* 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] Journal of Polymer Science, 1959, vol. 40, p. 377,384
2
[ 626-64-2 ]
[ 5382-16-1 ]
Reference：
[1] Patent: US6018048, 2000, A,
[2] Journal of the American Chemical Society, 1958, vol. 80, p. 6412,6419
[3] Journal of Polymer Science, 1959, vol. 40, p. 377,384
3
[ 1692-15-5 ]
[ 626-64-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
With copper(ll) sulfate pentahydrate; ellagic acid In methanol at 60℃; for 8 h; Green chemistry
General procedure: In a typical reaction, 10 molpercent CuSO4·5H2O, (0.049 g, 0.2 mmol)and 6.7 molpercent EA (20 mg) were mixed in methanol followed by2 mmol of phenylboronic acid. This reaction mixture was kept ina preheated oil bath by maintaining the temperature at 60 °C andstirred under atmospheric pressure. After completion of the reac-tion, modified by TLC, the mixture was washed twice with hot ethylacetate to remove the reactant and product. The hot ethyl acetatewas removed from the reaction mixture and the resulting crudeproduct was purified by a column chromatography using silicagel 260 mesh (pet ether:ethyl acetate) ratio (25:75). The recov-ered catalyst was reused for the next run. All the products werecharacterized by1H and13C NMR spectra.
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 395, p. 500 - 505
4
[ 1338215-40-9 ]
[ 626-64-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With cesium fluoride In N,N-dimethyl-formamide at 60℃; for 1 h; Inert atmosphere Stage #2: With water In N,N-dimethyl-formamideInert atmosphere
General procedure: To a solution of [2-(phenoxy)-ethyl]-trimethyl-silane (Table-3, entry-1) (195mg, 1.0 mmol) in dry DMF (2 ml) was added cesium fluoride (576 mg, 3.0 mmol) and heated at 60°C for 1 h. Reaction mass was diluted with water and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduce pressure to give phenol 92mg (93percent yield). Phenols of Table-3 are commercially available from Aldrich and its identity was confirmed by comparison of 1H NMR data with authentic sample.
General procedure: In a typical experiment, benzyl 4-methoxyphenyl carbamate (1a, 1 mmol) and 10 cm3 methanol were placed in a 100 cm3 round-bottomed flask fitted with a water condenser and placed over a magnetic stirrer. Nickel(II) chloride hexahydrate (5 mmol) was added to the flask, followed by slow addition of sodium borohydride (15 mmol) with vigorous stirring. A vigorous reaction took place and the reaction mixture turned black due to in situ formation of nickel boride. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate 80:20, v/v). After completion, the reaction mixture was filtered through a Celite pad (~2.5 cm) and washed with methanol (3x10 cm3). The solution was concentrated ona rotavapor and diluted with water (~50 cm3), followed by extraction with dichloromethane (3x10 cm3). The combined dichloromethane extract was washed with water and dried over anhyd. K2CO3. The solvent was removed ona rotary evaporator and the product was dried. 4-Anisidine(2a) was obtained as colourless solid in 88percent yield. The products were identified by m.p., IR, and NMR spectra. The products Scheme 1, entry 24 and Scheme 2, entry 8 were purified by flash column chromatography on silica gel using petroleum ether:ethyl acetate (95:5, v/v) as eluent.
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 8, p. 2366 - 2370
[2] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5338 - 5341
8
[ 6890-62-6 ]
[ 626-64-2 ]
Reference：
[1] Yakugaku Zasshi, 1945, vol. 65, # 4/8, p. 435,439[2] Chem.Abstr., 1951, p. 8527
[3] Yakugaku Zasshi, 1951, vol. 71, p. 1097[4] Chem.Abstr., 1952, p. 5042
[5] Yakugaku Zasshi, 1955, vol. 75, p. 127[6] Chem.Abstr., 1956, p. 1817
[7] Yakugaku Zasshi, 1955, vol. 75, p. 127[8] Chem.Abstr., 1956, p. 1817
[9] Journal of the Chemical Society, 1958, p. 1263,1264, 1266
9
[ 5421-92-1 ]
[ 626-64-2 ]
Reference：
[1] Chemische Berichte, 1931, vol. 64, p. 1045,1047
[2] Journal of the American Chemical Society, 1945, vol. 67, p. 79
[3] Journal of the Chemical Society, 1954, p. 1795,1797
[4] Acta Chemica Scandinavica (1947-1973), 1954, vol. 8, p. 390,392
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2335 - 2338
17
[ 1381932-78-0 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
18
[ 36228-61-2 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
19
[ 24762-89-8 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
20
[ 74669-53-7 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
21
[ 74669-51-5 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
22
[ 74669-54-8 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
23
[ 74669-55-9 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
24
[ 74669-56-0 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
25
[ 74669-62-8 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
26
[ 108-96-3 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 8, p. 1354 - 1362
[2] Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, p. 1153 - 1158[3] Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 6, p. 1268 - 1274
[4] Journal fuer Praktische Chemie (Leipzig), 1982, vol. 324, # 3, p. 369 - 378
27
[ 626-61-9 ]
[ 626-64-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1885, vol. 6, p. 315[2] Chemische Berichte, 1885, vol. 18, p. 930
28
[ 110-89-4 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 776-75-0 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
29
[ 110-91-8 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 1468-28-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
30
[ 110-85-0 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 13754-38-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
31
[ 103-76-4 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 56227-56-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
32
[ 110-89-4 ]
[ 74669-53-7 ]
[ 626-64-2 ]
[ 13707-23-8 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
33
[ 110-89-4 ]
[ 74669-51-5 ]
[ 626-64-2 ]
[ 26163-40-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
34
[ 110-89-4 ]
[ 74669-54-8 ]
[ 626-64-2 ]
[ 57700-94-4 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
35
[ 110-89-4 ]
[ 74669-56-0 ]
[ 626-64-2 ]
[ 26163-45-1 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
36
[ 7755-92-2 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 57238-77-4 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
37
[ 36228-61-2 ]
[ 626-56-2 ]
[ 626-64-2 ]
[ 19202-02-9 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
38
[ 110-89-4 ]
[ 626-64-2 ]
[ 15563-40-3 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
39
[ 626-56-2 ]
[ 626-64-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
40
[ 110-85-0 ]
[ 626-64-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
41
[ 103-76-4 ]
[ 626-64-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
42
[ 110-91-8 ]
[ 626-64-2 ]
[ 2032-36-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
43
[ 110-86-1 ]
[ 109-00-2 ]
[ 142-08-5 ]
[ 626-64-2 ]
Reference：
[1] Journal of Physical Chemistry, 1980, vol. 84, # 20, p. 2548 - 2551
44
[ 101349-88-6 ]
[ 67-66-3 ]
[ 7719-12-2 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 1953, vol. 18, p. 534,541
[2] Yakugaku Zasshi, 1951, vol. 71, p. 263,265[3] Yakugaku Zasshi, 1955, vol. 75, p. 130,133[4] Chem.Abstr., 1956, p. 1817
45
[ 110-86-1 ]
[ 7664-93-9 ]
[ 626-64-2 ]
[ 5402-20-0 ]
[ 636-73-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 963,968, 970
46
[ 7732-18-5 ]
[ 5421-92-1 ]
[ 626-64-2 ]
Reference：
[1] Chemische Berichte, 1931, vol. 64, p. 1045,1047
[2] Journal of the Chemical Society, 1954, p. 1795,1797
47
[ 626-64-2 ]
[ 36953-41-0 ]
[ 25813-25-6 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
48
[ 626-64-2 ]
[ 36953-41-0 ]
Reference：
[1] Patent: WO2012/148808, 2012, A1,
49
[ 626-64-2 ]
[ 89282-03-1 ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium hydroxide; iodine In water at 85℃; for 16 h;
Step 1. 3-iodopyridin-4-ol (46)[00370] To a stirred solution of 4-hydroxypyridine (5.0 g, 52.6 mmol) in water (90 ml) were successively added sodium hydroxide (5.4 g, 135 mmol) and iodine (28.0 g,1 10 mmol). The reaction mixture was heated 85°C for 16 hours then cooled-down to room temperature. The product was collected by filtration and dry under high vacuum to afford the title compound 46 (7.56 g, 34.2 mmol, 65percent) as a white solid. MS: 222.0(M+l).
32%
With potassium iodide; iodine; sodium carbonate In water
4-Hydroxy-pyridine (23.8 g, 250 mmol) and Na2CO3 (7.4 g, 70 mmol) are added to 80 mL water. The reaction mixture is heated to reflux and a solution of iodine (23.2 g, 92 mmol) and potassium iodide (80 g, 482 mmol) in 250 mL water is slowly added drop-wise. The reaction is refluxed for 1 h after the addition. The mixture is filtered hot to remove a by-product, and the filtrate is cooled to rt, a solid is removed and dried to afford 3-iodo-4-pyridinol (C10) (32percent yield). HRMS (FAB) calculated for C5H4INO+H: 221.9418, found 221.9416 (M+H)+.
31%
With iodine; sodium carbonate In water at 20℃; for 12 h;
Add 10.6 g (0.10 mol) of Na2CO3 and 12.7 g (0.05 mol) of I2 to a solution of 4.76 g (0.05 mol) pyridin-4-ol in 200 ml of water. Stir the reaction mass at room temperature for 12 h; use the TLC method to ensure the completeness of the reaction. Add 12 ml of HCl to =5, Na2S2O3 till color removal. Filtrate the resulting precipitate, mix the precipitate with 200 ml of boiling ethanol and filtrate one more time. Concentrate the filtrate under reduced pressure, re-crystallize residue from methanol. Yield: 3.4 g (31percent).
37a. 4-hydroxy-3-iodopyridine To a solution of 4-hydroxypyridine (4.76 g, 50.1 mmol) and Na2 CO3 (10.8 g, 100 mmol) in 200 mL of water was added I2 (12.7 g, 50.1 mmol). The reaction mixture was stirred for 14 h then adjusted to pH 5 with concentrated HCl. The resulting solids were suspended in boiling ethanol and hot filtered. The solvent was removed and the resulting solids recrystallized from MeOH to afford 5.1 g (46percent) of the title compound: 1 H NMR (DMSO-d6) d 8.26 (br s, 1H), 7.70 (s, 1H), 7.69 (d, J=7 Hz, 1H), 6.14 (d, J=7 Hz, 1H); MS (DCI/NH3) m/z: 222 (M+H)+, 239 (M+NH4)+.
Reference：
[1] Patent: US6001849, 1999, A,
51
[ 626-64-2 ]
[ 54-96-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[3] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
52
[ 626-64-2 ]
[ 33631-09-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
[2] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
53
[ 626-64-2 ]
[ 4783-86-2 ]
Reference：
[1] Chemical Science, 2015, vol. 6, # 2, p. 1277 - 1281
54
[ 626-64-2 ]
[ 24388-23-6 ]
[ 4783-86-2 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 13, p. 4769 - 4779
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
Step 36-1.; To a solution of 4-hydroxypyridine (T96-1, 7.0 g, 74 mmol) in CCl4 (360 mL) at rt was added NBS (26.2 g, 0.147 mol). The solution was stirred for 24 h in the dark (covered with aluminum foil). The mixture was concentrated under reduced pressure and the resulting residue triturated with MeOH, then with acetone to give 18.9 g (100percent) of T96-2.
88%
With N-Bromosuccinimide In tetrachloromethane at 25℃; for 30 h; Inert atmosphere
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 500 mL of tetrachloromethane, 23.75 g (250 mmol) of 4-hydroxypyridine, and 89 g (500 mmol) of N-bromosuccinimide. Stir at 25 °C for 30 hours. Filter the precipitate, wash with 50 mL of tetrachloromethane; stir the precipitate in a mixture of 500 mL of acetone and 150 mL of methanol for 15 minutes. Filter the suspension; stir the precipitate in a mixture of 400 mL of acetone and 400 mL of dichloromethane for 15 minutes. Filter the suspension; mix the precipitate vigorously in 400 mL of acetonitrile for 20 minutes. Filter the suspension; dry the precipitate under vacuum at 40 °C. Yield: 56 g (88percent).
86%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
4-Pyridinol (M-40) (20.0 g, 210 mmol) was suspended in carbon tetrachloride (400 mL), NBS (77.0 g, 431mmol) was added, and the mixture was stirred under shading at room temperature for 24 hr. The solvent was evaporatedunder reduced pressure, and the residue was suspended in acetone (400 mL)/methanol (120 mL), and the mixture wasstirred at room temperature for 30 min. The precipitated solid was collected by filtration and suspended in acetonitrile(1.0 L), and the suspension was stirred at room temperature for 1 hr. The solid were collected by filtration, and driedunder reduced pressure to give compound (M-41) (yield 46.0 g, 86percent) as a white solid
86%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
4-pyridinol (M-40) (20.0 g, 210 mmol)Was suspended in carbon tetrachloride (400 mL)NBS (77.0 g, 431 mmol) was added and, under light shielding,And the mixture was stirred at room temperature for 24 hours.After distilling off the solvent under reduced pressure,The residue was suspended in acetone (400 mL) / methanol (120 mL) and stirred at room temperature for 30 minutes.The precipitated solid was collected by filtration,This was suspended in acetonitrile (1.0 L)And the mixture was stirred at room temperature for 1 hour. After collecting the solid by filtration,After drying under reduced pressure, the compound (M-41)(Yield 46.0 g, yield 86percent)As a white solidIt was.
68%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h; Darkness
To a stirring solution of pyridine-4-ol (5g, 52.6 mmol) in CC14 (100 mL) at room temperature was added N-bromosuccinimide (18.72g, 105 mmol). The reaction mixture was allowed to stir under cover of darkness for 24 hours. The solvent was removed under reduced pressure, and the obtained solid was dissolved with acetone (100 mL) and MeOH (30 mL) and stirred for 5 min. The resulting slurry was filtered and the solid was rinsed with excess acetone/CH2Cl2. The solid material was vigorously stirred with acetonitrile, and filtered to yield Intermediate 31A (9.04g, 35.7 mmol, 68percent yield) as an off-white solid. MS (ES): m/z=253.8 [M+H]+. 3/4 NMR (400 MHz, MeOD) δ ppm 8.30 (2 H, s).
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
61
[ 626-64-2 ]
[ 7153-08-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
With iodine; sodium acetate; sodium hydroxide In water for 0.333333 h; Reflux
To a solution of starting material 4-hydroxypyridine (9) (5.01 g, 52.6mmol, 1.0equiv) in H2O (67 mL) was added a solution of NaOH (13.2 g, 330mmol, 6.3 equiv) and NaOAc (40.1 g, 489mmol, 9.3 equiv) in H2O (167 mL). After the solution was stirred and refluxed,powdered I2 (46.9 g, 184mmol, 3.5 equiv) was added to the solution. The solution was then acidified with 50percent AcOH, and neutralized with 40percent NaOH. This acidification neutralization procedure was conducted under reflux and repeated three times in 20min. The forth acidification was made until free iodine was precipitated. After sublimation of the I2 by boiling, the residue was filtered, washed with boiling water, and then dried to give the product 12 as a colorless powder (17.18 g, 49.5mmol, 94percent); mp 280 °C with decomposition; IR (KBr, cm-1): 3166, 2952, 2880, 2805, 2360, 1605, 1525, 1334, 1270, 1038, 846, 746, 712, 597; 1HNMR (300 MHz, DMSO-d6): δ 11.95 (1H, s, OH), 8.27 (2H, s, H2/6); 13CNMR (75 MHz, DMSO-d6): δ 170.52, 143.04, 86.59; ESI-HRMS (m/z) calcd for C5H2I2NO [M-H]- 345.8231, found 345.8231.
Reference：
[1] Tetrahedron Letters, 1997, vol. 38, # 14, p. 2467 - 2470
[2] Chemical Communications, 2012, vol. 48, # 26, p. 3233 - 3235
[3] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 5, p. 673 - 683
[4] Journal of Materials Chemistry, 2001, vol. 11, # 9, p. 2271 - 2281
[5] Angewandte Chemie - International Edition, 2016, vol. 55, # 40, p. 12398 - 12402[6] Angew. Chem., 2016, vol. 128, # 40, p. 12586 - 12590,5
[7] Patent: US6642237, 2003, B1, . Location in patent: Page/Page column 79; 186
62
[ 626-64-2 ]
[ 100-39-0 ]
[ 49826-70-2 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 80℃; for 2 h; Green chemistry
General procedure: Phenol (0.5 mmol), benzyl bromide(1.2 mmol) and KOH (2.0 mmol) was added to the DES (1 mL) and heated at temperature (80°C) for 2 h. After cooling to room temperature water was added and the product was extracted with ethyl acetate (1 3 mL) andanalyzed by GC–MS after the addition of hexamethylbenzene as an internal standard. The product was purified using column chromatography on silica gel(hexane/EtOAc::99:1). The pure product was characterized by 1H NMR and 13CNMR.Table 4 Comparison of different methodologies for benzylation of phenols with benzyl bromide
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 8, p. 800 - 802
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 8, p. 800 - 802
64
[ 626-64-2 ]
[ 33544-42-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
65
[ 626-64-2 ]
[ 1681-37-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
66
[ 626-64-2 ]
[ 5435-54-1 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 60 - 70℃; for 3 h; Inert atmosphere
Pyridin-4-ol 29 (300g, 3.15mol, 1wt) was charged portionwise to concentrated sulphuric acid (1500mL, 5vol) in a 20000mL flask under an atmosphere of nitrogen. The nitrating mixture was prepared by the cautious addition of concentrated sulphuric acid to concentrated nitric acid with stirring. The nitrating mixture was then carefully charged to the 20000mL reactor. The reaction mixture was heated at 60oC to 70oC over a period of 3 hours and allowed to cool to ambient temperature over 16 hours. The resulting reaction mixture was poured into 10000mL of ice/water. The mixture was basified to pH 11-12 by the dropwise addition of concentrated ammonia solution (8000mL, 26.7vol). The reaction mixture was concentrated under reduced pressure, the residue stirred in pyridine (10000mL, 33vol) and filtered. The resulting inorganic solids were dissolved in water (10000mL, 33vol) and extracted with 3 portions of pyridine (3x 2500L, 3x 8.3vol) the combined pyridine extractions were concentrated. The residue was stirred in acetone (6600mL, 22vol) for 1.5 hours, filtered and dried over 16 hours to give 716.1g of crude product. Crude 4-hydroxy-3-nitropyridine (623.6g) was slurried in water (1250mL, 2vol) for 60 minutes to remove residual inorganic material. The resulting slurry was filtered and dried for 72 hours to give the title compound (334.4g, 76percent, KF: 0.25percent).1H NMR (400MHz, DMSO): d 6.58 (d, J=6Hz, 1H), 7.85 (d, J=6Hz, 1H), 8.88 (s, 1H).
Reference：
[1] Organic Process Research and Development, 2004, vol. 8, # 6, p. 903 - 908
[2] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 8, p. 1235 - 1250[3] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 8, p. 1235 - 1250,16
[4] Journal of Materials Chemistry C, 2014, vol. 2, # 48, p. 10343 - 10356
[5] Heterocycles, 1999, vol. 51, # 4, p. 721 - 726
[6] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5292 - 5296
[7] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[8] Tetrahedron, 2006, vol. 62, # 48, p. 11054 - 11062
[9] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[10] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
[11] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
[12] Patent: CN105622495, 2016, A, . Location in patent: Paragraph 0020; 0021
67
[ 626-64-2 ]
[ 13091-23-1 ]
Reference：
[1] Tetrahedron, 2006, vol. 62, # 48, p. 11054 - 11062
[2] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[3] Patent: US5550118, 1996, A,
[4] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5292 - 5296
[5] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 8, p. 1235 - 1250[6] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 8, p. 1235 - 1250,16
[7] Journal of Materials Chemistry C, 2014, vol. 2, # 48, p. 10343 - 10356
68
[ 626-64-2 ]
[ 31872-62-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
[2] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NaH; In 1,4-dioxane;
Preparation of 4-aminopyridine To a solution of 4-hydroxypyridine (352 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2 CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150 C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2*50 mL), dried (Na2 SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove most of the residual NMP and DMPU. At this point there was evidence of 4-aminopyridine in the crude NMR: 1 H NMR (300 MHz, CDCl3) delta8.2 (d, 2 H), 6.6 (d, 2 H) as well as peaks characteristic of NMP and DMPU.
With potassium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dimethyl sulfoxide;
REFERENCE EXAMPLE 6 STR14 4-Amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride First, a mixture containing 2.40 g of 4-amino-2-chloro-5-nitrobenzotrifluoride, 2.0 g of 4-hydroxypyridine, 684 mg of 86% potassium hydroxide, 15 ml of dimethylsulfoxide was heated in an oil bath at 70 C. for 2 hours. The mixture was cooled and ice water was added to the mixture. Precipitated crude crystals were filtered and recrystallized with methanol/ethyl acetate to give 2.69 g of crystals of 4-amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride. Melting point: 274-275 C. Elemental analysis (analyzed as C12 H8 N3 O3 F3) Calculated: C,48.17; H,2.70; N,14.04; F,19.05 (%) Found: C,48.12; H,2.78; N,13.98; F,19.11 (%) H1 -NMR (d6 -DMSO)delta: 6.19 (2H, d, J=8 Hz), 7.17 (1H, s), 7.74 (2H, d, J=8 Hz), 8.17 (2H, br.s), 8.38 (1H, s).
EXAMPLE 1 There are prepared 4-dibutylaminopyridine by adding 0.1 mole of 4-hydroxypyridine and 15 grams of phosphorous pentoxide in the presence of 0.2 mole of dibutylamine at 250° C. for 16 hours. The dimethylaminopyridine was obtained from the Aldrich Chemical Company of Milwaukee, Wis. and the 4-pyrrolidinopyridine was obtained from the Reilley Tar and Chemical Company, Indianapolis, Ind.
In dibutylamine;
Example 1. There was prepared 4-dibutylaminopyridine by adding 0.1 mole of 4-hydroxypyridine and 15 grams of phosphorous pentoxide in the presence of 0.2 mole of dibutylamine at 250oC for 16 hours. The dimethylaminopyridine was obtained from the Aldrich Chemical Company of Milwaukee, Wisconsin and the 4-pyrrolidinopyridine was obtained from the Reilley Tar and Chemical Company, Indianapolis, Indiana.
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NaH; caesium carbonate; In 1,4-dioxane;
Preparation of 4-aminopyridine. To a solution of 4-hydroxypyridine (352 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150 C for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove most of the residual NMP and DMPU. At this point there was evidence of 4-aminopyridine in the crude NMR: 1H NMR (300 MHz, CDCl3) delta 8.2 (d, 2 H), 6.6 (d, 2 H) as well as peaks characteristic of NMP and DMPU.
(a) (S)-4-(1-methoxypropan-2-yloxy)pyridine (91) Pyridin-4-ol (10 g, 105.15 mmol), <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25 C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0HCl, extracted with Et2O (1*75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3*75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80 C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) delta 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168).
Example 106 2-Chloro-N-(1 -hydroxy-cyclohexylmethyl)-5-(pyridin-4-yloxy)- benzamide106.1 Sodium 2-chloro-5-(Dyridin-4-yloxy)benzoateA microwave vial was charged with copper (I) bromide (23 mg), Cs2C03 (2055 mg), 4- hydroxypyridine (300 mg) and <strong>[620621-48-9]methyl-2-chloro-5-iodobenzoate</strong> (1 122 mg) and flushed with argon. DMSO (4.7 mL) was added followed by 2-pyridyl acetone (0.043 mL) and the reaction mixture was heated to 100C for 3h in the microwave. It was diluted with EtOAc, filtered and the filtrate was washed with H20. The aqueous phase was basified with a 1 M solution of NaOH and extracted with EtOAc. The crude was purified by CC (RP C18, H20/CH3CN 1/0 to 8/2) to give 1 .2 g of the titled compound as a white powder.LC-MS (B): tR = 0.34 min; [M+H]+: 249.98
1.2 g
With 2-acetonylpyridine; caesium carbonate; copper(I) bromide; In dimethyl sulfoxide; at 100℃; for 3h;Microwave irradiation; Inert atmosphere;
106.1 Sodium 2-chloro-5-(pyridin-4-yloxy)benzoate A microwave vial was charged with copper (I) bromide (23 mg), Cs2CO3 (2055 mg), 4-hydroxypyridine (300 mg) and <strong>[620621-48-9]methyl-2-chloro-5-iodobenzoate</strong> (1122 mg) and flushed with argon. DMSO (4.7 mL) was added followed by 2-pyridyl acetone (0.043 mL) and the reaction mixture was heated to 100 C. for 3 h in the microwave. It was diluted with EtOAc, filtered and the filtrate was washed with H2O. The aqueous phase was basified with a 1M solution of NaOH and extracted with EtOAc. The crude was purified by CC(RP C18, H2O/CH3CN 1/0 to 8/2) to give 1.2 g of the titled compound as a white powder. LC-MS (B): tR=0.34 min; [M+H]+: 249.98
With choline chloride; urea; potassium hydroxide; at 80℃; for 2h;Green chemistry;
General procedure: Phenol (0.5 mmol), benzyl bromide(1.2 mmol) and KOH (2.0 mmol) was added to the DES (1 mL) and heated at temperature (80C) for 2 h. After cooling to room temperature water was added and the product was extracted with ethyl acetate (1 3 mL) andanalyzed by GC-MS after the addition of hexamethylbenzene as an internal standard. The product was purified using column chromatography on silica gel(hexane/EtOAc::99:1). The pure product was characterized by 1H NMR and 13CNMR.Table 4 Comparison of different methodologies for benzylation of phenols with benzyl bromide
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
To a mixture of <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (800 mg, 3.50 mmol) and pyridin- 4-ol (367 mg, 3.86 mmol) in N,N-dimethylformamide (10 mL) was added K2CO3 (1453 mg, 10.51 mmol). The mixture was heated to 80 C and stirred for 12 hours. The mixture was poured onto water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were concentrated to give crude 4-(oxetan-3-yloxy) pyridine which was combined with a batch of material that was prepared in a similar manner and purified by column chromatography (PE/EA = 2/1) to give 4-(oxetan-3-yloxy)-pyridine.
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃;
Take a 250mL eggplant-shaped bottle,Weigh 1.0 g of intermediate III-2 (5.0 mmol; 1.0 equiv),0.48 g of 4-hydroxypyridine (5.0 mmol; 1.0 equiv),2.5 g cesium carbonate (7.5 mmol; 1.5 equiv),0.6g potassium iodide (3.0mmol; 0.6equiv),40mL of N,N-dimethylformamide added to the bottle,Stir well,Then it was heated to 40C and reacted overnight.Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction. Then the reaction solution was filtered and evaporated to dryness.The resulting residue was treated with 2 mol/L NaOH aqueous solution,The ethyl acetate was re-dissolved and added to a separatory funnel.The aqueous phase is extracted 2 to 3 times with an equal volume of ethyl acetate.Combine the ethyl acetate layers,Add saturated aqueous sodium chloride,Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 5g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 10:1.The resulting etherification reaction product is collected,A total of 0.24 g of yellow solid IV-2c was obtained.Yield: 22.2%.
With N-chloro-succinamide; In water; acetonitrile; at 40 - 55℃;
A stirred solution of 4-pyridinol (1.0 eq.) in acetonitrile (15.0 vol.) and water(0.1 vol.) was heated to 40 C and then added N-chloro succinamide (2.2 eq.) in portions at 40-55 C. The reaction mixture was stirred for 6-8h at 45-55C, the progress of reaction was monitored by H PLC. After completion of the reaction the reaction were cooled and stirred for 3-4h. The solid was filtered and washed with acetonitrile (1x2.0 vol.) and water (5.0 vol + 2.0 vol). The product was dried in oven up to constant weight.
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