mixture was stirred at -78 C. for 1 hour. The reaction was quenched by the addition of 1M hydrochloric acid solution (20 mL), warmed to r.t. and stirred at 23 C. for 30 minutes. After extraction with AcOEt (2×150 mL), the combined organic extracts were washed with brine (50 mL), dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/THF/toluene 8:1:1) to give: [0197] 1. intermediate 6a (3.44 g-yellow oil) [0198] 2. intermediate 6b (530 mg-white solid). [0199] Intermediate 6a [0200] T.I.c.: CH/THF/toluene 7:2:1, Rf=0.59. [0201] IR (nujol, cm-1): 1718 and 1675 (CO). [0202] NMR (d6-DMSO): 6 (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95 (m, 1H); 5.68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m, 11H). [0203] Intermediate 6b [0204] M.p.: 117-120 C. [0205] T.I.c.: CH/THF/toluene 7:2:1, Rf=0.56. [0206] IR (nujol, cm-1): 1718 and 1669 (CO). [0207] NMR (d6-DMSO): 6 (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, 1H); 5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m, 3H); 1.2-0.7 (m, 8H); 0.51-0.34 (bs, 6H):
Stage #1: 4-methoxypyridine With O-(2,4-dinitrophenyl)hydroxylamine In acetonitrile at 40℃; for 18h;
Stage #2: propynoic acid ethyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h;
4.1.1. Synthesis of ethyl pyrazolo[1,5-a]pyridine-3-carboxylates 3
General procedure: These were made using MSH or DNPH as detailed below, unless otherwise stated. A fresh solution of MSH23 in CH2Cl2 (1 equiv) was added to the substituted pyridine (1 equiv) in CH2Cl2 (10 mL) at 0 °C. After 2 h, the solvent was removed in vacuo. Alternatively, a solution of DNPH12 (1 equiv) and the substituted pyridine (1 equiv) in MeCN (40 mL) was heated at 40 °C for 18 h. The solvent was removed in vacuo. The method continues by taking the residue from either method in dry DMF (8 mL), and then ethyl propiolate (1 equiv) and K2CO3 (2 equiv) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient, unless otherwise stated) gave the pyrazolo[1,5-a]pyridine.
23%
Stage #1: 4-methoxypyridine With O-(2,4-dinitrophenyl)hydroxylamine at 40℃; for 18h;
Stage #2: propynoic acid ethyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;
9.9.1
Step 9.1 : A solution of 0-(2,4-dinitrophenyl)hydroxylamine (741 mg, 2.2 mmol) [C. Legault et a/., J. Org. Chem. 2003, 68(18), 7119] and 4-methoxypyridine (1: X = OMe) (244 mg, 2.24 mmol) were heated at 40 0C for 18 h. The solvent was removed in vacuo, then the residue was taken up in dry DMF (10 mL). Ethyl propiolate (0.27 mL, 2.7 mmol) and K2CO3 (6180 mg, 4.47 mmol) were added, and the suspension stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with hexanes: EtOAc 9:1 to 4:1) gave ethyl 5-methoxypyrazolo[1 ,5-a]pyridine-3-carboxylate (27) as a yellow solid (114 mg, 23%). 1H NMR δ (400 MHz, CDCI3) 8.31 (d, J 7.5 Hz, 1H), 8.28 (S, 1 H), 7.43 (d, J 2.8 Hz, 1H), 6.61 (dd, J 7.5, 2.8 Hz, 1 H), 4.37 (q, J 7.1 Hz, 2H), 3.93 (S1 3H), 1.41 (t, J 7.1 Hz, 3H). LCMS (APCI+) 221 (MH+, 100%).
Stage #1: 4-methoxypyridine; acetyl chloride With trimethylsilyl trifluoromethanesulfonate In tetrahydrofuran at -78 - 20℃;
Stage #2: phenylmagnesium bromide In tetrahydrofuran at -78℃; for 1h;
4.B.i; 4.B.ii
Synthesis of 4-phenyl-3-(piperidin-1 -ylmethyl)-4,5,6,7-tetrahydroisoxazolo[4,5- c]pyridine (AM7) Step (i) and step (ii): 1-Acetyl-2-phenyl-2,3-dihydropyridin-4(1 H)-oneTo a solution of 4-methoxypyridine (45.871 mmol, 1.0 eq.) in dry tetrahydrofuran (200 ml) was added acetyl chloride (45.871 mmol, 1.0 eq.), followed by TMSOTf (45.871 mmol, 1.0 eq.) at room temperature. The reaction mixture was cooled to -780C and stirred for 1 h. PhMgCI (3.0 eq., 2M solution in THF) was added dropwise to the reaction mixture at -780C and mixture was allowed to stir at same temperature for additional 1 h. The reaction mixture was quenched with 2M HCI and warmed to room temperature. The mixture was extracted with ethyl acetate, dried over sodium sulfate and solvent was evaporated under reduced pressure to get crude product which was purified by column chromatography. Yield: 65%
TERT-BUTYLLITHIUM (90.6 mL, 154 mmol; 1.7 M in pentane) was added via cannula to a stirred solution of tetrahydrofuran (380 mL) under an atmosphere of nitrogen at room temperature. The reaction mixture was cooled to-78C before adding 2-bromomesitylene (11.3 mL, 74.1 mmol) dropwise. The reaction mixture was allowed to stir for 1 hour at- 78C. To the reaction mixture at-78C was added 4-methoxypyridine (5.79 ML, 57 mmol) dropwise, and the resulting mixture was stirred AT-23C for 3 hours. The reaction mixture was then re-cooled to-78C and DIMETHYLFORMAMIDE (6.62 mL, 85.5 mmol) was added and stirring was continued for 1 hour AT-78C. The reaction mixture was quenched slowly AT-78C with saturated aqueous sodium chloride solution (100 mL) and allowed to warm to room temperature slowly. To the reaction mixture was added diethyl ether (200 mL) and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150 mL) and the combined organic layers were dried over potassium carbonate (20 g). The potassium carbonate was removed by filtration and washed with diethyl ether (100 mL) and the solvent removed under reduced pressure. The resulting crude 4-methoxy-3- pyridinecarboxaldehyde was purified by column chromatography (SiO2, 5: 95 ethanol: ethyl acetate) to give 4.79 g of the title intermediate as a yellow solid (61% yield; >98% purity by'H NMR). Analytical Data : HNMR (300 MHz, CDCL) 8 10.43 (s, 1H, CHO), 8.87 (s, 1H, ArH), 8.63 (d, 1H, J= 6, ARH), 6.92 (d, 1H, J= 6, ART), 3.98 (s, 3H, CH30).
A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47%) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine in 20 mL tetrahydrofuran was cooled to -40C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75%) of the title compound. ISMS: m/e = 346 (M+H)
Stage #1: 4-methoxypyridine; phenylmagnesium bromide In tetrahydrofuran at -25℃; for 0.0833333h; Inert atmosphere;
Stage #2: 6-bromohomoveratric acid at -25℃;
Stage #3: With hydrogenchloride; water at -25 - 20℃;
1.F 1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one
Example 1 1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one The synthetic procedure used in this preparation is outlined in Scheme F. To a stirring solution of 4-methoxypyridine (336 mg, 3.08 mmol) in THF (7 mL) at -25° C. was added phenylmagnesium bromide (3M in ether, 1.13 mL, 3.39 mmol) under Ar atmosphere. After 5 minutes a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (904 mg, 3.08 mL) in THF (2 mL) was added slowly. The mixture was stirred at -25° C. for 90 minutes. 2N HCl was added at -25° C., and the mixture was allowed to warm to room temperature and was stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexane/ethyl acetate gradient) gave 1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one (742 mg, 57%). MS (M+H) 431.
Stage #1: 4-methoxypyridine; phenethylmagnesium chloride In tetrahydrofuran at -20 - -15℃; Inert atmosphere;
Stage #2: methyl chloroformate In tetrahydrofuran at -10℃; for 1h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
3.1
4-Methoxypyridine (9.30 mL, 91.64 mmol) was dissolved in THF (150 mL) under nitrogen atmosphere and cooled to -15° C. Phenethylmagnesium chloride (93 mL, 93.47 mmol, 1 M in THF) was added dropwise and a suspension was formed. After stirring at -20° C. for 30 minutes methyl chloroformate (9.23 mL, 119.13 mmol) was added over 1 minute. Stirring was continued at -10° C. for 1 h and then HCl (10%) was added. The mixture was stirred for 20 minutes and then concentrated. The aqueous phase was extracted with ether (×2) and the organic phase was dried (MgSO4) and evaporated to yield methyl 4-oxo-2-phenethyl-3,4-dihydropyridine-1(2H)-carboxylate (21.7 g, 82%) as an oil. 1H NMR (600 MHz, cdcl3) δ 1.98 (m, 2H), 2.54 (m, 2H), 2.69 (m, 1H), 2.81 (m, 1H), 3.83 (s, 3H), 4.62 (m, 1H), 5.33 (m, 1H), 7.12-7.38 (m, 5H), 7.72 (m, 1H); MS m/z 260 (M+H)+.
To cone. H2SO4 (5 mL) chilled in an ice bathm is added 4-methoxypyridine (0.5 mL, 4.9 mmol) dropwise over a 20 s period. Cone. Fuming nitric acid (5 mL) is added, and the reaction mixture is heated at 70 °C for 2.5 days. This mixture is cooled to rt, and then is poured into ice. Soild K2CO3 is added until the pH of the mixture is basic. The mixture is partitioned between H20 and EtOAc. The two layers is separated, and the aqueous layer is extracted with EtOAc once. The combined organic layers are washed with H2O and brine, dried over MgS04, filtered, and concentrated in vacuo to yield 0.7 g (92percent) of the product a yellow powder. 1H NMR (CDC13, 300 MHz) delta 9.02 (s, 1H), 8.65 (d, J= 5.8, 1 H), 7.04 (d, J = 5.9, 1H), 4.05 (s, 3H). LC Rt: 0.5 min; LCMS m/z 155 (M+l, 100percent).
Stage #1: 4-methoxypyridine With (THF)Li(TMP)Zn(tBu)2 In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
Stage #2: bromochlorobenzene With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In tetrahydrofuran at 100℃; for 0.166667h; Inert atmosphere; Microwave irradiation;
Synthesis of 4-(4-chlorophenyl)-3-methoxypyridine 3b
General procedure: [Li(TMP)Zn(tBu)2] 1 was made according to the literature procedure2 on a 0.4 mmol scale in THF solution. To this solution 3-methoxypyridine (0.042 mL, 0.4 mmol) was added and the resultant light orange reaction allowed to stir at room temperature for 2 hours. This solution was then transferred to a THF (1 mL) solution of PdCl2(dppf) (29.3 mg, 10 mol %) and 1-bromo-4-chlorobenzene (76.6 mg, 0.4 mmol) to give a heterogeneous red solution. The reaction mixture was then reacted in the microwave at 100°C for 10 minutes. The reaction was then quenched with saturated NH4Cl solution (2 mL) and extracted with DCM (3 x 1 mL). The organic fractions were combined and dried by passing through a phase separator cartridge with a hydrophobic frit and the solvent removed under reduced pressure. The residue was purified by column chromatography using a 4 g C18 silica cartridge and eluent Acetonitrile + 0.1 % formic acid:H2O + 0.1 % formic acid (5:95 to 95:5) to give compound 3b as an off white solid 26.5 mg (30% yield)
Stage #1: 4-methoxypyridine With n-butyllithium; CuCl2*TMEDA; 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran; hexanes at 20℃; for 2h; Inert atmosphere;
Stage #2: o-chlorobenzoyl chloride In tetrahydrofuran; hexanes at 0 - 20℃; for 16h; Inert atmosphere;
57%
Stage #1: 4-methoxypyridine With N,N,N,N,-tetramethylethylenediamine; 2,2,6,6-tetramethylpiperidinyl-lithium; copper(l) chloride In tetrahydrofuran at 20℃; for 2h; Schlenk technique; Inert atmosphere;
Stage #2: o-chlorobenzoyl chloride In tetrahydrofuran at 20℃; Schlenk technique; Inert atmosphere;
5.2. General procedure 1: deprotonation using the lithium-copper base prepared from CuCl (1 equiv) and LiTMP (2 equiv) before trapping with an aroyl chloride
General procedure: A stirred cooled (0 °C) solution of LiTMP prepared at 0 °C in THF (6 mL) from 2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and BuLi (1.6 M hexanes solution, 10 mmol) was treated with TMEDA (0.77 mL, 5.0 mmol) and CuCl (495 mg, 5.0 mmol). The mixture was stirred for 15 min at 0 °C before introduction of the required substrate (5 mmol). After 2 h at rt, a solution of the required aroyl chloride (10 mmol) in THF (3 mL) was added. The mixture was stirred at rt or 60 °C overnight before addition of a 1 M aqueous solution of NaOH (20 mL) and extraction with Et2O (220 mL). After washing the organic phase with an aqueous saturated solutionof NH4Cl (10 mL) and drying over anhydrous Na2SO4, the solvent was evaporated under reduced pressure, and the product was isolated after purification by flash chromatography on silica gel (the eluent is given in the product description).
With sodium hydroxide; In acetonitrile; at 20℃; for 69h;Reflux;
Method B (refPreviewPlaceHolderScheme 2). A mixture of 1 (1.93 g, 10 mmol) and 4-methoxypyridine (1.3 g, 12 mmol) in dry acetonitrile (35 ml) was stirred a room temperature for 24 h, followed at reflux for 45 h. After cooling to room temperature the suspension was left overnight. The precipitate was collected by filtration, washed successively with acetonitrile (3 .x. 1.5 ml), water (5 .x. 3 ml) and acetonitrile (3 .x. 2 ml), the dried at temperatures gradually increasing to 100 °C. Yield 1.7 g (68percent), m.p. 234-236 °C; IR and 1H NMR were identical with authentic sample 9 described in method A.
4-Methoxy-1-(2-methoxy-2-oxoethyl)pyridinium Bromide(9a)
Methyl bromoacetate (1.4 g, 9.17 mmol) was added to a solutionof 4-methoxypyridine (1.0 g, 9.17 mmol) in acetone (4 mL).The mixture was stirred at rt for 24 h then filtered, washed withEt2O, and dried under reduced pressure to give a white solid;yield: 1.92 g (80%); mp 120-122 °C. 1H NMR (300 MHz, DMSOd6):δ = 8.92 (d, J = 7.3 Hz, 2 H), 7.74 (d, J = 7.4 Hz, 2 H), 5.61 (s, 2 H), 4.12 (s, 3 H), 3.74 (s, 3 H). 13C NMR (75 MHz, DMSO-d6): δ =171.7, 167.8, 147.9, 113.7, 58.9, 58.8, 53.5. HRMS (ESI+): m/z [M- Br]+ calcd for C9H12NO3: 182.0812; found: 182.0819.
In ethyl acetate Reflux;
32
Reference Example 32 7-Methoxyindolizine-1-carbonitrile To a solution of 4-methoxypyridine (3.0 g) in ethyl acetate (30 mL) was added methyl bromoacetate (4.6 g), and the mixture was heated under reflux overnight. After cooling to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give 4-methoxy-1-methoxycarbonylmethylpyridinium bromide (7.0 g).
With bis(1,5-cyclooctadiene)nickel(0); sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride; In toluene; at 100℃; for 12h;Inert atmosphere; Sealed vessel;
General procedure: Ni(cod)2(27.5 mg, 0.1 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (85.0 mg, 0.2 mmol), sodium tert-butoxide (288.3 mg, 3.0 mmol), 6-methoxyquinoline (1,79.6 mg, 0.5 mmol), morpholine (2, 217.8 mg, 2.5 mmol) and toluene (1.5 mL) were added to a 10 mL sample vial with a Teflon-sealed screwcap in a glovebox filled withnitrogen. After the cap was closed, the vial was stirred at 100 C for 12 h. After cooling to room temperature, the crude mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc = 1:1) to give 4-(quinolin-6-yl)morpholine (3, 58.9 mg, 74 %) as a white solid.
1,1'-(phenyl-λ3-iodanediyl)-bis(4-methoxypyridinium)-bis(trifluormethansulfonate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In dichloromethane at 23℃; for 0.1h; Inert atmosphere;
90%
In dichloromethane at 20℃; for 0.25h; Inert atmosphere;
1,1'-(Phenyl-λ3-iodanediyl)-bis(4-methoxypyridinium)-bis(trifluormethansulfonate) (18)
18 was synthesized according to the procedure of Wei and Seubert [42]. All operations were carried out in a dry reaction vessel in anhydrous solvent under argon atmosphere. (Diacetoxyiodo)benzene (3.0 g, 9.3 mmol) was dissolved in dichloromethane (100 mL) under argon atmosphere.Trimethylsilyl trifluormethansulfonate (3.4 mL, 18.6 mmol) was added dropwise to this solution at ambient temperature. A solution of 4-methoxypyridine (1.9 mL, 2.03 g, 18.6mmol) in dihloromethan (15 mL) was dropped in and the reaction mixture was stirred for 15 min at room temperature. The solvent was removed under diminished pressure and anhydrous diethyl ether (100 mL) was given to the residue.The mixture was stirred for 1 h under argon, the precipitated solid was filtered off and washed with dry diethyl ether (40mL). The product was dried in vacuo (3 x 10-1 mbar, 16 h).Yield: 6.06 g (90 %) off white solid. 1H-NMR (CD3CN) δ= 4.04 (s, 6H, 2 x OCH3), 7.30 (d, J = 6.5 Hz, 4H, H-3,5pyridine), 7.36 (t, J = Hz, 7.5 H, H-2,6 Ph), 7.56 (t, J = 7.5Hz, 1H, H-4 Ph), 7.85 (d, J = Hz, 2H, H-3,5 Ph), 8.43 (d, J =7.5 Hz, 4H, H-2,6 pyridine). 13C-NMR (CDCl3) δ = 58.9(OCH3), 94.8 (C-1 Ph), 114.0 (C-3,5 pyridine), 122.1 (q, JC,F= 320.7 Hz, CF3SO3), 128.8 (C-4 Ph), 131.6 (C-3,5 Ph),138.5 (C-2,6 Ph), 144.0 (C-2,6 pyridine), 173.8 (C-4pyridine). 19F-NMR (CDCl3): δ = - 79.3 C20H19F6IN2O8S2 (720.40).
74%
In dichloromethane at 20℃; for 0.166667h; Inert atmosphere;
68%
Stage #1: trimethylsilyl trifluoromethanesulfonate; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 0.0333333h; Inert atmosphere; Glovebox;
Stage #2: 4-methoxypyridine In dichloromethane at 20℃; for 0.0833333h; Inert atmosphere; Glovebox;
Stage #1: 4-methoxypyridine With hydroxylamine-O-sulfonic acid In water at 90℃; for 0.5h; Inert atmosphere;
Stage #2: With potassium carbonate In water at 20℃; Inert atmosphere;
Stage #3: With hydrogen iodide In ethanol at -20℃; for 1h;
8.1 Step 1. 1-Amino-4-methoxypyridinium iodide
A solution of aminooxysulfonic acid ( 1 1 .4 g, 100.80 mmol, 0,50 equiv) and 4-methoxypyridine (22 g, 201 .60 mmol, 1 .00 equiv) in water (200 mL) was stirred under nitrogen for 0.5 h at 90 °C. Potassium carbonate (14 g, 101 .30 mmol, 0,50 equiv) was added at rt. The resulting mixture was concentrated under vacuum then ethanol ( 150 mL) was added to dissolve the residue. The insoluble material was removed by filtration. The filtrate was cooled to -20 °C and then hydro iodic acid (16 g, 40%) was added. The resulting solution was stirred for 1 h at -20 °C. The precipitated product was collected by filtration and washed with cold ethanol to give 9.3 g (46%) of the title compound as a white solid. TLC: 1 :5 MeOH/DCM, Rf = 0.02
46%
Stage #1: 4-methoxypyridine With hydroxylamine-O-sulfonic acid In water at 90℃; for 0.5h; Inert atmosphere;
Stage #2: With hydrogen iodide In ethanol at -20℃; for 1h; Inert atmosphere;
8.1 Step 1. 1 -Amino-4-methoxypyridinium iodide
A solution of aminooxysulfonic acid ( 1 1 .4 g, 100.80 mmol, 0,50 equiv) and 4-methoxypyridine (22 g, 201 .60 mmol, 1 .00 equiv) in water (200 mL) was stirred under nitrogen for 0.5 h at 90 °C. Potassium carbonate (14 g, 101 .30 mmol, 0,50 equiv) was added at rt. The resulting mixture was concentrated under vacuum then ethanol ( 150 mL) was added to dissolve the residue. The insoluble material was removed by filtration. The filtrate was cooled to -20 °C and then hydro iodic acid (16 g, 40%) was added. The resulting solution was stirred for 1 h at -20 °C. The precipitated product was collected by filtration and washed with cold ethanol to give 9.3 g (46%) of the title compound as a white solid. TLC: 1 :5 MeOH/DCM, Rf = 0.02
46%
Stage #1: 4-methoxypyridine With hydroxylamine-O-sulfonic acid In water at 90℃; for 0.5h; Inert atmosphere;
Stage #2: With hydrogen iodide In ethanol at -20℃; for 1h;
8.1 Step 1. 1-Amino-4-methoxypyridinium iodide.
[0194] Step 1. 1-Amino-4-methoxypyridinium iodide. A solution of aminooxysulfonic acid (11.4 g, 100.80 mmol, 0.50 equiv) and 4-methoxypyridine (22 g, 201.60 mmol, 1.00 equiv) in water (200 mL) was stirred under nitrogen for 0.5 h at 90 °C. Potassium carbonate (14 g, 101.30 mmol, 0.50 equiv) was added at rt. The resulting mixture was concentrated under vacuum then ethanol (150 mL) was added to dissolve the residue. The insoluble material was removed by filtration. The filtrate was cooled to -20 °C and then hydroiodic acid (16 g, 40%) was added. The resulting solution was stirred for 1 h at -20 °C. The precipitated product was collected by filtration and washed with cold ethanol to give 9.3 g (46%) of the title compound as a white solid. TLC: 1:5 MeOH/DCM, Rf = 0.02.
46%
Stage #1: 4-methoxypyridine With hydroxylamine-O-sulfonic acid In water at 90℃; for 0.5h; Inert atmosphere;
Stage #2: With potassium carbonate In water at 20℃;
Step 1. l-Amino-4-methoxypyridinium iodide
[0202] Step 1. l-Amino-4-methoxypyridinium iodide. A solution of aminooxysulfonic acid (11.4 g, 100.80 mmol, 0.50 equiv) and 4-methoxypyridine (22 g, 201.60 mmol, 1.00 equiv) in water (200 mL) was stirred under nitrogen for 0.5 h at 90 °C. Potassium carbonate (14 g, 101.30 mmol, 0.50 equiv) was added at rt. The resulting mixture was concentrated under vacuum then ethanol (150 mL) was added to dissolve the residue. The insoluble material was removed by filtration. The filtrate was cooled to -20 °C and then hydroiodic acid (16 g, 40%) was added. The resulting solution was stirred for 1 h at -20 °C. The precipitated product was collected by filtration and washed with cold ethanol to give 9.3 g (46%) of the title compound as a white solid. TLC: 1:5 MeOH/DCM, Rf = 0.02.
Stage #1: 4-methoxypyridine; di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 0℃; Inert atmosphere;
Stage #2: vinyl magnesium bromide In tetrahydrofuran at 0 - 25℃; for 3h; Inert atmosphere;
Stage #3: With hydrogenchloride In tetrahydrofuran; water at 5℃; for 0.166667h; Inert atmosphere;
A.A6.a a) Preparation of intermediate 21
Di-tert-butyl dicarbonate (58.333 mmol) was added portionwise under a N2atmosphere and with rapid stirring to a solution of 4-methoxypyridine (58.333 mmol) in THF(60ml). The mixture was cooled to 0°C, vinylmagnesium bromide (70 mmol) was added dropwise and the mixture was stirred for 3 hours at room temperature. HCl (IN) (about 150ml) was added at 5°C (ambient temperature of 25°C) and the mixture was stirred for 10 minutes. The mixture was extracted with EtOAc. The organic layer was washed with 10%) aqueous NaHC03solution then brine, dried over MgS04, filtered and evaporated to dryness, yielding 10.7g (82.1%) of intermediate 21.
82.1%
Stage #1: 4-methoxypyridine; di-<i>tert</i>-butyl dicarbonate; vinyl magnesium bromide In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;
Stage #2: With hydrogenchloride In tetrahydrofuran; water at 5℃; for 0.166667h;
A6.a a) Preparation of Intermediate 21
a) Preparation of Intermediate 21 Di-tert-butyl dicarbonate (58.333 mmol) was added portionwise under a N2 atmosphere and with rapid stirring to a solution of 4-methoxypyridine (58.333 mmol) in THF (60 ml). The mixture was cooled to 0° C., vinylmagnesium bromide (70 mmol) was added dropwise and the mixture was stirred for 3 hours at room temperature. HCl (1N) (about 150 ml) was added at 5° C. (ambient temperature of 25° C.) and the mixture was stirred for 10 minutes. The mixture was extracted with EtOAc. The organic layer was washed with 10% aqueous NaHCO3 solution then brine, dried over MgSO4, filtered and evaporated to dryness, yielding 10.7 g (82.1%) of intermediate 21.
(±)-benzyl 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: 4-bromobenzenecarbonitrile With isopropylmagnesium chloride lithium chloride complex In tetrahydrofuran at 20℃; for 2.25h;
Stage #2: 4-Methoxypyridine; benzyl carbonochloridate In tetrahydrofuran at -5 - 20℃; for 16.5h;
23%
Stage #1: 4-bromobenzenecarbonitrile With isopropylmagnesium chloride lithium chloride complex In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
Stage #2: 4-Methoxypyridine; benzyl carbonochloridate In tetrahydrofuran at 0 - 20℃; for 18h;
1 Intermediate 1:
In the three-necked flask of 3L, add tetrahydrofuran (150mL) and 4-bromobenzonitrile (50g) successively,Isopropylmagnesium chloride lithium chloride complex (1.3M, 210 mL) was slowly added to the reaction system under nitrogen protection. After the reaction was carried out at room temperature for 2 hours, the reaction system was diluted with anhydrous tetrahydrofuran (500 mL), cooled to -5 °C, 4-methoxypyridine (25 mL) was added, and benzyl chloroformate (35 mL) was slowly added dropwise ( The temperature of the system was maintained below 0° C.), after the dropwise addition, the reaction was continued at 0° C. for 2 hours, then raised to room temperature and reacted at this temperature for 16 hours. After the reaction, hydrochloric acid solution (6M, 150mL) was added, stirred at room temperature for half an hour and diluted with water (1000mL), extracted twice with ethyl acetate (500mL), and the extract was washed with saturated brine (50mL), and then washed with ethyl acetate (500mL). Dry over sodium sulfate and filter. The crude product obtained after the filtrate was concentrated was separated and purified by silica gel column (petroleum ether:ethyl acetate=3:1-1:1) to obtain Intermediate 1 (23 g, yield: 23%).
Stage #1: 4-bromobenzenecarbonitrile With isopropylmagnesium chloride lithium chloride complex In tetrahydrofuran at 20℃; for 2.25h; Inert atmosphere;
Stage #2: 4-Methoxypyridine; benzyl carbonochloridate In tetrahydrofuran at -5 - 20℃; for 17.5h;
Intermediate 2-1 2-A; (±)-benzyl 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate
To a solution of 4-bromobenzonitrile (i7 g, 93 mmol) in THF (50 mL) at room temperaturewas added isopropylmagnesium chloride lithium chloride complex solution (i .3M in THF, 70 mL, 9i mmol) dropwise over 0.25h. The mixture was then stirred at room temperature for 2h. The mixture was diluted with THF (300 mL), and then cooled to -5 °C. To the mixture was then added 4-methoxypyridine (8.37 mL, 82 mmol), followed by Cbz-Cl (i2 mL, 84 mmol) while maintain theinternal temperature below 0 °C. The mixture was then stirred at 0 °C for i .5h, and then stirred atroom temperature for i6h. The reaction was then quenched with SM aq. HCI. The mixture was then stirred at room temperature for 0.5h. The mixture was then diluted with EtOAc. The mixture was then washed with H20 twice, 5% aq. NaHCO3, and brine, dried over Na2SO4. The extract was then filtered through a plug of silica gel, which was rinsed with EtOAc. The filtrate was concentrated. The resulting residue was then triturated with Et20 (ca. 100 mL). The resulted solidwas collected by filtration to give the title compound. MS (ESl+) m/z 333.3 (M+H).
2.1 Preparation of [Cd2(μ2-κ2:κ1-OAc)2(μ2-κ1:κ1-OAc)2(NC5H5)2] (1)
General procedure: Cd(OAc)2*2H2O (500 mg, 1.88 mmol) was dissolved in methanol (30 mL) and stirred. To this solution, methanolic (5 mL) solution of pyridine (149 mg, 1.88 mmol)/(300 mg, 3.76 mmol) was separately added and the resulting solution stirred at ambient temperature for 24 h, filtered and the filtrate concentrated under vacuum to about 5 mL. The solution was stored at ambient temperature for several days to afford 1 as colourless crystals. The crystals were separated, washed with n-hexane and dried under vacuum to afford 1 in 94% (548 mg, 1.67 mmol)/90% (555 mg, 1.69 mmol) yields.
4-methoxy-1-(2-oxopropyl)pyridin-1-ium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In ethyl acetate at 80℃; for 3h;
93%
In acetone at 60℃;
1.3 Step 3. Synthesis of 4-methoxy-1-(2-oxopropyl)pyridine-1-chloride
The pyridine derivative (2.0 g, 18.3 mmol) was added to a solution of 1-chloropropan-2-one in acetone (1.7 g, 21.9 mmol). The reaction was stirred at 60°C overnight. After the reaction is completed, cool to room temperature, filter the obtained precipitate, wash with ethyl acetate or acetone, and recrystallize with ethanol to obtain the corresponding pure pyridine salt (2.0 g, 93%).
93%
In acetone at 60℃;
1.3 Step 3 Synthesis of 4-methoxy-1-(2-oxopropyl)pyridine-1-chloride
The pyridine derivative (2.0 g, 18.3 mmol) was added to a solution of 1-chloropropan-2-one in acetone (1.7 g, 21.9 mmol). The reaction was stirred at 60°C overnight. After the reaction, cool to room temperature, filter the resulting precipitate, wash with ethyl acetate or acetone, and recrystallize with ethanol to obtain the corresponding pure pyridine salt (2.0g, 93%)
84%
In acetone at 60℃;
In tetrahydrofuran at 20℃; for 48h;
2.1 General procedure for thepreparation of pyridinium salts (4a-f)
General procedure: Chloroacetone (1.2equiv) was added to a solution of pyridine derivatives in THF (1 equiv) and the mixture was stirred at room temperature for 48 hours.
In tetrahydrofuran at 20℃;
4.2 General procedure for the synthesis of pyridinium salts 19a-g
General procedure: Chloroacetone (1.2 equiv.) was added to a solution of pyridine 18a-g (1 equiv.) in THF. The resulting mixture was stirred at rt for 24-48h. The precipitate formed was filtered, washed with cold acetone and dried to provide pure pyridinium salt 19a-g in very good yields.
With copper(l) iodide; oxygen In 1-methyl-pyrrolidin-2-one at 100℃;
Imidazo[1,2-a]pyridines 3; General Procedure
General procedure: The appropriate ketoxime acetate 1 (0.5 mmol), CuI (10 mol%, 9.5mg), and pyridine derivative 2 (0.6 mmol) were added successively toNMP (1.5 mL) in a 25 mL round-bottomed flask, and the mixture wasstirred at 100 °C under dry air for 4-6 h. When the reaction was complete(TLC), the mixture was cooled to r.t., and the reaction wasquenched with 30% aq NH3 (5 mL). The mixture was extracted withEtOAc (10 mL), and the extracts were washed with H2O (10 mL) andbrine (10 mL). The organic layer was removed under reduced pressureto give a crude product that was further purified by chromatography(silica gel, PE-EtOAc).
With dipotassium peroxodisulfate; oxygen; sodium formate; silver nitrate; In water; at 80℃; for 4.0h;Schlenk technique;
General procedure: A 25 mL Schlenk flask was charged with AgNO3 (17.2 mg, 20 mol% Ag), K2S2O8(408 mg, 1.5 mmol), and HCOONa (129 mg, 1.0 mmol) before standard cycles of evacuation and back-filling with dry and pure oxygen (three times). Corresponding pyridine 1 (0.5 mmol), formamide 2 (2 mL), and H2O (0.4 mL) were added successively. The mixture was stirred at 80 C for the indicated time (monitored byTLC). At the end of the reaction, the reaction mixture was cooled to room temperature, poured into a saturated aqueous NaCl solution (15 mL), and extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, and the volatile components were evaporated in a rotary evaporator. The residue was purified by flash column chromatography on silica gel to afford the corresponding product 3
88%
With dipotassium peroxodisulfate; oxygen; sodium acetate; iron; In water; at 80℃; for 4.0h;Green chemistry;
Compound 9: Under oxygen atmosphere, to a 25 ml reaction flask are sequentially added iron powder (0.1mmol), 4-methoxypyridine (0.5mmol), sodium acetate (1.0mmol), potassium persulfate (1.5mmol), formamide (2.0 ml) and water (0.4 ml). The mixture at 80 C reacts for 4h. Cooling to room temperature, reducing pressure and evaporating the solvent column chromatography separation to obtain the product, yield 88%.
Stage #1: 4-methoxypyridine With 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex; boron trifluoride diethyl etherate In tetrahydrofuran; toluene at -20℃; for 20h;
Stage #2: With iodine In tetrahydrofuran; toluene at 20℃;
2-iodo-4 methoxypyridine (8) [30]
A solution of 4-methoxypyridine (2 g, 18.3 mmol) in 90 mL of dry THF containing BF3Et2O(2.5 mL, 20 mmol) was treated with TMPMgClLiCl (27 mL, 27 mmol, 1M toluene) at 20 C for 20 h,and the resulting mixture was quenched by adding the solution of iodine (9.14 g, 36 mmol) in 37 mL ofTHF. Following the warming to room temperature, the resulting mixture was quenched by adding100 mL of sat. aqueous NH4Cl and NH3 (9 mL) and sat. aqueous Na2S2O3 solution (18 mL), followedby extraction with Et2O (4 100 mL). The combined organic layer was dried over MgSO4, and thefiltrate was concentrated at reduced pressure. The residue was purified on silica gel using heptane andEt2O (4:1) as eluent, and 8 was isolated as light brown oil (1.65 g, 39% yield).1H-NMR (500MHz, DMSO): 8.13 (d, J = 5.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 5.8 Hz,J = 2.4 Hz, 1H), 3.82 (s, 3H). 13C-NMR (124 MHz, DMSO): 166.0, 151.9, 120.3, 119.8, 111.4, 56.3. HR-MS:m/z calculated for C6H7INO ([M+H+]): 235.9567, found: 235.9571.
Stage #1: 4-methoxypyridine With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; dichloro(N,N,N’,N‘-tetramethylethylenediamine)zinc In tetrahydrofuran; hexane at 20℃; for 2h; Inert atmosphere; Schlenk technique;
Stage #2: With iodine In tetrahydrofuran; hexane Inert atmosphere; Schlenk technique;
2 General procedure 1
General procedure: To a stirred, cooled (0°C) solution of 2,2,6,6-tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2-3 mL) were successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min later, ZnCl2*TMEDA (0.13 g, 0.50 mmol). The mixture was stirred for 15 min at 0°C before introduction of the substrate (1.0 mmol) at 0-10°C. After 2 h at room temperature, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was stirred overnight before addition of an aqueous saturated solution of Na2S2O3 (4 mL) and extraction with AcOEt (3x20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. To the crude iodide were added Cs2CO3 (0.65 g, 2.0 mmol), Cu powder (13 mg, 0.20 mmol), the azole (1.5 mmol) and MeCN (5 mL) and the resulting mixture was heated under reflux for 24 h. Filtration over Celite, washing with AcOEt, removal of the solvent and purification by chromatography on silica gel (the eluent is given in the product description) led to the compound described below.
2.2.2. Synthesis of [Cu(dca)2(4-OMP)2]n (2)
General procedure: 40 mL of aqua dest. were used to dissolve 0.48 g Cu(NO3)2.3H2O(2 mmol), 0.36 g sodium dicyanamide (4 mmol) and 0.44 g 4-hydroxymethylpyridine (4 mmol). The mixture was stirred 2 h at70 C and then filtered. The clear blue solution was allowed to coolto RT. After one day blue plate-like crystals were obtained (yield:0.48 g, 58%).
With oxygen; copper dichloride In acetonitrile at 80℃; for 12h; Sealed tube;
1
The synthesis method of I-1 is:Using CuCl2 as a catalyst,Acetonitrile as a solvent,To a solution of 3.0 mmol of 4-methoxypyridine and 3.0 mmol of methyl bromoacetate in acetonitrile, 0.2 mmol of CuCl 2 was added under an oxygen atmosphere.Sealing reaction,The reaction temperature is 80 ° C.The reaction time is 12h.Silica gel filtration removes CuCl2,The filtrate was concentrated in vacuo.The crude product was separated by column chromatography to give a yellow oil I-1.Yield: 70%.
4-methoxy-1-(2-(3-indolyl)-2-oxoethyl)pyridinium iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With iodine In 1,4-dioxane at 80℃; for 1.16667h;
4-Methoxy-1-(2-(3-indolyl)-2-oxoethyl)pyridinium iodide (4)
A mixture of 5.00 g(0.031 mol) of 2 (Sigma) and 7.02 g (0.064 mol) of 3 in 50mL of dry dioxane washeated on a steam bath until solution was complete. Iodine (4.82 g) was added and heatingwas continued for 10 min. More iodine (3.15 g) was added (a total of 7.97 g;0.031 mol) and the solution was heated for 1 h with occasional swirling. The reactionmixture was cooled to room temperature and 50mL of absolute ethanol was added.Upon cooling to 0 C there was deposited in several crops 4.51 g (37%) of crystalline 4.Recrystallization from ethanol yielded 4 as golden needles: mp >250 C; TLC (40%CH3OH in CHCl3) Rf0.10, stains purple.Anal. Calcd. for C16H15N2O2I: C, 48.75; H, 3.84; N, 7.11. Found: C, 48.24; H,3.36; N, 7.11.
With potassium hexamethylsilazane In tetrahydrofuran at 100℃; for 16h; Inert atmosphere;
3 Example 3 (different amine substrate expansion)
General procedure: Under the N2 atmosphere,A mixture of 2a or 2f (0.5 mmol), 3y (0.75 mmol) and KHMDS (0.75 mmol) previously dissolved in THF at 1.0 M was added to the reaction tube in that order.Heat to 100 ° C, stir the reaction for about 16h until the conversion of the raw materials is completed.Down to room temperature,Diluted with THF (3 ml) to the reaction mixture.Filtered with silica gel or diatomaceous earth,After washing with THF, the crude product was concentrated in vacuo to silica gel column chromatography to give the corresponding product 1ay or 1fy.
60%
With potassium hexamethylsilazane In tetrahydrofuran at 100℃; for 16h; Inert atmosphere; Schlenk technique; Sealed tube; Green chemistry;
With potassium hexamethylsilazane In tetrahydrofuran at 100℃; for 16h; Inert atmosphere;
1.1-1.13; 3 Example 1 (reaction conditions screening)
4-methoxypyridine 2a (0.5 mmol) and aniline 3a (0.75 mmol) were sequentially added to the reaction tube under N2 atmosphere.a mixture obtained by dissolving a base (0.75 mmol) of THF and a solvent (0.5 ml) in a concentration of 1.0 M in advance,Heat to T ° C, stir the reaction for about 16 h until the conversion of the raw materials is completed, and return to room temperature.Diluted with THF (3 ml) to the reaction mixture.Filtered on silica gel or diatomaceous earth, washed with THF,The crude product was concentrated in vacuo and subjected to silica gel column chromatography to give the corresponding product 1aa.
98%
With potassium hexamethylsilazane In tetrahydrofuran at 100℃; for 16h; Inert atmosphere; Schlenk technique; Sealed tube; Green chemistry;
methyl 3-benzoyl-7-methoxyindolizine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With copper(l) iodide; iodine; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h;
General Procedure for the Product
General procedure: An test tube was charged with acetophenone (1a, 0.6 mmol, 72.1 mg), pyridine (2a, 0.6 mmol, 47.5 mg), methyl acrylate (3a, 0.3 mmol, 25.8 mg), K2CO3 (2.4 mmol, 331.7 mg) , I2 (1.2 mmol, 304.6 mg), CuI (0.06 mmol, 11.4 mg) and 1 mL DMF. The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with EtOAc, and washed with 10% Na2S2O3 solution (50 mL). Then the mixture was extracted with EtOAc (20 mL×3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated invacuo. The remaining crude product was then purified through column chromatography using silica gel (EtOAc/petroleum ether = 1/10) to afford 4a as a yellow solid in 66% yield.
61%
With sodium carbonate; copper(l) chloride In 1-methyl-pyrrolidin-2-one at 90℃; for 16h; Sealed tube;
8 Examples 1 to 13
General procedure: According to the raw material ratio of Table 1, a copper additive, elemental iodine, alkali, aryl ethyl ketone (IV), pyridine derivative (III), electron-deficient olefin (II) and organic solvent 1 ml were added to a 10 ml sealed tube, and the mixture was stirred and mixed uniformly. In Table 1, A is cuprous chloride; B is cuprous iodide; C is sodium carbonate; D is potassium carbonate; E is N-methylpyrrolidone; and F is N,N-dimethylformamide. After completion of the reaction according to the reaction conditions of Table 2, the reaction solution was transferred to a separatory funnel containing 10% sodium thiosulfate solution, and the aqueous phase was extracted three times with ethyl acetate. The mixture was dried, filtered, and the filtrate was added to a silica gel mixture, and the solvent was evaporated to dryness, and purified by silica gel column chromatography (eluent ethyl acetate and petroleum ether mixture) to obtain the corresponding C-3 arylformylpyridazine compound (I)
benzyl 2-[4-(methoxycarbonyl)phenyl]-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.65%
Stage #1: 4-methoxypyridine With Bis<2-(N,N-dimethylamino)aethyl>aether; isopropylmagnesium chloride In tetrahydrofuran at 15 - 30℃; for 1h;
Stage #2: methyl 4-iodobenzoate; benzyl chloroformate In tetrahydrofuran at -30℃; for 2h;
1.1 Step 1 : Synthesis of benzyl-2-[4-(methoxycarbonyl)phenyl]-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (C3, wherein Pi = Cbz and R = methyl)
iPrMgCI (2N THF, 109.96 g, 54.98 ml_, 2.0 eq) was charged in a reactor. A solution of bis[2 -(N,N- dimethylaminoethyl)] ether (2.5 eq, 22.03 g, 137.46 mmol) in THF (24 ml.) was added at 15 - 25 °C. The mixture was stirred for 1 hour. A solution of C1 (20.17 g, 76.98 mmol, 1.4 eq) in THF (102 ml.) was added slowly at 15 - 25 °C. The mixture was heated to 25 - 30 °C, stirred for more than 1 hour, and checked by HPLC. The mixture was cooled to -30 °C. A solution of C2 (methyl 4- iodobenzoate, 6.0 g, 54.98 mmol, 1.0 eq) in THF (20 ml.) was added, followed by a solution of benzyl chloroformate (1.15 eq, 10.79 g, 63.23 mmol) in THF (36 ml_). The mixture was stirred for 2 hours and quenched with AcOH (6.60 g, 109.96 mmol, 2 eq). Isopropyl acetate (60 ml.) was added. Hydrogen chloride (15%, 90 g) was added to adjust the pH = 1 - 2. The organic layer was separated and washed with brine (15%, 100 g), and concentrated. Isopropyl acetate (160 ml.) was added and concentrated to remove the THF. The crude product was recrystallized in Isopropyl acetate (1 14 ml.) and n-heptane (120 ml_). The product was dried at 60 °C to provide C3 as light yellow solid (16.0 g, 79.65 % yield). 1 H-NMR (400 MHz, DMSO-d6) d (ppm) = 8.1 1 (dd, J=8.39, 1.01Hz, 1H), 7.91 (d, J=8.39 Hz, 2H), 7.33 - 7.37 (m, 6H), 5.82 (d, J= 7.20 Hz, 1H), 5.20 - 5.35 (m, 3H), 3.83 (s, 3H), 3.41 (br. s, 1H), 3.31 (dd, J=16.64, 7.52 Hz, 1H), 2.66 (br. d, J=16.55 Hz, 1H).
Stage #1: 4-methoxypyridine With n-butyllithium; 2-(N,N-dimethylamino)ethanol In hexane at -20℃; for 1h; Inert atmosphere;
Stage #2: With 1,2-dibromo-1,1,2,2-tetrachloroethane In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere;
4-Methoxy-2-bromopyridine (2).
A solution of N,N-dimethylethanolamine (1.40 mL, 13.93 mmol) in hexanes (10 mL) at -20 oC was treated with n-BuLi (11.91 mL, 27.86 mmol, 2.34M in hexanes). The reaction mixture was stirred under nitrogen for 30 minutes. Neat 4-methoxypyridine (0.70 mL, 6.90 mmol) was added dropwise. The orange solution was stirred for one hour and then cooled to -78 oC. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.40 g, 16.57 mmol) in THF (5 mL) was added dropwise, and the mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched with water at 0 oC and extracted with diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate and concentrated. The desired product was distilled (70 °C, 3 mmHg) to yield 0.81 g (62%) of 2 as yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 6.78-6.80 (dd, J 2.1, 2.4, 5.9 Hz, 1H), 7.00-7.01 (d, J 2.4 Hz, 1H), 8.16-8.18 (d, J 6.0 Hz, 1H);13C NMR (75 MHz, CDCl3) δ 55.6, 110.2, 113.2, 143.0, 150.6, 166.8; FTIR (film) 2321, 2350, 2371, 2851, 2925,2956 cm-1; HRMS (FAB) calcd for C6H6BrNO (M+1) 187.9711; found 187.9708.
With potassium carbonate In acetonitrile at 84℃; for 24h;
Compound [ 2 ].
General procedure: To a mixture of triazolium iodide salt 1 (0.025 g, 0.064 mmol), K 2 CO 3 (0.010 g, 0.072 mmol), PdCl 2 (0.012 g, 0.068 mmol) and KI (excess) was added pyridine (5 mL). The sus- pension was stirred for 24 h at 84 °C. After the removal of pyri- dine in vacuo, the portion of the crude mixture was extracted with dichloromethane (15 mL). Removal of solvents gave a yel- low residue. It was then charged onto a silica gel column. A yel- low solid [ 2 ] was obtained on eluting with hexane:ethylacetate (90:10, v:v). Yield: 0.028g (0.040 mmol, 62.5 %).
12-benzoyl-2-methoxybenzo[f]pyrido[1,2-a]indole-6,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With iodine In acetonitrile at 90℃; for 12h; Sealed tube;
General Procedure for the preparation of 4
General procedure: Substituted pyridines 1 (1.5 mmol), methyl ketones 2 (0.6 mmol), 1,4-naphthoquinone 3(0.5 mmol) and iodine (1.0 mmol) were mixed in 10mL CH3CN and heated at 90oC for 12 h in a sealed tube.After completion of the reaction, chromatographic separation of the reaction mixture after removal of the solvent gave product 5.
With tert-Butyl peroxybenzoate; iodine In 1,4-dioxane at 110℃; for 10h; Sealed tube;
44
The preparation method of the compound as described in formula 21,The specific steps are: add 0.2mmol ethyl-3-(2-acetphenoxy) acrylate, 0.6mmol 4-methoxypyridine, 0.2mmol elemental iodine,0.6mmol tert-butyl peroxybenzoate and 2mL 1,4-dioxane were sealed at 110°C and reacted with magnetic stirring for 10 hours. After the reaction was completed, the reaction solution was extracted, and the organic layer was washed, dried, and distilled under reduced pressure. The crude product is obtained by removing the solvent. The crude product is separated and purified by column chromatography with petroleum ether/ethyl acetate=5:1 (V/V) as the eluent to obtain the desired product. The product is a white solid and the yield is 68%. .
benzyl 2-(2-cyclopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: 1-bromo-2-cyclopropylbenzene With iodine; magnesium In tetrahydrofuran at 70℃; for 1h; Inert atmosphere;
Stage #2: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -20℃; for 1h;
1 Step 1: benzyl 2- (2-cyclopropylphenyl) -4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate
A small amount of I2(10 mg, catalyst) was added to the solution of Mg (0.9 g, 38 mmol) in THF (20 mL) at 25 under N2, then 1-bromo-2-cyclopropylbenzene (5.0 g, 25 mmol) was added in drops. The mixture was heated to 70 for 1 hr until the brown color disappeared. The solution of Grignard Reagent was added dropwise to the pyridinium salt obtained from 4-methoxypyridine (1.85 g, 0.017 mol) and benzyl carbonochloridate (3.2 mL, 0.022 mol) in dry THF (50 mL) at -20 . The mixture was stirred at -20 for 1 hr. The HCl (1 M, 50 mL) was added to the mixture, extracted with EtOAc (20 mL ×3) . The combined organic phases were washed with brine (20 mL*2) , dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, eluent: PE/EA (v/v) = 10/1) to give benzyl 2- (2-cyclopropylphenyl) -4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate (4.0 g, yield: 68%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm: 8.20 (d, J=8.4 Hz, 1H) , 7.40-7.27 (m, 3H) , 7.21-7.08 (m, 5H) , 6.26 (br d, J= 8.8 Hz, 1H) , 5.47 (d, J= 8.4 Hz, 1H) , 5.20-5.11 (m, 2H) , 3.23-3.17 (m, 1H) , 2.72 (d, J= 16.4 Hz, 1H) , 1.80 (br s, 1H) , 0.98-0.83 (m, 2H) , 0.72-0.49 (m, 2H) .
benzyl 2-(2-isopropylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: 4-methoxypyridine; benzyl chloroformate In tetrahydrofuran at -20℃; for 1h;
Stage #2: 1-bromo-2-isopropylbenzene With iodine; magnesium In tetrahydrofuran at -20℃; for 1h; Inert atmosphere;
1 Step 1: benzyl 2- (2-isopropylphenyl) -4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate
To a solution of 4-methoxypyridine (1.82 g, 17 mmol) in dry THF (50 mL) was added benzyl carbonochloridate (3.2 mL, 22 mmol) in drops at -20 . The mixture was stirred at -20 for 1 hr. To another flask was added magnesite (0.9 g, 38 mmol) in THF (20 mL) at 25 under N2. A small amount of I2(22 mg, 0.17 mmol) was added, then 1-bromo-2-isopropylbenzene (5.0 g, 25 mmol) was added in drops. The mixture was heated to 70 for 1 hr until the brown color disappeared completely. The obtained Grignard Reagent solution was added dropwise to the above pyridinium salt at -20 . The mixture was stirred at -20 for 1 hr. The mixture was poured into HCl (1 M, 50 mL) , extracted with EtOAc (20 mL × 3) . The combined organic phases were washed with brine (20 mL × 2) , dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, eluent: PE/EA (v/v) =10/1) to give benzyl 2- (2-isopropylphenyl) -4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate (5.5 g, yield: 92%) as a brown oil.1H NMR (400 MHz, CDCl3) δ ppm: 8.23 (d, J= 8.4 Hz, 1H) , 7.36-7.32 (m, 1H) , 7.31-7.22 (m, 4H) , 7.15-7.06 (m, 2H) , 7.05-7.00 (m, 1H) , 5.97 (d, J=8.4 Hz, 1H) , 5.37 (d, J= 8.4 Hz, 1H) , 5.22-5.11 (m, 2H) , 3.38 (m, 1H) , 3.06 (t, 1H) , 2.24 (m, 1H) , 1.23 (d, J=6.8 Hz, 3H) , 1.05 (m, 3H) .
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