* 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.
With tetrakis(triphenylphosphine) palladium(0) In toluene for 1.5 h; Reflux
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25percent EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99percent). LRMS m/z (M+H) 156.1 found, 156.2
99%
With tetrakis(triphenylphosphine) palladium(0) In toluene for 1.5 h; Reflux
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25percent EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99percent). All spectral data matched literature values. LRMS m/z (M+H) 156.1 found, 156.2 required. (1 .)
74%
With tetrakis(triphenylphosphine) palladium(0) In toluene at 125℃; for 1 h; Inert atmosphere
1 2- vinylquinoline (1-2) 2-chloroquinoline (1-1) (1.00 g, 6.1 mmol) in toluene (25 mL) was sparged with N2 gas for 5 min, and tributyl(vinyl)stannane (2.52 g, 2.33 mL, 8.0 mmol) and tetrakis(triphenylphosphine)palladium (0.353 g, 0.31 mmol) were added. The mixture was heated at 125 °C for 1 h, then cooled and concentrated in vacuo. The residue was suspended in CH2C12 (20 mL) and purified by silica gel flash column chromatography (80 g cartridge), eluting with 0-30percent EtOAc/hexanes over 20 min. The fractions containing the desired product (1-2) were pooled, and after solvent removal in vacuo, 700 mg (74percent) of a clear oil were obtained. LC/MS: m/z (M+H) = 156.0.
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 20, p. 8428 - 8431
[2] Chemical Communications, 2016, vol. 52, # 19, p. 3770 - 3772
3
[ 612-62-4 ]
[ 2005-43-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[2] Tetrahedron, 2005, vol. 61, # 6, p. 1407 - 1411
4
[ 67-66-3 ]
[ 95-53-4 ]
[ 91-22-5 ]
[ 120-72-9 ]
[ 612-62-4 ]
[ 612-59-9 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
5
[ 67-66-3 ]
[ 100-61-8 ]
[ 612-62-4 ]
[ 612-59-9 ]
[ 19493-45-9 ]
[ 25836-11-7 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
6
[ 67-66-3 ]
[ 121-69-7 ]
[ 91-22-5 ]
[ 612-62-4 ]
[ 612-59-9 ]
[ 25836-11-7 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
7
[ 67-66-3 ]
[ 100-61-8 ]
[ 612-62-4 ]
[ 612-59-9 ]
[ 19493-45-9 ]
[ 25836-11-7 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
8
[ 67-66-3 ]
[ 100-61-8 ]
[ 612-62-4 ]
[ 19493-45-9 ]
[ 25836-11-7 ]
[ 100-47-0 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
9
[ 612-62-4 ]
[ 124-41-4 ]
[ 6931-16-4 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 6, p. 1125 - 1129
[2] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1341 - 1346
[3] European Journal of Medicinal Chemistry, 2010, vol. 45, # 4, p. 1657 - 1662
[4] Chemische Berichte, 1882, vol. 15, p. 335
[5] Journal of the American Chemical Society, 1983, vol. 105, p. 1204
[6] Australian Journal of Chemistry, 2003, vol. 56, # 9, p. 913 - 916
10
[ 612-62-4 ]
[ 3315-60-4 ]
[ 91-22-5 ]
[ 6931-16-4 ]
[ 50-00-0 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 7, p. 1979 - 1986
[2] Journal of the American Chemical Society, 1982, vol. 104, # 7, p. 1979 - 1986
11
[ 67-56-1 ]
[ 612-62-4 ]
[ 124-41-4 ]
[ 6931-16-4 ]
Reference：
[1] Chemische Berichte, 1882, vol. 15, p. 335
12
[ 612-62-4 ]
[ 15793-77-8 ]
Yield
Reaction Conditions
Operation in experiment
71%
With hydrazine hydrate In ethanol for 16 h; Reflux
21.0 g (128.4 mmol) of 2-chloroquinoline are initially charged in 210 ml of ethanol. 64.3 g (1.3 mol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off and washed with a little ethanol. The product is initially air-dried and then dried under high vacuum.Yield: 14.5 g (71percent of theory)LC-MS (Method 1): Rt=1.95 min; MS (ESIpos): m/z=160 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.08 (br. s, 1H), 7.87 (d, 1H), 7.63 (d, 1H), 7.57-7.43 (m, 2H), 7.16 (t, 1H), 6.85 (d, 1H), 4.35 (br. s, 2H).
Reference：
[1] Patent: US2012/264704, 2012, A1, . Location in patent: Page/Page column 17
[2] Journal of the Chemical Society, 1913, vol. 103, p. 1981
[3] Journal of the Indian Chemical Society, 1981, vol. 58, p. 840 - 843
[4] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2006, vol. 65, # 2, p. 463 - 466
[5] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2007, vol. 66, # 4-5, p. 972 - 975
[6] European Journal of Medicinal Chemistry, 2011, vol. 46, # 10, p. 5021 - 5033
[7] Medicinal Chemistry Research, 2013, vol. 22, # 2, p. 782 - 793
[8] Polyhedron, 2013, vol. 54, p. 39 - 46
[9] Journal of Solution Chemistry, 2017, vol. 46, # 8, p. 1575 - 1595
[10] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1463 - 1473
[11] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2018, vol. 73, # 11, p. 885 - 893
13
[ 612-62-4 ]
[ 7803-57-8 ]
[ 15793-77-8 ]
Yield
Reaction Conditions
Operation in experiment
82%
for 2 h; Reflux
A suspension of 2-chloroquinoline (1.50 g,9.17 mmol) in hydrazine monohydrate (3 mL, 61.85 mmol) wasstirred under reflux for 2 h. The orange solid formed was collectedby filtration, washed with 100 mL of water and dried in vacuo. C9H9N3 (159.19): calcd. C 67.90, H 5.70, N26.40; found C 67.50, H 5.64, N 26.30.
Reference：
[1] European Journal of Inorganic Chemistry, 2013, # 1, p. 80 - 90
14
[ 612-62-4 ]
[ 15793-77-8 ]
[ 100146-17-6 ]
Reference：
[1] Chemische Berichte, 1900, vol. 33, p. 1885
15
[ 612-62-4 ]
[ 95-92-1 ]
[ 4491-33-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 15, p. 2699 - 2704
16
[ 612-62-4 ]
[ 75-00-3 ]
[ 124-38-9 ]
[ 91-22-5 ]
[ 4491-33-2 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1981, vol. 35, # 3, p. 185 - 192
17
[ 612-62-4 ]
[ 91-22-5 ]
[ 4491-33-2 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1981, vol. 35, # 3, p. 185 - 192
18
[ 612-62-4 ]
[ 108-20-3 ]
[ 108-18-9 ]
[ 73776-25-7 ]
Reference：
[1] Patent: US4592866, 1986, A,
[2] Patent: US4705853, 1987, A,
19
[ 612-62-4 ]
[ 73776-25-7 ]
Reference：
[1] Patent: US6228871, 2001, B1,
20
[ 612-62-4 ]
[ 124-38-9 ]
[ 73776-25-7 ]
Reference：
[1] Tetrahedron Asymmetry, 2004, vol. 15, # 24, p. 3919 - 3928
[2] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2178 - 2199
21
[ 612-62-4 ]
[ 13067-94-2 ]
[ 4225-86-9 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: at 0 - 20℃; for 1 h; Stage #2: With sodium carbonate In water
Pure H2SO4 was added onto 1 equiv of 29 at 0 °C. 3 equiv of 65percent HNO3 were then added dropwise and the reaction mixture was stirred at rt for 1 h. After the reaction mixture was poured into water, the solution was neutralized with Na2CO3 and extracted twice with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo.Compound 30 was obtained, after purification by column chromatography (eluent: cyclohexane-ethyl acetate 8:2), as a white solid in 54percent yield; mp 152 °C, Lit: 149 °C [40]. 1H NMR (200 MHz, CDCl3) δ: 7.52-7.56 (d, J = 8.6 Hz, 1H), 7.60-7.68 (m, 1H), 8.02-8.11 (m, 2H), 8.20 (d, J = 8.6 Hz, 1H). 13C NMR (50 MHz, CDCl3) δ: 124.6 (CH), 124.9 (CH), 125.8 (CH), 127.6 (C), 131.8 (CH), 138.6 (CH), 139.0 (C), 147.3 (C), 153.6 (C).Compound 31 was obtained, after purification by column chromatography (eluent: cyclohexane-ethyl acetate 8:2), as a pale yellow solid in 14percent yield; mp 134 °C, Lit: 133-134 °C [41]. 1H NMR (200 MHz, CDCl3) δ: 7.63 (d, J = 9.2 Hz, 1H), 7.80-7.88 (m, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.40 (dd, J = 1.1 and 7.7 Hz, 1H), 8.99 (d, J = 9.2 Hz, 1H). 13C NMR (50 MHz, CDCl3) δ: 119.9 (C), 124.9 (CH), 125.4 (CH), 128.8 (CH), 134.9 (CH), 135.5 (CH), 145.4 (C), 148.0 (C), 152.5 (C).
50%
With sulfuric acid; nitric acid In water at 0 - 20℃; for 2 h;
General procedure: H2SO4 (98percent) was added onto 1 equiv. of the quinoline derivatives, cooled with an ice bath. 5 equiv. of 65percent HNO3 were then added dropwise at 0 °C and the reaction mixture was stirred at rt for 1–4 h. The reaction mixture was successively poured into ice, neutralized with NaOH and extracted three times with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The crude residue was purified by chromatography on silica gel using adapted eluent and recrystallized if necessary to give compounds 1, 4, 6, 12, 15, 17 and 18. 8-nitroquinoline 1 (C9H6N2O2) was purified by chromatography on silica gel using dichloromethane as an eluent, separated from its 5-nitro isomer and isolated to yield a pale yellow solid (35percent, 2.7 mmol, 470 mg).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 75 - 86
[2] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 135 - 152
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8603 - 8614
[4] Journal fuer Praktische Chemie (Leipzig), 1916, vol. <2> 93, p. 379
[5] Journal of the American Chemical Society, 2017, vol. 139, # 44, p. 15576 - 15579
22
[ 612-62-4 ]
[ 13067-94-2 ]
Yield
Reaction Conditions
Operation in experiment
19%
at 0 - 40℃; for 0.833333 h;
A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 °C. The reaction mixture was heated at 40 °C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-5-nitroquinoline in 19percent yield as a yellow solid.
19%
at 0 - 40℃;
20: Synthesis of 2-oxo-l,2-dihydroquinoline-5-sulfonyl chloride.1. Synthesis of 2-chloro-5-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-5-nitroquinoline in 19percent yield as a yellow solid.
19%
at 0 - 40℃;
1. Synthesis of 2-chloro-5-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-5-nitroquinoline in 19percent yield as a yellow solid.
Reference：
[1] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 108
[2] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 71
[3] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 89
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6559 - 6578,20
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 22, p. 6559 - 6578
23
[ 612-62-4 ]
[ 13067-94-2 ]
[ 4225-86-9 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: at 0 - 20℃; for 1 h; Stage #2: With sodium carbonate In water
Pure H2SO4 was added onto 1 equiv of 29 at 0 °C. 3 equiv of 65percent HNO3 were then added dropwise and the reaction mixture was stirred at rt for 1 h. After the reaction mixture was poured into water, the solution was neutralized with Na2CO3 and extracted twice with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo.Compound 30 was obtained, after purification by column chromatography (eluent: cyclohexane-ethyl acetate 8:2), as a white solid in 54percent yield; mp 152 °C, Lit: 149 °C [40]. 1H NMR (200 MHz, CDCl3) δ: 7.52-7.56 (d, J = 8.6 Hz, 1H), 7.60-7.68 (m, 1H), 8.02-8.11 (m, 2H), 8.20 (d, J = 8.6 Hz, 1H). 13C NMR (50 MHz, CDCl3) δ: 124.6 (CH), 124.9 (CH), 125.8 (CH), 127.6 (C), 131.8 (CH), 138.6 (CH), 139.0 (C), 147.3 (C), 153.6 (C).Compound 31 was obtained, after purification by column chromatography (eluent: cyclohexane-ethyl acetate 8:2), as a pale yellow solid in 14percent yield; mp 134 °C, Lit: 133-134 °C [41]. 1H NMR (200 MHz, CDCl3) δ: 7.63 (d, J = 9.2 Hz, 1H), 7.80-7.88 (m, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.40 (dd, J = 1.1 and 7.7 Hz, 1H), 8.99 (d, J = 9.2 Hz, 1H). 13C NMR (50 MHz, CDCl3) δ: 119.9 (C), 124.9 (CH), 125.4 (CH), 128.8 (CH), 134.9 (CH), 135.5 (CH), 145.4 (C), 148.0 (C), 152.5 (C).
50%
With sulfuric acid; nitric acid In water at 0 - 20℃; for 2 h;
General procedure: H2SO4 (98percent) was added onto 1 equiv. of the quinoline derivatives, cooled with an ice bath. 5 equiv. of 65percent HNO3 were then added dropwise at 0 °C and the reaction mixture was stirred at rt for 1–4 h. The reaction mixture was successively poured into ice, neutralized with NaOH and extracted three times with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The crude residue was purified by chromatography on silica gel using adapted eluent and recrystallized if necessary to give compounds 1, 4, 6, 12, 15, 17 and 18. 8-nitroquinoline 1 (C9H6N2O2) was purified by chromatography on silica gel using dichloromethane as an eluent, separated from its 5-nitro isomer and isolated to yield a pale yellow solid (35percent, 2.7 mmol, 470 mg).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 75 - 86
[2] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 135 - 152
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8603 - 8614
[4] Journal fuer Praktische Chemie (Leipzig), 1916, vol. <2> 93, p. 379
[5] Journal of the American Chemical Society, 2017, vol. 139, # 44, p. 15576 - 15579
24
[ 612-62-4 ]
[ 4225-86-9 ]
Yield
Reaction Conditions
Operation in experiment
64%
at 0 - 40℃; for 0.833333 h;
A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 °C. The reaction mixture was heated at 40 °C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-8-nitroquinoline in 64percent yield as a yellow solid.
64%
at 0 - 40℃;
Intermediate 23: Synthesis of 2-oxo-l,2-dihydroquinoline-8-sulfonyl chloride.1. Synthesis of 2-chloro-8-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-8-nitroquinoline in 64percent yield as a yellow solid.
64%
at 0 - 40℃;
Intermediate 23: Synthesis of 2-oxo-l,2-dihydroquinoline-8-suIfonyl chloride. 1. Synthesis of 2-chloro-8-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-8-nitroquinoline in 64percent yield as a yellow solid.
38%
at 0 - 20℃;
General Procedure 15: 2-Chloro-8-nitroquinoline (Intermediate 24)Conc. H2SO4 was added slowly to 2-chloroquinoline (1.0 g, 6.13 mmol), followed by portionwise addition of potassium nitrate (800 mg, 7.97 mmol) at 0° C. The mixture was allowed to warm to room temperature overnight. After completion of the reaction (monitored by TLC and HPLCMS), the solution was poured slowly over ice, and the precipitate was extracted with EtOAc. The organic phase was washed with brine and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAC (17:3) as the eluent to give the title compound (450 mg, 38percent).MW: 208.61HPLCMS (4.5 min): [m/z]: 209
Reference：
[1] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 112
[2] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 75-76
[3] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 93; 94
[4] ChemMedChem, 2018,
[5] Australian Journal of Chemistry, 2003, vol. 56, # 1, p. 39 - 44
[6] Journal of the American Chemical Society, 2017, vol. 139, # 44, p. 15576 - 15579
[7] Patent: US2012/214803, 2012, A1, . Location in patent: Page/Page column 126
25
[ 612-62-4 ]
[ 100-51-6 ]
[ 116249-87-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1649 - 1655
26
[ 612-62-4 ]
[ 3492-64-6 ]
[ 116249-87-7 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 4452
27
[ 612-62-4 ]
[ 100-53-8 ]
[ 116249-87-7 ]
Reference：
[1] Patent: US2185182, 1937, ,
[2] Journal of Organic Chemistry, 1981, vol. 46, p. 5300 - 5304
28
[ 110-85-0 ]
[ 612-62-4 ]
[ 4774-24-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 140℃; for 2 h;
To a solution formed by dissolving 4.31 g of anhydrous piperazine in 30 ml of ethylene glycol, 818 mg of 2-chloroquinoline was added, and stirred at 140°C for 2 hours. After cooling, saturated aqueous sodium hydrogencarbonate solution was added, and the system was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (chloroform: methanol = 2:1) to provide 1.09 g (100percent) of 2-piperazin-1-ylquinoline. 1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz, 1H), 7.59(dd,J=1.5Hz,8.0Hz,1H), 7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.26~7.22(m,1H), 6.97(d,J=9.2Hz,1H),3.70(t,J=5.0Hz,4H),3.01(t,J=5.0Hz,4H) Mass,m/e:213(M+),145(base)To a solution formed by dissolving 4.31 g of anhydrous piperazine in 30 ml of ethylene glycol, 818 mg of 2-chloroquinoline was added, and stirred at 140°C for 2 hours. After cooling the reaction mixture, saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (chloroform : methanol = 2:1) to provide 1.09 g (100percent) of 2-piperazin-1-ylquinoline. 1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H), 7.59(dd,J=1.5Hz,8.0Hz,1H), 7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.26.similar.7.22(m,1H), 6.97(d,J=9.2Hz,1H),3.70(t,J=5.0Hz,4H),3.01(t,J=5.0Hz,4H) Mass,m/e:213(M+),145(base)
55%
for 2 h; Heating / reflux
A mixture of 2-chloroquinoline (2 g; 0.0122 mole ; 1EQ) and piperazine (10.5 g; 0.122 mole ; 10 eq. ) in DMSO (5 ml) was refluxed for 2h. The reaction mixture was cooled to RT, diluted with H20 (20 mi) and extracted with DCM (3X20ML). The organic phases were combined, dried (NA2SO4) and concentrated in vacuo. The crude product was purified by SPE cartridge (Si, 10G), ELUTING with a gradient of 0 to 1percent of MeOH in DCM affording the title compound (1.42 g; yield 55percent). MS; (ES) m/z: 214.3 [MH+]. C13H15N3 requires 213.28. 'H NMR (300MHZ, CDCI3) 5 : 7.85 (d, 1H), 7.74 (d, 1H), 7.97-7. 45 (t/d, 2H), 7.2 (t, 1 H), 6.9 (d, 1H), 3.67 (t, 4H), 2.98 (t, 4H).
52.2%
for 6 h; Reflux
A mixture of 2-chloroquinoline (2.0 g, 0.012 mol) and piperazine(2.1 g 0.024 mol) in toluene (15 mL) was refluxed stirring for 6 h.The reaction mixture was placed in an ice bath, diluted with 15 mLof water, acidified with concentrated HCl and filtrated. 40 mL ofwater was added to the filtrate and organic phase was separated.The aqueous phase was washed with ethyl ether and alkalized withsolid NaOH. The solid free base was separated by filtration andcrystallized from the mixture of ethanol and water to give compound(7).The title compound was isolated as a white powder. Yield: 52.2percent1.361 g, m.p. 81e84 C (lit. 81e83 C [23]).
36%
for 24 h; Heating / reflux
Step l0.20 g (2.45 mmol) of piperazine was dissolved in 15 mL of isopropanol in a dried round flask provided with nitrogen gas, 2-chloroquinoline 0.20 g (1.2 mmol) was added thereto, and the mixture was refluxed with stirring for 24 hrs. After adding water thereto, the reaction was extracted with ethyl acetate. The formed organic layer was washed with a saturated NaCl solution, dried over anhydrous magnesium sulfate, <n="48"/>and concentrated under a reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichlorornethane:methanol=4:l) to obtain 2-(piperazin-l-yl)quinoline (yield: 36percent).
Reference：
[1] Patent: EP1724267, 2006, A1, . Location in patent: Page/Page column 35; 68
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 21, p. 7549 - 7563
[3] Journal of Pharmaceutical Sciences, 1992, vol. 81, # 1, p. 99 - 103
[4] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 10, p. 1314 - 1320
[5] Patent: WO2004/46124, 2004, A1, . Location in patent: Page 41
[6] European Journal of Medicinal Chemistry, 2015, vol. 98, p. 221 - 236
[7] Patent: WO2008/153325, 2008, A1, . Location in patent: Page/Page column 45-46
[8] Polish Journal of Chemistry, 2001, vol. 75, # 1, p. 71 - 78
[9] Bulletin de la Societe Chimique de France, 1929, vol. <4> 45, p. 1177,1178
[10] Patent: US6043247, 2000, A,
[11] Molecules, 2008, vol. 13, # 10, p. 2426 - 2441
[12] Acta Poloniae Pharmaceutica - Drug Research, 2018, vol. 75, # 4, p. 891 - 901
29
[ 612-62-4 ]
[ 73568-25-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
With n-butyllithium; diisopropylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; acetic acid
EXAMPLE 7 2-Chloro-3-quinolinecarboxaldehyde To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92percent) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1 H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm-1.
92%
With n-butyllithium; diisopropylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; acetic acid
EXAMPLE 7 2-Chloro-3-quinolinecarboxaldehyde To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. Was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92percent) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 Hz), 8.0 (d, 1H, J=9 Hz), 7.90 (t, 1H, J=9 Hz), 7.67 (t, 1H, J=9 Hz); IR (nujol) 1685, 1575, 1045, 760, 745 cm-1.
Reference：
[1] Patent: US5212317, 1993, A,
[2] Patent: US5162532, 1992, A,
30
[ 612-62-4 ]
[ 68-12-2 ]
[ 73568-25-9 ]
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[ 612-62-4 ]
[ 7461-12-3 ]
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[ 612-62-4 ]
[ 128676-94-8 ]
[ 206563-13-5 ]
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[ 612-62-4 ]
[ 128676-85-7 ]
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[3] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 6, p. 958 - 961
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[ 612-62-4 ]
[ 455955-27-8 ]
[ 124467-23-8 ]
[ 77119-53-0 ]
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36
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[ 886853-93-6 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1341 - 1346
Pure H2SO4 was added onto 1 equiv of 29 at 0 C. 3 equiv of 65% HNO3 were then added dropwise and the reaction mixture was stirred at rt for 1 h. After the reaction mixture was poured into water, the solution was neutralized with Na2CO3 and extracted twice with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo.Compound 30 was obtained, after purification by column chromatography (eluent: cyclohexane-ethyl acetate 8:2), as a white solid in 54% yield; mp 152 C, Lit: 149 C [40]. 1H NMR (200 MHz, CDCl3) delta: 7.52-7.56 (d, J = 8.6 Hz, 1H), 7.60-7.68 (m, 1H), 8.02-8.11 (m, 2H), 8.20 (d, J = 8.6 Hz, 1H). 13C NMR (50 MHz, CDCl3) delta: 124.6 (CH), 124.9 (CH), 125.8 (CH), 127.6 (C), 131.8 (CH), 138.6 (CH), 139.0 (C), 147.3 (C), 153.6 (C).Compound 31 was obtained, after purification by column chromatography (eluent: cyclohexane-ethyl acetate 8:2), as a pale yellow solid in 14% yield; mp 134 C, Lit: 133-134 C [41]. 1H NMR (200 MHz, CDCl3) delta: 7.63 (d, J = 9.2 Hz, 1H), 7.80-7.88 (m, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.40 (dd, J = 1.1 and 7.7 Hz, 1H), 8.99 (d, J = 9.2 Hz, 1H). 13C NMR (50 MHz, CDCl3) delta: 119.9 (C), 124.9 (CH), 125.4 (CH), 128.8 (CH), 134.9 (CH), 135.5 (CH), 145.4 (C), 148.0 (C), 152.5 (C).
14%; 50%
With sulfuric acid; nitric acid; In water; at 0 - 20℃; for 2.0h;
General procedure: H2SO4 (98%) was added onto 1 equiv. of the quinoline derivatives, cooled with an ice bath. 5 equiv. of 65% HNO3 were then added dropwise at 0 C and the reaction mixture was stirred at rt for 1-4 h. The reaction mixture was successively poured into ice, neutralized with NaOH and extracted three times with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The crude residue was purified by chromatography on silica gel using adapted eluent and recrystallized if necessary to give compounds 1, 4, 6, 12, 15, 17 and 18. 8-nitroquinoline 1 (C9H6N2O2) was purified by chromatography on silica gel using dichloromethane as an eluent, separated from its 5-nitro isomer and isolated to yield a pale yellow solid (35%, 2.7 mmol, 470 mg).
With tetrakis(triphenylphosphine) palladium(0); In toluene; for 1.5h;Reflux;
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). LRMS m/z (M+H) 156.1 found, 156.2
99%
With tetrakis(triphenylphosphine) palladium(0); In toluene; for 1.5h;Reflux;
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). All spectral data matched literature values. LRMS m/z (M+H) 156.1 found, 156.2 required. (1 .)
74%
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 125℃; for 1h;Inert atmosphere;
1 2- vinylquinoline (1-2) 2-chloroquinoline (1-1) (1.00 g, 6.1 mmol) in toluene (25 mL) was sparged with N2 gas for 5 min, and tributyl(vinyl)stannane (2.52 g, 2.33 mL, 8.0 mmol) and tetrakis(triphenylphosphine)palladium (0.353 g, 0.31 mmol) were added. The mixture was heated at 125 C for 1 h, then cooled and concentrated in vacuo. The residue was suspended in CH2C12 (20 mL) and purified by silica gel flash column chromatography (80 g cartridge), eluting with 0-30% EtOAc/hexanes over 20 min. The fractions containing the desired product (1-2) were pooled, and after solvent removal in vacuo, 700 mg (74%) of a clear oil were obtained. LC/MS: m/z (M+H) = 156.0.
EXAMPLE 2 2-Vinylquinoline (G1) A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). All spectral data matched literature values. . LRMS m/z (M+H) 156.1 found, 156.2 required.
With sulfuric acid; nitric acid; at 0 - 40℃; for 0.833333h;
A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 C. The reaction mixture was heated at 40 C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-8-nitroquinoline in 64% yield as a yellow solid.
64%
With sulfuric acid; nitric acid; at 0 - 40℃;
Intermediate 23: Synthesis of 2-oxo-l,2-dihydroquinoline-8-sulfonyl chloride.1. Synthesis of 2-chloro-8-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-8-nitroquinoline in 64% yield as a yellow solid.
64%
With sulfuric acid; nitric acid; at 0 - 40℃;
Intermediate 23: Synthesis of 2-oxo-l,2-dihydroquinoline-8-suIfonyl chloride. 1. Synthesis of 2-chloro-8-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-8-nitroquinoline in 64% yield as a yellow solid.
52.3%
With sulfuric acid; nitric acid; at 0 - 40℃; for 0.833333h;
In a 2 L three-necked flask2-chloroquinoline Was dissolved 30 g (183.3 mmol) in 450 ml of sulfuric acid was cooled to 0 .A mixed solution of 48 ml of nitric acid and 24 ml of sulfuric acid was added over 20 minutes. The reaction mixture was heated at 40 for 30 minutes. When the reaction was completed, the mixture was quenched with 2500 ml of ice water. The precipitated solid was collected by filtration and purified by column chromatography to give 20 g (52.3%) of intermediate A.
38%
With sulfuric acid; potassium nitrate; at 0 - 20℃;
General Procedure 15: 2-Chloro-8-nitroquinoline (Intermediate 24)Conc. H2SO4 was added slowly to 2-chloroquinoline (1.0 g, 6.13 mmol), followed by portionwise addition of potassium nitrate (800 mg, 7.97 mmol) at 0 C. The mixture was allowed to warm to room temperature overnight. After completion of the reaction (monitored by TLC and HPLCMS), the solution was poured slowly over ice, and the precipitate was extracted with EtOAc. The organic phase was washed with brine and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAC (17:3) as the eluent to give the title compound (450 mg, 38%).MW: 208.61HPLCMS (4.5 min): [m/z]: 209
1.3 g
With sulfuric acid; nitric acid; at 0 - 25℃; for 1.0h;
A solution of 2-chloroquinoline B18 (2.00 g, 12.2 mmol) in H2S04 (20 mL) was cooled to 0C. HNO3 (3.55 g, 36.7 mmol) was added dropwise. The reaction solution was stirred at 25C for 1 hour to give a black brown solution. TLC showed the reaction was completed. The reaction solution was poured into water (50 mL), neutralized to pH = 7-8 with saturated Na2C03. The resulting mixture was extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by Combi Flash to give compound B19 (1.30 g) as a yellow solid.
EXAMPLE 108. Synthesis of 2-Chloro-5-(Quinolin-2-ylaminoVBenzoic Acid(Intermediate 56)56[0310] A solution of 2-chloro-quinoline (0.50 g, 3.1 mmol) and 5-amino-2-chloro- benzoic acid (0.53 g, 3.1 mmol) in acetic acid (10 mL) was heated at 100 0C for 2 h. Acetic acid was removed and the residue triturated in ethyl acetate. The title compound was obtained as a white solid (0.55 g, 59percent) after the filtration. MS (ES+): m/z 299 (M+H)+.
With n-butyllithium; nitrogen; In tetrahydrofuran; hexane; water;
Preparation 25 2-Chloro-3-quinolinecarboxylic acid To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in 300 ml of dry tetrahydrofuran under a continuous nitrogen blanket, at -70 C., was added 61.6 ml of 2.7M n-butyllithium in hexane (0.165 mole) while maintaining the temperature at -60 to -70 C. Subsequent to this addition, the temperature was maintained at -65 C. for approximately 20 minutes. A solution of 20 g (0.12 mole) of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise while maintaining the temperature at -60 to -70 C. After holding the temperature at -65 C. for 20 minutes subsequent to this addition, the entire reaction mixture was poured onto a large excess of dry ice. Most of the solvent was evaporated in a stream of air; the residual solvent was removed by rotary evaporation. The residue was taken up in 300 ml water, made basic with dil aq. sodium hydroxide and washed with 3*50 ml of isopropyl ether. The aqueous layer was filtered and made acidic (4 to 5 pH) with dilute aqueous hydrochloric acid. The precipitate was collected, washed with water, isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%) of white crystals, m.p. 190-210 C. (decomp.). A sample was recrystallized from isopropyl alcohol giving an analytical sample, m.p. 190-210 C. (decomp.). Analysis: Calculated for C10 H6 NO2: C, 57.85; H, 2.91; N, 6.75. Found: C, 57.80; H, 2.96; N, 6.6.
With n-butyllithium; nitrogen; In tetrahydrofuran; hexane; water;
PREPARATION 25 2-Chloro-3-quinolinecarboxylic acid To a solution of 21.3 ml (0.15 mole) of diisopropyl amine in 300 ml of dry tetrahydrofuran under a continuous nitrogen blanket, at -70 C., was added 61.6 ml of 2.7M n-butyllithium in hexane (0.165 mole) while maintaining the temperature at -60 to -70 C. Subsequent to this addition, the temperature was maintained at -65 C. for approximately 20 minutes. A solution of 20 g (0.12 mole) of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise while maintaining the temperature at -60 to -70 C. After holding the temperature at -65 C. for 20 minutes subsequent to this addition, the entire reaction mixture was poured onto a large excess of dry ice. Most of the solvent was evaporated in a stream of air; the residual solvent was removed by rotary evaporation. The residue was taken up in 300 ml water, made basic with dil aq. sodium hydroxide and washed with 3*50 ml of isopropyl ether. The aqueous layer was filtered and made acidic (4 to 5 pH) with dilute aqueous hydrochloric acid. The precipitate was collected, washed with water, isopropyl alcohol, and isopropyl ether, and dried, giving 15.4 g (62%) of white crystals, m.p. 190-210 C. (decomp.). A sample was recrystallized from isopropyl alcohol giving an analytical sample, m.p. 190- 210 C. (decomp.). Analysis: Calculated for C10 H8 NO2: C, 57.85; H, 2.91; N, 6.75. Found: C, 57.80; H, 2.96; N, 6.6.
With hydrogenchloride; n-butyllithium; triethylamine; diisopropylamine; triphenylphosphine; In tetrahydrofuran; tetrachloromethane; chloroform; water; toluene;
2-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinolin-5(4H)-one To 21.3 ml (0.15 mole) of diisopropylamine in 300 ml of tetrahydrofuran at -70° C. was added dropwise, at a rate to keep the temperature between -70° and -60° C., 61.1 ml of 2.7M n-butyllithium (0.16 mole). The temperature was maintained at -70° C.+-3° C. for 20 minutes. A solution of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise at a rate such that temperature remained between -70° and -60° C. After 20 minutes, the darkened reaction solution was poured onto a large excess of dry ice. The solvent was evaporated with a stream of air. The residue was taken up in 300 ml of water, made basic with dilute aqueous sodium hydroxide and washed with 3*50 ml of isopropyl ether. The aqueous phase was filtered and treated with dilute hydrochloric acid to ~pH 4-5, at which time a copious precipitate formed. The precipitate was collected and the filtrate reacidified yielding more precipitate. The precipitates were combined and washed with water, isopropyl alcohol, and isopropyl ether. Approximately 15.4 g (61.5percent) of off-white crystals were collected. To a suspension of 4.0 g of 60percent sodium hydride in oil (0.10 mole) in 100 ml tetrahydrofuran heated to reflux was added a solution of 5.5 g (0.048 mole) of N-methyl-3-pyrrolidinol and 10 g (0.048 mole) of the above prepared 2-chloro-3-quinolinecarboxylic and in 50 ml of tetrahydrofuran at such rate as to maintain good reflux. Reflux was maintained for 1.5 hr and the reaction mixture cooled. The solvent was removed by rotary evaporation yielding 26 g crude product. The entire crude product from above was suspended in 150 ml chloroform and hydrogen chloride bubbled in until pH of 5.76 was reached (note: after hydrogen chloride addition ceased, the pH continued to lower to 1.7). To this suspension was added 25.0 g (0.096 mole) of triphenylphosphine and 25 g of carbon tetrachloride. After 45 min, an additional 10 g (0.038 mole) of triphenylphosphine and 10 g of carbon tetrachloride was added. After 30 minutes, the heat was removed and the reaction driven to completion by dropwise addition of 20 ml of triethylamine. The reaction mixture was extracted with 3*50 ml of 3N hydrochloric acid. The aqueous extracts were combined, washed with 2*50 ml chloroform, made basic with concentrated sodium hydroxide and extracted with 3*50 ml of chloroform. The organic extracts were combined and concentrated by rotary evaporation. The syrupy residue was taken up in 100 ml of toluene and treated with activated charcoal. The toluene was removed by rotary evaporation and the syrupy residue crystallized from isopropyl alcohol, giving 1.5 g (11percent) of white crystals, m.p. 133°-134° C. Analysis: Calculated for C15 H15 N2 Cl: C, 61.97; H, 5.20; N, 9.63. Found: C, 61.73; H, 5.18 N, 9.54.
With hydrogenchloride; n-butyllithium; triethylamine; diisopropylamine; triphenylphosphine; In tetrahydrofuran; tetrachloromethane; chloroform; water; toluene;
2-(2-Chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinolin-5(4H)-one To 21.3 ml (0.15 mole) of diisopropylamine in 300 ml of tetrahydrofuran at -70° C. was added dropwise, at a rate to keep the temperature between -70° and -60° C., 61.1 ml of 2.7M n-butyllithium (0.16 mole). The temperature was maintained at -70° C.+-3° C. for 20 minutes. A solution of 2-chloroquinoline in 60 ml of tetrahydrofuran was added dropwise at a rate such that temperature remained between -70° and -60° C. After 20 minutes, the darkened reaction solution was poured onto a large excess of dry ice. The solvent was evaporated with a stream of air. The residue was taken up in 300 ml of water, made basic with dilute aqueous sodium hydroxide and washed with 3*50 ml of isopropyl ether. The aqueous phase was filtered and treated with dilute hydrochloric acid to ~pH 4-5, at which time a copious precipitate formed. The precipitate was collected and the filtrate reacidified yielding more precipitate. The precipitates were combined and washed with water, isopropyl alcohol, and isopropyl ether. Approximately 15.4 g (61.5percent) of off-white crystals were collected. To a suspension of 4.0 g of 60percent sodium hydride in oil (0.10 mole) in 100 ml tetrahydrofuran heated to reflux was added a solution of 5.5 g (0.048 mole) of N-methyl-3-pyrrolidinol and 10 g (0.048 mole) of the above prepared 2-chloro-3-quinolinecarboxylic and in 50 ml of tetrahydrofuran at such rate as to maintain good reflux. Reflux was maintained for 1.5 hr and the reaction mixture cooled. The solvent was removed by rotary evaporation yielding 26 g crude product. The entire crude product from above was suspended in 150 ml chloroform and hydrogen chloride bubbled in until pH of 5.76 was reached (note: after hydrogen chloride addition ceased, the pH continued to lower to 1.7). To this suspension was added 25.0 g (0.096 mole) of triphenylphosphine and 25 g of carbon tetrachloride. After 45 min, an additional 10 g (0.038 mole) of triphenylphosphine and 10 g of carbon tetrachloride was added. After 30 minutes, the heat was removed and the reaction driven to completion by dropwise addition of 20 ml of triethylamine. The reaction mixture was extracted with 3*50 ml of 3N hydrochloric acid. The aqueous extracts were combined, washed with 2*50 ml chloroform, made basic with concentrated sodium hydroxide and extracted with 3*50 ml of chloroform. The organic extracts were combined and concentrated by rotary evaporation. The syrupy residue was taken up in 100 ml of toluene and treated with activated charcoal. The toluene was removed by rotary evaporation and the syrupy residue crystallized from isopropyl alcohol, giving 1.5 g (11percent) of white crystals, m.p. 133°-134° C. Analysis: Calculated for C15 H15 N2 O2 Cl: C, 61.97; H, 5.20; N, 9.63. Found: C, 61.73; H, 5.18; N, 9.54.
N-[2-[(quinolin-2-yl)amino]ethyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.8 g (49%)
With sodium carbonate;
Step 1) Preparation of N-[2-[(Quinolin-2-yl)amino]ethyl]acetamide A mixture of 2-chloroquinoline (10.00 g, 0.061 mol), <strong>[1001-53-2]N-acetylethylenediamine</strong> (6.24 g, 0.061 mol), sodium carbonate (6.48 g, 0.061 mol), and 3-methyl-1-butanol (125 mL) was heated under reflux for 3 days. The mixture was cooled, filtered, and the filtrate was concentrated to give 16.3 g (>100%) of a yellow oil. Purification by flash chromatography (eluent 5% MeOH/CHCl3; 10% MeOH/1% Et3 N/CHCl3) gave 6.8 g (49%) of a yellow oil. NMR (DMSO-d6, 300 MH): delta1.82 (s, 3H), 3.28 (m, 2H), 3.45 (m, 2H), 6.75 (d, J=8.6, 1H), 7.14 (m, 2H), 7.48 (m, 2H), 7.61 (d, J=7.9, 1H), 7.84 (d, J=8.9, 1H), 8.02 (t, 1H).
5-(2-quinolinyloxy)-2-pyridine carboxaldehyde[ No CAS ]
[ 31191-08-9 ]
[ 110-53-2 ]
[ 693-25-4 ]
2-[2-(1-Hydroxyhexyl)-5-pyridyloxy]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.6 g (35%)
With ammonium chloride; In tetrahydrofuran; hexane; ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 6 2-[2-(1-Hydroxyhexyl)-5-pyridyloxy]quinoline To a suspension of sodium hydride (3.6 g, 0.15 mol) in dry DMF (150 ml) containing 2-chloroquinoline (24.5 g, 0.15 mol) was added dropwise a solution of <strong>[31191-08-9]5-hydroxypyridine-2-carboxaldehyde</strong> (18.5 g, 0.15 mol) in dry DMF (75 ml). The solution was stirred vigorously with a mechanical stirrer. After the addition was complete (90 min.), the reaction was heated to about 90° C. for 12 hours. Most of the DMF was removed, and the residue was carefully poured into cold water. The aqueous solution was extracted with ethyl acetate (4*30 ml), and the organic extract was washed with water, brine, and then dried over MgSO4. All volatiles were removed to leave the crude aldehyde intermediate (26 g) which was pure enough to be used in the next step. To a cold (-30° C.) solution of 5-(2-quinolinyloxy)-2-pyridine carboxaldehyde (8 g, 0.032 mol) in dry THF (125 ml) was added a solution of pentylmagnesium bromide (prepared from 4.83 g (0.032 mol) of 1-bromopentane and 0.78 g (0.032 mol) of Mg turnings in THF (60 ml). After the addition of the Grignard reagent was complete (-45° C.), the solution was stirred at this temperature for 90 minutes, and allowed to slowly warm up to room temperature in about 2 hours. The reaction was quenched by adding a saturated solution of ammonium chloride. The clear organic layer was decanted, and most of the volatiles were removed. The residue was taken up in ethyl acetate, and then washed with water, brine, and dried over MgSO4. After removal of the ethyl acetate the crude residue (7.7 g) was purified by HPLC (silica gel; 25percent ethyl acetate in hexane) to give 3.6 g (35percent) of pure product.
With diisopropylamine; In tetrahydrofuran; diethyl ether;
Step 1 2-chloro-quinoline-3-carboxylic acid To a cold solution LDA (60 mL, 120 mmol, 2M solution) in THF (400 mL) was added 2-chloroquinoline in THF(100 mL) at such a rate to maintain temperature <70 C. The reaction was stirred for 2 hours at which point C)2 was bubbled through the solution until the internal temperature reached -78 C. (-69 C. to -78 C.). The reaction was then allowed to gradually warm to room temperature overnight. After concentration to dryness, the residue taken up into diethylether and water. The layers were then separated, the aqueous phase acidified with 6N HCl and the solids collected. This material was used without further purification.
3-ethoxycarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.75 g (17.9 [MMOL)] of 3-ethoxycarbonyl-2-methyl-1 H-pyrrole are added at [20C] under an argon atmosphere to 0.756 g (18.9 [MMOL)] of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 cm3 [OF DIMETHYLFORMAMIDE.] After stirring at [20C] for 0.2 hour, 0.114 g (1.79 mmol) of copper powder and 2.93 g (17. [9 MMOL)] of 2-chloroquinoline are added. After stirring at [140C] for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 cm3 of water and then extracted with 4 times 50 cm3 of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 6 g of an oil, which oil is purified by flash chromatography [eluent : cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 2.2 g [OF 3-ETHOXYCARBONYL-2-METHYL-1-(QUINOL-2-YL)-] 1 H-pyrrole are obtained in the form of a yellow oil. Mass spectrum [(EL)] : m/e 280 (M+.), m/e 251, m/e 206.
3-methoxycarbonyl-5-methyl-1-(quinol-2-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.63 g (11.8 [MMOL)] of potassium carbonate are added at [25C] under an argon atmosphere to 0.895 g (4.73 [MMOL)] of [3-METHOXYCARBONYL-5-METHYL-1 H-INDOLE] in 10 cm3 of dimethyl sulphoxide. After stirring at [25C] for 0.5 hour, 0.774 g (4.73 [MMOL)] of 2-chloroquinoline is added. After stirring at [100C] for 48 hours, the reaction mixture is cooled and diluted with 100 cm3 ethyl acetate and then washed with 3 times 50 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.2 g of a residue which is recrystallised under hot conditions from 30 cm3 of cyclohexane and 6 cm3 of ethyl acetate to give 0. 8 g of [3-METHOXYCARBONYL-5-METHYL-] [1-(QUINOL-2-YL)-1 H-INDOLE] in the form of a white solid melting at [143C.]
With sulfuric acid; nitric acid; at 0 - 40℃; for 0.833333h;
A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 C. The reaction mixture was heated at 40 C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-5-nitroquinoline in 19% yield as a yellow solid.
19%
With sulfuric acid; nitric acid; at 0 - 40℃;
20: Synthesis of 2-oxo-l,2-dihydroquinoline-5-sulfonyl chloride.1. Synthesis of 2-chloro-5-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-5-nitroquinoline in 19% yield as a yellow solid.
19%
With sulfuric acid; nitric acid; at 0 - 40℃;
1. Synthesis of 2-chloro-5-nitroquinoline.A solution of nitric acid (16 mL) and sulfuric acid (8 mL) was added over period of 20 min to a solution of 2-chloroquinoline (61.1 mmol) in sulfuric acid (150 mL) at 0 0C. The reaction mixture was heated at 40 0C for 30 min and was quenched with ice water (800 mL). The precipitated solids were collected by filtration and purified by Flash chromatography (20/1 petroleum ether/ethyl acetate) to provide 2-chloro-5-nitroquinoline in 19% yield as a yellow solid.
With sulfuric acid; nitric acid; at -10 - 20℃; for 1.33h;
To a solution of 12b (5.00 g, 30.6 mmol) in H2SO4 (15 mL) was added HNO3 (2.04 mL, 45.9 mmol) at -10 C and the reaction mixture was stirred at -10 C for 20 min and at room temperature for 1 h. The mixture was poured into crushed-ice, filtered and, washed with water. The obtained crude title compound (5.64 g), which was used in the following reaction without further purification.
Preparation of 5-(Quinolin-2-yl)picolinonitrile (T124) 5-(Quinolin-2-yl)picolinonitrile T124 was prepared using general procedure A from 2-chloroquinoline (82 mg, 0.5 mmol) and <strong>[741709-63-7]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile</strong> (115 mg, 0.5 mmol). The product was obtained as yellow solid (3 mg, 3%). NMR (400 MHz, CDCl3): delta 9.48 (dd, J=2.4, 0.8 Hz, 1H), 8.69 (dd, J=8.0, 2.0 Hz, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.90 (dd, J=8.4, 1.2 Hz, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H); MS (ESI):232 (M+H+).
3%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation;
General procedure: A mixture of aryl/heterocyclic halide (1.0 equiv.), boronic acid or boronate ester (1.1-1.5 equiv.), K2CO3 (3.0 equiv.) and Pd[PPh3]4 (0.01 -0.05 equiv) in DMF (30 mL) was irradiated in a Biotage Emrys Initiator microwave reactor (250 W) at 100 C for 30 min. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified on flash column chromatography over silica gel using EtOAc:Hexanes or EtOAc:DCM or MeOH:DCM as the eluent to afford the desired biaryl products. 5-(Quinolin-2-yl)picolinonitrile T124 was prepared using general procedure A from 2-chloroquinoline (82 mg, 0.5 mmol} and 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)picolinonitrile (1 15 mg, 0,5 mmol). The product was obtained as yellow solid (3 mg, 3%).
at 150℃; for 0.25h;Microwave irradiation; Neat (no solvent);
General procedure: A mixture of 2-chloroquinoline 17 (200 mg, 1.22 mmol) and aniline (455 mg, 4.89 mmol) was heated 15 min at 150 C using microwave synthesizer. The resulting reaction mixture was dissolved in ethyl acetate (50 ml) and washed with saturated Na2CO3 (2× 50 ml) and H2O (2× 50 ml). The organic phase was dried (Na2SO4) and evaporated to leave a clear oil. This oil was purified by flash chromatography (silica gel) eluting with dichloromethane to give 12a as a light brown solid (133 mg, 49%).
(2-methoxy-5-trifluoromethyl-phenyl)-quinolin-2-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
at 150℃; for 0.25h;Microwave irradiation; Neat (no solvent);
General procedure: A mixture of 2-chloroquinoline 17 (200 mg, 1.22 mmol) and aniline (455 mg, 4.89 mmol) was heated 15 min at 150 C using microwave synthesizer. The resulting reaction mixture was dissolved in ethyl acetate (50 ml) and washed with saturated Na2CO3 (2× 50 ml) and H2O (2× 50 ml). The organic phase was dried (Na2SO4) and evaporated to leave a clear oil. This oil was purified by flash chromatography (silica gel) eluting with dichloromethane to give 12a as a light brown solid (133 mg, 49%).
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;
A mixture of Cs2C03 (3.2 g, 10.0 mmol), 2-chloro-quinoline (0.8 g, 5.0 mmol) and tert-butyl azetidin-3-ylcarbamate (0.8 g, 5.0 mmol) was dissolved in DMF (20 mL) and the resulting mixture was heated to 100 C overnight. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2S04, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give tert-butyl (l-(quinolin-2-yl)azetidin-3- yl)carbamate (0.8 g, 2.9 mmol, 53% yield) as white solid. ESI-MS (M+l): 300 calc. for
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; lithium hydroxide; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere;
General procedure: To a solution of 2-chloroheteroaryl compound 1 (0.50 mmol) in 1,4-dioxane (4.0 mL) were added pinacol boronate 3, 5, or 7 (0.60 mmol), Pd(OAc)2 (1.1 mg, 5.0 mumol), S-Phos (4.1 mg, 10.0 mumol), and 2 M LiOH solution (1.0 mL, 2.0 mmol) at room temperature, and the mixture was stirred for 30 min at 80 C under N2 atmosphere. The reaction was quenched by adding water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica-gel column chromatography. The solvent was removed in vacuo, and the residue was triturated with Et2O to give biaryl compounds.
General procedure: A mixture of 5 (1 eq), substituted aniline (1 eq), and EtOH (30 mL) was refluxed for an appropriate time. After the completion of the reaction (TLC monitoring), the reaction mixture was neutralized with saturated NaHCO3 until pH 7 and then partitioned between H2O (50 mL) and CH2Cl2 (50 mL × 3). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The resulting residue was purified by column chromatography (hexane/CH2Cl2) and crystallized from EtOH to give 6-23.
General procedure: A mixture of 5 (1 eq), substituted aniline (1 eq), and EtOH (30 mL) was refluxed for an appropriate time. After the completion of the reaction (TLC monitoring), the reaction mixture was neutralized with saturated NaHCO3 until pH 7 and then partitioned between H2O (50 mL) and CH2Cl2 (50 mL × 3). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The resulting residue was purified by column chromatography (hexane/CH2Cl2) and crystallized from EtOH to give 6-23.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1.0h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added <strong>[113853-16-0]ethyl 2-amino-1,3-oxazole-5-carboxylate</strong> (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃;
Cesium carbonate (4.68 g, 14.4 mmol), 2-chloroquinoline (0.782 g, 4.8 mmol) and <strong>[217806-26-3]tert-butyl azetidin-3-yl-carbamate hydrochloride</strong> (1.0 g, 4.8 mmol) were dissolved in dry dimethylformamide (15 mL) and the resulting mixture was heated at 120 C. overnight. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2*50 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), then dried over sodium sulfate. The organic was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 40% ethyl acetate in petroleum ether) to give tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)-carbamate (1.14 g, 3.84 mmol, 80% yield) as white solid.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 130℃; for 4h;Inert atmosphere;
0376] Sodium carbonate (43.5 g, 411 mmol) was added to a mixture of 3-bromophenylboronic acid (25.0 g, 124 mmol), 1-chloroquinoline (20.3 g, 124 mmol), and toluene (250 mL). Nitrogen bubbling was conducted for 30 minutes while stirring the resultant mixture. Pd(PPh3)4 (4.31 g, 3.73 mmol) was added thereto, and this mixture was stirred at 130°C for 3.5 hours. After the disappearance of the starting materials was ascertained by TLC, the reaction mixture was extracted twice with toluene. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain intermediate 39 (28.4 g; yield, 80percent).
80%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 130℃; for 3.5h;
Sodium carbonate (43.5 g, 411 mmol) was added to a mixture of 3-bromophenylboronic acid (25.0 g, 124 mmol), 1-chloroquinoline (20.3 g, 124 mmol), and toluene (250 mL). Nitrogen bubbling was conducted for 30 minutes while stirring the resultant mixture. Thereto was added Pd(PPh3)4 (4.31 g, 3.73 mmol). This mixture was stirred at 130° C. for 3.5 hours. After the disappearance of the starting materials was ascertained by TLC, the reaction mixture was extracted with toluene twice. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain intermediate 25 (28.4 g; yield, 80percent).
methyl 3-methyl-4-(quinolin-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 8h;Inert atmosphere;
Compound 26 was prepared from 2-chloroquinoline and <strong>[473596-87-1]methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (25) in a manner similar to that described for compound 11a, with a yield of 67% as a beige solid. 1H NMR (DMSO-d6) d 2.45(s, 3H), 3.90 (s, 3H), 7.63-7.69 (m, 2H), 7.75 (d, 1H, J = 8.5 Hz),7.79-7.84 (m, 1H), 7.91-7.98 (m, 2H), 8.04-8.08 (m, 2H), 8.49 (d,1H, J = 8.3 Hz); MS (ESI) m/z 278 [M+H]+.
3-[methyl(quinolin-2-yl)amino]propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;
To a mixture of 2-chloroquinoline (2.50 g, 15.3 mmol) and piperidine-4-ylmethanol (18, 5.28 g, 45.8 mmol) in DMF (20 mL) was added K2CO3 (3.17 g, 22.9 mmol), and the mixture was stirred at 110°C for 1 d. After cooling at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water, and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (20?50percent EtOAc in hexane) to give 15e (3.69 g, quant) as a pale yellow solid.
tert-butyl 3-((quinolin-2-ylamino)methyl)-pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2-[di-(3S,5S,7S)-adamantan-1-ylphosphino]-N,N-dimethylaniline; sodium t-butanolate; In toluene; at 65℃; for 16h;Inert atmosphere;
To a solution of tert-butyl 3 -(aminomethyl)pyrrolidine- 1 -carboxylate (0.2 mmol), 2- chloroquinoline (0.2 mmol) and sodium tert-butoxide (0.6 mmol) in toluene (1 ml) were added catalytic amounts of allyl palladium and Me-Dalphos at rt under nitrogen. The reaction mixture was stirred at 65C for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc 1:1) yielding tert-butyl 3-((quinolin-2- ylamino)methyl)-pyrrolidine- 1 -carboxylate. MS: ES+ 328.4.
2-(3,5-dichloro-2-fluorophenyl)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); tetrabutylammomium bromide; potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
2-(6-chloro-2,3-difluorophenyl)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); tetrabutylammomium bromide; potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
2-(2,3-dichloro-6-fluorophenyl)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With PdCl(1,4-bis(diphenylphosphino)butane)(C3H5); tetrabutylammomium bromide; potassium pivalate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Green chemistry;
General procedure: As a typical experiment, the reaction of the 2-halopyridine (1 mmol), fluorobenzene derivative (2.5 mmol) and PivOK (0.154 g, 1.1 mmol) at 150 C during 16 h in DMA (3 mL) in the presence of PdCl(C3H5)(dppb) (12 mg, 0.02 mmol) (see tables or schemes) under argon affords the arylation product after evaporation of the solvent and filtration on silica gel
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