* 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] Chemistry of Heterocyclic Compounds, 1982, vol. 18, # 2, p. 212 - 212
[2] Chemistry of Heterocyclic Compounds, 1982, vol. 18, # 2, p. 212 - 212
2
[ 5029-67-4 ]
[ 108-95-2 ]
[ 51035-40-6 ]
[ 33421-36-2 ]
[ 98061-22-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 3, p. 1009 - 1015
3
[ 1008-89-5 ]
[ 33421-36-2 ]
Yield
Reaction Conditions
Operation in experiment
75%
With oxone; Ru(MesCO2)(4,4'-dibromobipyridine)(p-cymene); trifluoroacetic acid; trifluoroacetic anhydride In 1,2-dichloro-ethane at 140℃; for 8 h; Sealed tube; Green chemistry
General procedure: A mixture of 2-arylpyridines (1 eq), Ru(MesCO2)(L) (p-cymene) [L- 2,2’-bypyridine or 4,4’-dibromobipyridine] (5 molpercent), TFA: TFAA=0.6 ml:0.4 ml and Oxone (4 eq) was taken in a 30 ml sealed tube. 1 ml of DCE was added and the tube was then placed in an oil bath, stirred, and heated at 140°C. The progress of the reaction was checked after every 8 hrs. After complete consumption of starting material the reaction mixture was cooled to room temperature, quenched with brine and extracted with dichloromethane. The combined organic layer was dried with anhydrous Na2SO4, and vacuum evaporated. The crude product was purified over a column of silica gel (eluent: hexane/ethyl acetate) to afford the desired products.
67%
With water; oxygen In acetonitrile at 130℃; for 36 h;
EXAMPLE 1; Synthesis of 2-(pyridine-2-yl)phenol (Ib)In a 20 mL tube, 2-phenylpyridine (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under * oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 36 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.35 in 2:1 hexane: ether), the title product was obtained as a colorless oil (34.4 mg, 67percent). 1H NMR (400 MHz, CDCl3) δ 14.39 (s, IH), 8.52 (d, J== 4.8 Hz, IH), 7.93 (d, J= 8.4 Hz, IH), 7.87-7.84 (m, IH), 7.81 (d, J= 8.0 Hz, IH), 7.31 (td, J= 7.6, 1.2 Hz, IH), 7.27-7.24 (m, IH), 7.03 (d, J= 8.0 Hz, IH), 6.92 (td, J = 7.6, 1.2 Hz, IH); 13C NMR (100 MHz5 CDCl3) δ 160.29, 158.10, 146.08, 138.05, 131.77, 126.39, 121.79, 119.31, 119.05, 118.89; IR (thin film) v 2923, 1594, 1477, 1270 cm"1; HRMS (TOF) Calcd for CnH10NO (M+ H) 172.0762, found 172.0768.
30%
With 18O-labeled water In acetonitrile at 130℃; for 36 h;
EXAMPLE 6; Labeling ExperimentIn a 20 mL tube, substrate (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H218O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under N2. The <n="42"/>tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130°C for 24 h. The reaction mixture was diluted with 20 mL of CH2CI2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.35, in 2:1 hexane and ether) to give the product in 30percent yield. By the analysis of GC-MS, no I8O-labeled hydroxylated product was detected and only hydroxylated product Ib was obtained.
22%
With water; oxygen In dimethyl sulfoxide at 130℃; for 24 h;
Hydroxylation by CuF 2In a 20 mL tube, substrate (0.3 mmol, 1 equiv), CuF2 (30.5 mg, 0.3 mmol, 1 equiv) andH2O (27 μL, 1.5 mmol, 5 equiv) were dissolved in 1 mL of dry DMSO under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated <n="39"/>with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.35 in 2:1 hexane: ether), Ib was obtained as a colorless oil (11.2 mg, 22percent).
Reference：
[1] ACS Catalysis, 2016, vol. 6, # 9, p. 6050 - 6054
[2] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2925 - 2929
[3] Organic Letters, 2017, vol. 19, # 13, p. 3532 - 3535
[4] Tetrahedron Letters, 2017, vol. 58, # 38, p. 3743 - 3746
[5] Angewandte Chemie - International Edition, 2013, vol. 52, # 22, p. 5827 - 5831[6] Angew. Chem., 2013, vol. 125, # 22, p. 5939 - 5943,5
[7] Journal of the American Chemical Society, 2006, vol. 128, # 21, p. 6790 - 6791
[8] Patent: WO2007/123910, 2007, A2, . Location in patent: Page/Page column 27; 37
[9] Organic Letters, 2018, vol. 20, # 18, p. 5533 - 5536
[10] Advanced Synthesis and Catalysis, 2015, vol. 357, # 9, p. 2017 - 2021
[11] Organic Letters, 2018, vol. 20, # 21, p. 6799 - 6803
[12] Organic Letters, 2011, vol. 13, # 24, p. 6536 - 6539
[13] Patent: WO2007/123910, 2007, A2, . Location in patent: Page/Page column 27; 40-41
[14] Patent: WO2007/123910, 2007, A2, . Location in patent: Page/Page column 29-30; 37-38
[15] Synlett, 2013, vol. 24, # 20, p. 2687 - 2690
[16] Organometallics, 2014, vol. 33, # 17, p. 4442 - 4448
[17] Chemical Communications, 2018, vol. 54, # 59, p. 8202 - 8205
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 10, p. 3981 - 3994
[2] Tetrahedron Letters, 1984, vol. 25, # 36, p. 4045 - 4048
8
[ 502159-04-8 ]
[ 33421-36-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2002, vol. 344, # 8, p. 868 - 883
9
[ 694-59-7 ]
[ 88284-48-4 ]
[ 33421-36-2 ]
[ 54168-07-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 34, p. 6834 - 6839
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 34, p. 6834 - 6839
10
[ 109-04-6 ]
[ 33421-36-2 ]
Reference：
[1] Chemistry Letters, 2001, # 10, p. 1060 - 1061
[2] Synthetic Communications, 2001, vol. 31, # 6, p. 869 - 875
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1994, # 7, p. 1603 - 1610
[4] Organic Letters, 2018, vol. 20, # 18, p. 5533 - 5536
11
[ 694-59-7 ]
[ 73501-39-0 ]
[ 88284-48-4 ]
[ 33421-36-2 ]
[ 54168-07-9 ]
[ 1394900-26-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 34, p. 6834 - 6839
12
[ 58861-53-3 ]
[ 33421-36-2 ]
[ 1452876-10-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 22, p. 5827 - 5831[2] Angew. Chem., 2013, vol. 125, # 22, p. 5939 - 5943,5
With oxone; Ru(MesCO2)(4,4'-dibromobipyridine)(p-cymene); trifluoroacetic acid; trifluoroacetic anhydride; In 1,2-dichloro-ethane; at 140℃; for 8h;Sealed tube; Green chemistry;
General procedure: A mixture of 2-arylpyridines (1 eq), Ru(MesCO2)(L) (p-cymene) [L- 2,2?-bypyridine or 4,4?-dibromobipyridine] (5 mol%), TFA: TFAA=0.6 ml:0.4 ml and Oxone (4 eq) was taken in a 30 ml sealed tube. 1 ml of DCE was added and the tube was then placed in an oil bath, stirred, and heated at 140C. The progress of the reaction was checked after every 8 hrs. After complete consumption of starting material the reaction mixture was cooled to room temperature, quenched with brine and extracted with dichloromethane. The combined organic layer was dried with anhydrous Na2SO4, and vacuum evaporated. The crude product was purified over a column of silica gel (eluent: hexane/ethyl acetate) to afford the desired products.
67%
With water; oxygen;copper diacetate; In acetonitrile; at 130℃; for 36h;Product distribution / selectivity;
EXAMPLE 1; Synthesis of 2-(pyridine-2-yl)phenol (Ib)In a 20 mL tube, 2-phenylpyridine (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 muL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under * oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 36 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.35 in 2:1 hexane: ether), the title product was obtained as a colorless oil (34.4 mg, 67%). 1H NMR (400 MHz, CDCl3) delta 14.39 (s, IH), 8.52 (d, J== 4.8 Hz, IH), 7.93 (d, J= 8.4 Hz, IH), 7.87-7.84 (m, IH), 7.81 (d, J= 8.0 Hz, IH), 7.31 (td, J= 7.6, 1.2 Hz, IH), 7.27-7.24 (m, IH), 7.03 (d, J= 8.0 Hz, IH), 6.92 (td, J = 7.6, 1.2 Hz, IH); 13C NMR (100 MHz5 CDCl3) delta 160.29, 158.10, 146.08, 138.05, 131.77, 126.39, 121.79, 119.31, 119.05, 118.89; IR (thin film) v 2923, 1594, 1477, 1270 cm"1; HRMS (TOF) Calcd for CnH10NO (M+ H) 172.0762, found 172.0768.
30%
With 18O-labeled water;copper diacetate; In acetonitrile; at 130℃; for 36h;Mechanism;
EXAMPLE 6; Labeling ExperimentIn a 20 mL tube, substrate (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H218O (5.4 muL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under N2. The <n="42"/>tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130C for 24 h. The reaction mixture was diluted with 20 mL of CH2CI2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.35, in 2:1 hexane and ether) to give the product in 30% yield. By the analysis of GC-MS, no I8O-labeled hydroxylated product was detected and only hydroxylated product Ib was obtained.
22%
With water; oxygen;copper (II)-fluoride; In dimethyl sulfoxide; at 130℃; for 24h;Product distribution / selectivity;
Hydroxylation by CuF 2In a 20 mL tube, substrate (0.3 mmol, 1 equiv), CuF2 (30.5 mg, 0.3 mmol, 1 equiv) andH2O (27 muL, 1.5 mmol, 5 equiv) were dissolved in 1 mL of dry DMSO under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated <n="39"/>with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.35 in 2:1 hexane: ether), Ib was obtained as a colorless oil (11.2 mg, 22%).
With tert.-butylhydroperoxide; palladium dichloride; In water; chlorobenzene; at 140℃; for 24h;Green chemistry;
To a clean, dry carousel tube, PdCl2 (0.05mmol,8.87mg), 2-phenylpyridine (2mmol,0.286ml), tbutylhydroperoxide (70%solutioninwater, 6mmol, 1.04ml) and chlorobenzene (5mL) were added. The reaction was heated to 140 oC with stirring for 24 h before being cooled to rt. The reaction mixture was filtered through celite and the solvent removed. The crude mixture was then purified by flash column chromatography eluting with dichloromethane to give the phenolic intermediate.
Synthesis of Comparative Example 1 Bis[((pyridin-1-yl)-2-yl)phenoxy]zinc A 15 wt % solution of diethylzinc in toluene (24.4 mL, 27.16 mmol, 1.0 equiv) was added dropwise to a solution of <strong>[33421-36-2]2-(pyridin-2-yl)phenol</strong> (9.3 g, 54.32 mmol, 2.0 equiv) in tetrahydrofuran (100 mL) at room temperature, using a water-bath as a heat sink. The reaction mixture was stirred for 2 hours at room temperature under nitrogen. The suspension was filtered, the solid washed with toluene (3*5 mL) and tetra-hydrofuran (3*5 mL) then dried in a vacuum oven at 50 C. for 4 hours to give bis[((pyridin-1-yl)-2-yl)phenoxy]zinc (11 g, 100% yield) as a light yellow solid.
The intermediate (1mmol,0.172g) was added to a slurry of K2CO3 (4mmol,0.552g) in DMF and stirred for 1h at rt before MeI (1.2mmol,0.118g) was a dded and stirred for 1h at rt. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over MgSO4 and the solvent removed to give the title compound as a white solid (52%yieldovertwosteps). 1H NMR (300MHz,CDCl3) 8.70 (ddd,J=4.9,1.8,0.9Hz,1H), 7.87-7.74 (m,2H),7.68 (td,J=7.7,1.9Hz,1H),7.37(ddd,J=8.3,7.4,1.8Hz,1H),7.19(ddd,J=7.4,4.9,1.2Hz,1H),7.08(td,J=7.5,1.1Hz,1H),6.99(d,J=9.0Hz,1H),3.84(s,3H). Inaccordance with the literature.3
5.14 g (30 mmol) of Ligand E and 2.04 g (10 mmol) of Al(OCH(CH3)2)3were placed into a pressure-resistant tube. 50 mL of ethanol was added thereto and then a reaction was allowed to proceed at a temperature of 85 C. for 20 hours, and then, when the reaction stopped, the resultant was filtered while in a hot state, and washed with ethanol, dichloromethane (CH2Cl2), and hexane and then dried to obtain 3.60 g (67%) of Compound A.
In a nitrogen-purged glovebox an oven-dried 20 mL vial with a PTFE-coated magnetic stirbar was charged with triisopropyl borate (0.092 mL, 0.399 mmol), 3 ml of dry, degassed toluene and the 4-carbazolylcatechol (100 mg, 0.363 mmol). The mixture was stirred at room temperature for 1 h, then placed in the glovebox freezer for 15 min to cool to - 30 C. The vial was removed from the freezer and a solution of 2-pyridinylphenol (69 mg, 0.363 mmol) in 1 mL of toluene which had also been cooled in the glovebox freezer for 15 min was slowly added. The yellow mixture was allowed to stir and come to room temperature for 1 hour during which a white precipitate formed and the yellow color disappeared. The solvent was removed under reduced pressure to yield the desired product as a white solid. A yield was not determined. H NMR (400 MHz, Chloroform-
General procedure: The reactions are set up and run in a nitrogen-purged glovebox. Combine borinic acid with methylene chloride and add the protonated chelating ligand. Allow mixture to stir for 3 hours to 15 hours. Remove solvent under vacuum. Recrystallize product from a 10: 1 mixture of hexanes to methylene chloride. 13 General Procedure A was followed with the following changes: The borinic acid Al (0.30 g, 0.35 mmol) was weighed into a 20 mL glass vial with a PTFE-coated stirbar. The solid was suspended in methylene chloride (10 mL). While stirring the reaction mixture, solid <strong>[33421-36-2]2-(2-hydroxyphenyl)pyridine</strong> (0.10 g, 0.35 mmol) was added. The product (0.27 g) was isolated in 69% yield. H NMR (500 MHz, CD2C12): delta 8.24 (ddd, J = 6.0, 1.7, 0.8 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.25 - 7.17 (m, 8H), 7.21 - 7.11 (m, 5H), 7.09 - 7.00 (m, 8H), 7.00 - 6.89 (m, 9H) ppm. 13C NMR (126 MHz, CD2C12): delta 160.6, 151.2, 148.7, 146.7, 144.6, 143.4 (br), 141.5, 134.7, 134.6, 129.6, 126.1, 124.4, 123.9, 122.8, 121.5, 121.4, 119.8, 119.1 ppm. nB NMR (160 MHz, CD2C12): delta 5.3 ppm.
In dichloromethane; at 20℃;Inert atmosphere; Glovebox;
The reaction was set up in a nitrogen-purged glovebox. The borinic acid A6(0.35 g, 0.83 mmol) was dissolved in methylene chloride (40 mL). 2-(Pyridine-2-yl)phenol (0.14 g, 0.83 mmol from ArkPharm) was added. The resulting mixture was stirred overnight at room temperature. The solution was combined with 40 mL toluene and placed under vacuum until only 30 mL solvent remained. The resulting solution was heated to 105 C and kept at that temperature for 2 hours. After cooling to room temperature, solvent was removed in vacuo. The product was precipitated from methylene chloride / hexanes and rinsed with a small amount of toluene to leave the desired product (0.140 g, 29% yield) in > 95% purity. H NMR (500 MHz, CD2C12): delta 8.20 (dd, J = 6.0, 1.8 Hz, 1H), 8.04 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.07 (dd, J = 33.2, 8.0 Hz, 7H), 6.98 - 6.80 (m, 7H), 6.65 (s, 2H), 2.29 (s, 6H), 2.17 (s, 3H), 1.86 (s, 6H) ppm. 13C NMR (126 MHz, CD2C12): delta 160.2, 151.5, 147.1, 146.3, 145.3, 143.3, 141.6, 136.0, 134.6, 134.4, 132.4, 130.2, 125.9, 124.6, 123.0, 121.6, 121.0, 119.6, 119.5, 24.3, 21.0 ppm. nB NMR (160 MHz, CD2C12): delta 5.5 ppm.
With oxygen; copper diacetate; palladium diacetate; In dimethyl sulfoxide; at 120℃; under 760.051 Torr; for 23h;
General procedure: Pd(OAc)2 (9.00 mg, 0.04 mmol) and () (14.6 mg, 0.08 mmol) were placed in a screw-top test tube, and a solution of 3,4-dihydronaphthalen-l(2H)-one (8) (58.6 mg, 0.40 mmol) in DMSO (0.08 mL) was added at room temperature. Then 1,3-diaminopropane (6) (0.10 mL, 1.20 mmol) was added to the reaction mixture. The test tube was filled with oxygen and then the resulting mixture was stirred at 120 C for 16 h. After cooling down to room temperature, the palladium residue was removed by filtering through Celite. The organic solvent was removed under reduced pressure, and then the reaction was quenched by addition of 10% aqueous NH3 solution. The solution was extracted three times with a 4:1 mixture of hexane and EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over anhydrous Na2S04, and filtered through Celite. The filtrate was concentrated to afford 5,6-dihydrobenzo[h]quinoline (9) (51.1 mg, 70%) as a yellow oil.
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