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Chemical Structure| 5332-25-2
Chemical Structure| 5332-25-2
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Product Details of [ 5332-25-2 ]

CAS No. :5332-25-2 MDL No. :MFCD00024023
Formula : C9H6BrN Boiling Point : -
Linear Structure Formula :- InChI Key :IFIHYLCUKYCKRH-UHFFFAOYSA-N
M.W : 208.05 Pubchem ID :79243
Synonyms :
6-Br-Quinoline

Calculated chemistry of [ 5332-25-2 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 49.44
TPSA : 12.89 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.56 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.19
Log Po/w (XLOGP3) : 2.83
Log Po/w (WLOGP) : 3.0
Log Po/w (MLOGP) : 2.56
Log Po/w (SILICOS-IT) : 3.17
Consensus Log Po/w : 2.75

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.59
Solubility : 0.054 mg/ml ; 0.00026 mol/l
Class : Soluble
Log S (Ali) : -2.76
Solubility : 0.363 mg/ml ; 0.00174 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.56
Solubility : 0.00574 mg/ml ; 0.0000276 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.19

Safety of [ 5332-25-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5332-25-2 ]

* 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.

  • Upstream synthesis route of [ 5332-25-2 ]
  • Downstream synthetic route of [ 5332-25-2 ]

[ 5332-25-2 ] Synthesis Path-Upstream   1~36

  • 1
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1894, vol. <2> 49, p. 534,539
  • 2
  • [ 5332-25-2 ]
  • [ 396-30-5 ]
Reference: [1] Applied Catalysis A: General, 2011, vol. 394, # 1-2, p. 191 - 194
  • 3
  • [ 56-81-5 ]
  • [ 106-40-1 ]
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YieldReaction ConditionsOperation in experiment
81% With tungstic acid functionalized KIT-6 In water at 200℃; for 3 h; Autoclave General procedure: All the reactions were carried out in a 50 mL stainless steel autoclave (Scheme 1). A mixture of glycerol (1 g, 1 equiv.), aniline (0.58 g, 0.5 equiv.), water (2.5 mL) and W-KIT-6 (100 mg) was charged in to the autoclave simultaneously and finally heated to 200 °C with stirring for 3 h. On completion of the reaction (monitored by TLC), the autoclave was cooled to room temperature and the catalyst was removed by filtration. Ethyl acetate (10 mL) and water (5 mL) were added to the reaction mixture and stirred well for few minutes. The organic layer was dried over anhydrous Na2SO4 and the crude was purified by column chromatography using 60-120 mesh silica with ethylacetate/hexane as eluent to afford the desired product in good yield. The product was analyzed and confirmed with GC-MS and 1H NMR and 13C NMR spectroscopy (Table 1 and Figs S1-S5, Supplementary Data).
42% With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 140℃; Step 1.
6-Bromoquinoline
4-Bromobenzenamine (25 g, 145.32 mmol, 1.00 equiv), sodium 3-nitrobenzenesulfonate (55.5 g, 246.64 mmol, 1.70 equiv), propane-1,2,3-triol (50.8 g, 551.63 mmol, 3.80 equiv), and sulfuric acid (170 mL, 70percent) were placed into a 500-mL round-bottom flask.
The resulting solution was stirred overnight at 140° C.
The pH value of the solution was adjusted to with 10percent aqueous sodium hydroxide.
The resulting solution was extracted with 5*150 mL of ethyl acetate.
The organic layers were combined and dried over anhydrous sodium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:50).
This resulted in 17.2 g (42percent) of 6-bromoquinoline as yellow oil.
28.6% at 100℃; for 20 h; Reflux Glycerol (60.0mL, 0.82mol), FeSO4·7H2O (7.00g, 0.025mol), p-bromoaniline (34.40g, 0.20mol), and nitrobenzene (12.5mL, 0.13mol) were added to a three-necked round bottom flask with mechanical stirring. H2SO4 (35.0mL, 0.64mol) was added to the system slowly while kept the temperature blow 100°C. The mixture was then heated to reflux for 20h. After cooling to r.t., adjusted pH to 7 with 50percent NaOH aq. solution and extracted with diethyl ether. The extraction was dried over MgSO4 and concentrated in vacuo. The product was isolated by reduced pressure distillation. Fraction was collected at 138–140°C, 16Torr (Ref.[13]. 161–162°C, 22Torr). Light yellow liquid was afforded (11.90g, 28.6percent yield). 1H NMR (300MHz, DMSO-d6) δ (ppm): 9.00 (d, J=4.1Hz, 1H), 8.37 (d, J=8.3Hz, 1H), 8.28 (d, J=1.7Hz, 1H), 8.02 (d, J=9.2Hz, 1H), 7.89 (dd, J1=9.0Hz, J2=2.1Hz, 1H), 7.62 (q, J=8.3Hz, 1H).
Reference: [1] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2016, vol. 55A, # 8, p. 919 - 928
[2] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 90
[3] Dyes and Pigments, 2013, vol. 99, # 1, p. 240 - 249
[4] Patent: WO2006/2981, 2006, A1, . Location in patent: Page/Page column 96
[5] Chemische Berichte, 1882, vol. 15, p. 559
[6] Patent: CN105837503, 2016, A, . Location in patent: Paragraph 0026-0027
  • 4
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YieldReaction ConditionsOperation in experiment
97% With diethylazodicarboxylate In chloroform; toluene for 12 h; Reflux General procedure: To a 10 mL round bottom flask equipped with a magnetic stir bar, 1,2,3,4-tetrahydroquinoline (0.5 mmol), DEAD solution 40 wtpercent in toluene (2.2 eq, 1.1 mmol, 0.5 mL), and CHCl3 (1.0 mL) was added. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated on rotary evaporator. The residue was purified by column chromatography with EtOAc:hexane (1:5) to give quinolines. In case of 2f and 2m, the product spot was close to the spot of the remained DEAD. To eliminate the remained DEAD, 1 equivalent of PPh3 was added after the reaction and the reaction mixture was stirred.[19] After 10 min, the reaction mixture was concentrated on rotary evaporator. The residue was purified by column chromatography with CHCl3:hexane (1:1) to give quinolines.
78% With cobalt(II) 5,10,15,20-tetraphenylporphyrin; oxygen In N,N-dimethyl-formamide for 12 h; General procedure: N-Heterocyclic amine (0.50 mmol), CoTPP (10 mg) and DMF (2 mL) were mixed in a carousel reaction tube. The reaction mixture was stirred at 120 C under oxygen atmosphere, the reaction was sampled periodically and monitored by TLC (petroleum ether/ethyl acetate (10:1 v/v)). After the reaction, the reaction mixture was then cooled to room temperature and purified using flash chromatography to give the corresponding product. All the dehydrogenation products are known, and their NMR spectra were consistent with the literature. NMR spectra were recorded at 25 C on an Bruker AVANCE III 400-NMR spectrometer at 400 MHz for 1H and 100 MHz for 13C, using CDCl3 as solvent with TMS as the internal standard. Thin-layer chromatography was performed on silica gel 60 F254 (Sinopharm) thin-layer chromatography plates using petroleum ether/ethyl acetate (10:1 v/v) as the mobile phase.
71% With oxygen; iron(II) chloride In para-xylene; dimethyl sulfoxide at 110℃; for 26 h; Schlenk technique General procedure: To a Schlenk tube equipped with a magnetic stir bar were added8-methyl-1,2,3,4-tetrohydroquinoline (0.50 mmol), FeCl2 (1.9mg, 1.5·10–2 mmol), DMSO (31.2 mg, 0.4 mmol), and p-xylene (1mL). The reaction mixture was stirred at 110 °C under anoxygen atmosphere using a balloon and monitored by TLC. Afterthe reaction, the mixture was cooled to room temperature andpurified using flash chromatography (hexane–EtOAc, 10:1) togive the corresponding product 8-methylquinoline in 70percent yield.8-MethylquinolineColorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.93 (m, 1 H), 8.10(m, 1 H), 7.64 (d, J = 4.0 Hz, 1 H), 7.54 (m, 1 H), 7.43–7.35 (m, 2H) 2.82 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 149.2, 147.3,137.1, 136.3, 129.6, 128.3, 126.3, 125.9, 120.8, 18.2. HRMS: m/zcalcd for [C10H9N + H+]: 144.0813; found: 144.0813.
Reference: [1] Organic Letters, 2015, vol. 17, # 18, p. 4404 - 4407
[2] Synthetic Communications, 2018, vol. 48, # 11, p. 1291 - 1298
[3] Chemistry - A European Journal, 2017, vol. 23, # 57, p. 14167 - 14172
[4] Angewandte Chemie - International Edition, 2017, vol. 56, # 11, p. 3080 - 3084[5] Angew. Chem., 2017, vol. 129, # 11, p. 3126 - 3130,5
[6] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10652 - 10658
[7] Organic Letters, 2016, vol. 18, # 24, p. 6300 - 6303
[8] Tetrahedron Letters, 2018, vol. 59, # 10, p. 949 - 953
[9] Synlett, 2016, vol. 27, # 12, p. 1806 - 1809
[10] Tetrahedron, 2008, vol. 64, # 43, p. 10068 - 10074
[11] ACS Catalysis, 2018, vol. 8, # 2, p. 1192 - 1196
[12] Organic Letters, 2018, vol. 20, # 20, p. 6436 - 6439
[13] Tetrahedron, 2017, vol. 73, # 36, p. 5389 - 5396
[14] Patent: CN107141252, 2017, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052
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Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 36, p. 14760 - 14763
[2] Organic Letters, 2011, vol. 13, # 18, p. 4974 - 4976
[3] Journal of the American Chemical Society, 2010, vol. 132, # 40, p. 14076 - 14078
  • 6
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Reference: [1] Organic Letters, 2018, vol. 20, # 23, p. 7712 - 7716
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  • [ 190843-73-3 ]
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Reference: [1] Tetrahedron, 2008, vol. 64, # 43, p. 10068 - 10074
  • 8
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Reference: [1] Organic Letters, 2016, vol. 18, # 24, p. 6300 - 6303
[2] Tetrahedron, 2017, vol. 73, # 36, p. 5389 - 5396
[3] Arkivoc, 2018, vol. 2018, # 3, p. 362 - 374
  • 9
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
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  • [ 1078160-86-7 ]
  • [ 927801-13-6 ]
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Reference: [1] Tetrahedron, 2008, vol. 64, # 43, p. 10068 - 10074
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  • [ 107-02-8 ]
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Reference: [1] Journal of the American Chemical Society, 1948, vol. 70, p. 254
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
[2] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
[3] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 779 - 782
  • 14
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Reference: [1] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 779 - 782
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
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Reference: [1] Heterocycles, 2001, vol. 54, # 1, p. 105 - 108
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  • [ 13327-31-6 ]
YieldReaction ConditionsOperation in experiment
97% With copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; sodium iodide In 1,4-dioxane at 110℃; for 15 h; Sealed tube Sodium iodide (4.32 g, 28.8 mmol), Copper (I) iodide (137 mg, 0.72 mmol) and N,N'-Dimethyl-cyclohexane-l,2-diamine (0.227 mL, 1.44 mmol) and 6- Bromoquinoline (3g, 14.4 mmol) in dioxane (15 mL) were charged in a 25 mL microwave tube. The tube was flushed with Nitrogen and sealed with a Teflon septum <n="119"/>and Nitrogen was bubbled in the solution for 10 minutes, allowing the gas to escape through a needle. After the removal of the needle, the reaction mixture was stirred at 110 0C for 15 hours. Then, the green suspension was allowed to reach room temperature, poured into ice-water and extracted with dichloromethane. The organic layer was collected, dried (MgSO4), filtered and concentrated in vacuum. The crude mixture was chromatographied over silica gel with CH2CI2 100percent and CH2Cl2ZMeOH : 95/5 to yield 3.56 g (97percent) of 6-Iodoquinoline as a light yellow solid. 1H-NMR (DMSO): δ 8.93 (IH, dd, /== 1.5, 4.1 Hz), 8.47 (IH, d, J = 2.0 Hz), 8.33 (IH, d, J= 8.6 Hz), 8.02 (IH, dd, J = 2.0, 8.6 Hz), 7.80 (IH, d, J = 8.6 Hz), 7.56 (IH, dd, J = 4.1, 8.6 Hz).
92% With copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; sodium iodide In 1,4-dioxane at 110℃; for 15 h; Inert atmosphere; Microwave irradiation; Sealed tube Intermediate M 6-[(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-difluoro-methyl]-quinoline N2H4 MeOHDifluoro-quinolin-6-yl-acetic acid ethyl ester (i) Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72 mmol), 6-bromo-quinoline (3 g, 14.4 mmol), N,N'-dimethyl-cyclohexane (0.227 ml, 1.44 mmol) and dioxane were charged in microwave tube (25 ml_). The tube was flushed with nitrogen for 10 min and sealed with a Teflon septum. The reaction mixture was stirred at 110 0C for 15 hours. Then the suspension was allowed to cooled to rt, poured into ice-water and extracted with DCM. The crude was purified by silica gel column to give 6-iodo-quinoline as a little green solid (3.5 g, 92percent).To a suspension of 6-iodo-quinoline (i) (1.0 g, 4 mmol) and Cu (0) (559 mg, 8.8 mmol) in dry DMSO was added bromo-difluoro-acetic acid ethyl ester (893 mg, 4.4 mmol). The reaction mixture was stirred under N2 at 550C for 15 hours. The mixture was poured into the solution of K2CO3 and extracted with EtOAc. The organic layer was collected and dried with MgSO4. The crude was purified by silica gel column to give difluoro-quinolin-6-yl-acetic acid ethyl ester as a red oil (310 mg, 30percent). 1H-NMR (CDCI3) δ ppm 1.33 (t, J=7.2, 3H); 4.334 (q, J=7.2, 2H); 7.52 (m, 1 H); 7.93 (m, 1 H); 8.15 (s, 1 H); 8.20-8.23 (m, 2H); 9.03 (s, 1 H).
92% With cis-N,N'-dimethyl-1,2-diaminocyclohexane; sodium iodide In 1,4-dioxane at 110℃; Microwave irradiation; Sealed tube; Inert atmosphere Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72 mmol), 6-bromo- quinoline (3 g, 14.4 mmol), N,N'-dimethyl-cyclohexane (0.227 ml_, 1 .44 mmol) and dioxane were charged in a microwave tube (25 ml_). The tube was purged with nitrogen for 10 min and sealed with a Teflon septum. The reaction mixture was stirred at 1 10 0C for 15 h. After cooling, the mixture was poured onto ice-water and extracted with DCM. The crude was purified by silica gel column to give 6-iodo-quinoline as light green solid (3.5 g, 92percent).
80% With sodium iodide; N,N`-dimethylethylenediamine In butan-1-ol at 120℃; Step 1 : 6-iodoquinoline6-bromoquinoline (80,1 g, 0,385 mol) is dissolved in n-butanol (0.8 L). Copper catalyst CuI (3,7 g, 0,019 mol), a copper-ligand N,N'-dimethylethylenediamine (3.4 g, 0,0385 mol) and an iodide source NaI (115,5 g, 0,770 mol) are added and the mixture is heated in a heating jacket, under inert atmosphere to 1200C. After work-up (0.8L water is added to the reaction mixture , the organic layer is separated off and evaporated) and purification (the <n="72"/>crude evaporation residu was crystallized from 15OmL diisopropylether), 6-iodoquinoline was obtained in 80percent yield.1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 7.39 (dd, J=8.31 , 4.15 Hz, 1 H) 7.83 (d, J=9.06 Hz, 1 H) 7.86 - 7.96 (m, 1 H) 8.02 (d, J=8.31 Hz, 1 H) 8.19 (s, 1 H) 8.91 (s, 1 H)
12.5 g With copper(l) iodide; N,N-dimethylethylenediamine; sodium iodide In 1,4-dioxane at 140℃; for 24 h; Inert atmosphere 6-bromoquinoline (10.4 g, 50.0 mmol), CuI (0.476 g, 2.5 mmol) NaI (15.0 g, 100.0 mmol) and DMEDA (0.5 mL, 5.0 mmol) Add 100mL dioxane, N2 protection, 140 for sealing reaction 24h LC-MS detection, the reaction is complete. After cooling, the filtrate was washed with saturated NaCl solution, Na2SO4, filtered, concentrated, and chromatographed to give 6-iodoquinoline as a yellow solid (12.5 g).

Reference: [1] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 117-118
[2] Patent: WO2011/18454, 2011, A1, . Location in patent: Page/Page column 63-64
[3] Patent: WO2011/20861, 2011, A1, . Location in patent: Page/Page column 69
[4] Patent: WO2008/155378, 2008, A1, . Location in patent: Page/Page column 70-71
[5] Patent: CN104250257, 2017, B, . Location in patent: Paragraph 0258-0260
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  • [ 68-12-2 ]
  • [ 4113-04-6 ]
YieldReaction ConditionsOperation in experiment
8.5% With n-butyllithium In diethyl ether; hexane at -70℃; for 2 h; n-Butyl lithium (19.2mL; 1.5M hexane solution) was added dropwise to a solution of 6-bromoquinoline (5g, 24.0mmol) in diethyl ether (20mL) that had been cooled to -70°C under nitrogen atmosphere, a solution of N,N-dimethylformamide (3.7mL, 48.0mmol) in diethyl ether was further added, and the solution was stirred at -70°C for 2 hours. The reaction solution was allowed to room temperature, then, an aqueous solution of saturated ammonium chloride was added, the solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane : ethyl acetate), and the title compound (320mg, 8.5percent) was obtained as a yellow oil. 1H-NMR Spectrum (CDCl3) δ(ppm) : 7.52-7.56(1H, m), 8.21-8.22(2H, m), 8.33-8.36(1 H, m), 8.37(1 H, s), 9.06-9.07(1 H, m), 10.2(1 H, s).
Reference: [1] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 75-76
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Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 6, p. 1500 - 1505[2] Angew. Chem., 2017, vol. 129, # 6, p. 1522 - 1527,6
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[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4281 - 4290
[3] Patent: CN105968115, 2016, A,
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  • [ 1810-71-5 ]
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 8, p. 1606 - 1611
[2] Patent: WO2009/155527, 2009, A2,
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Reference: [1] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 82, p. 11574 - 11577
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YieldReaction ConditionsOperation in experiment
84% With ethanol; Dimethylphenylsilane; Au-TiO2 In neat (no solvent) at 70℃; for 3 h; General procedure: To a dry vial containing 8-methoxyquinoline, 1 (0.048 g, 0.3 mmol), Me2PhSiH (185 μL, 1.2mmol) and ethanol (70 μL, 1.2 mmol), Au/TiO2 (60 mg, 1.0 molpercent) was added. The Au contentin catalyst was ~1 wtpercent. The mixture was heated to 70 oC and the progress of reaction wasmonitored by TLC and GC. After 15 min (100percent conversion), ethanol (1 mL) was added and theresulting slurry was filtered under reduced pressure through a short pad of silica gel with the aidof ethanol (2-3 mL) to withhold the supported catalyst. The filtrate was evaporated undervacuum and the residue was chromatographed (n-hexane/ethyl acetate, 10:1) to afford 8-methoxy-1,2,3,4-tetrahydroquinoline (1a) (41 mg, 84percent yield).
Reference: [1] Chemical Communications, 2013, vol. 49, # 63, p. 7052 - 7054
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 12, p. 3216 - 3220[3] Angew. Chem., 2017, vol. 129, # 12, p. 3264 - 3268,5
[4] ChemCatChem, 2017, vol. 9, # 13, p. 2496 - 2505
[5] Advanced Synthesis and Catalysis, 2015, vol. 357, # 16-17, p. 3529 - 3537
[6] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7547 - 7562
[7] Arkivoc, 2015, vol. 2015, # 3, p. 38 - 51
[8] Catalysis Science and Technology, 2017, vol. 7, # 10, p. 1981 - 1985
[9] Organometallics, 2013, vol. 32, # 16, p. 4501 - 4506
[10] Journal of Materials Chemistry A, 2017, vol. 5, # 7, p. 3260 - 3266
[11] Journal of the American Chemical Society, 2017, vol. 139, # 28, p. 9419 - 9422
[12] Tetrahedron Letters, 2018, vol. 59, # 10, p. 949 - 953
[13] Catalysis Science and Technology, 2018, vol. 8, # 19, p. 5019 - 5097
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Reference: [1] Synlett, 2004, # 15, p. 2827 - 2829
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  • [ 613-50-3 ]
YieldReaction ConditionsOperation in experiment
82% With potassium nitrite; copper(II) bis(trifluoromethanesulfonate) In dimethyl sulfoxide at 130℃; for 48 h; Inert atmosphere; Sealed tube General procedure: An oven dried pressure tube was charged with haloarenes (0.5 mmol), copper(II) triflate (45 mg, 0.125 mmol), KNO2 (128 mg, 1.5 mmol) and anhydrous DMSO (0.6 mL) under nitrogen atmosphere. The tube was sealed with a teflon screw cap having mininert valve and nitrogen is purged through it for 5 min. It is stirred at room temperature for 10 min and then the temperature was gradually increased to 130 oC and is maintained at the same for 48 h. The reaction mixture was then cooled to room temperature, washed with excess ice cold water and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography using silica gel (Table 2, entries 1-18) or basic alumina (Table 2, entries 19-23) and a mixture of ethyl acetate and hexane as the eluent to afford the desired products in good yields.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 12, p. 1511 - 1513
[2] Tetrahedron, 2013, vol. 69, # 31, p. 6409 - 6414
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1894, vol. &lt;2&gt; 49, p. 534,539
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  • [ 5332-25-2 ]
  • [ 98203-04-4 ]
YieldReaction ConditionsOperation in experiment
100% at -5 - 0℃; for 2 h; 6-Bromoquinoline (13) (0.190 g, 0.932 mmol) was dissolved in 4 mL of sulphuric acid, and cooled at -5 C with a salt-ice bath. A mixture of H2SO4 (1.5 mL) and HNO3 (1.5 mL) acid was prepared and the acid mixture was cooled at -5 C. The solution obtained was cooled at 0 C on a salt-ice bath. While the 6-bromoquinoline (13) solution was stirred with a magnetic stirrer, the H2SO4 / HNO3 mixture was added dropwise with the aid of a Pasteur Pipette within one hour so the solution temperature did not exceed 0 C. The dark brown color of the reaction solution turned into a dark yellow color. After one hour the reaction was compete. The reaction mixture was poured over crushed ice (20 g) in a beaker. After the ice melted, the mixture was extracted with CH2Cl2 (5 × 5 mL). The organic phase was neutralized with a NaHCO3 (10percent) solution and dried over Na2SO4. The solvent was removed in-vacuo. Yellow-colored needle crystals were obtained as the sole product in quantitative yield (0.23 g). mp 128-130 C. IR (solid KBr, vmax, cm-1): 3050, 3019, 2953, 2918, 2850, 1563, 1486, 1414, 1387, 1351, 1318, 1145, 1045, 831, 807, 755. 1H NMR (500 MHz, ppm, CDCl3): δH 9.05 (1H, dd, J2,3 4.2 Hz,J2,4 1.6 Hz, H-2), 8.15 (1H, d, J7,8 9.0 Hz, H-7), 8.05 (1H, d, J4,3 8.6 Hz, H-4), 7.92 (1H,d, J8,7 9.0 Hz, H-8), 7.61 (1H, dd, J3,4 8.6 Hz; J3,2 4.2 Hz, H-3). 13C NMR (125 MHz, CDCl3): δC 152.1, 146.6, 133.3, 132.9, 129.8, 123.8, 123.4, 121.4, 112.2 Anal. calcd for C9H5BrN2O2 (251.95): C, 42.72; H, 1.99; N, 11.07. Found: C, 42.54; H, 2.03; N, 11.12.
93%
Stage #1: at 0 - 20℃; for 1.75 h;
Example 1: Preparation of Intermediates; Intermediate 1: 6-Bromo-5-nitro-quinoline; [0301] A solution of 6-bromoquinoline (2.0 g, 9.61 mmol) in concentrated sulfuric acid (10 mL) was cooled to O0C. Sodium nitrite (27 mg, 0.384 mmol) was added, followed by dropwise addition of concentrated nitric acid (0.8 mL). The reaction mixture was stirred at O0C for 45 min. then at room temperature for Ih, before pouring onto ice, resulting into a yellow precipitate. The mixture was neutralized to pH 7 with ammonium hydroxide. The precipitate was filtered, washed with water and dried in vacuo to yield 2.26 g of 6-bromo-5- nitro-quinoline as a light green solid (93percent yield): ): 1H NMR (CDCl3) δ 7.62 (dd, IH), 7.94 (d, IH), 8.07 (d, IH), 8.17 (d, IH), 9.06 (dd, IH); MS (m/z) 253, 255 [M+H+]+.
Reference: [1] Arkivoc, 2018, vol. 2018, # 3, p. 362 - 374
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8374 - 8389
[3] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 78
[4] Organic Letters, 2016, vol. 18, # 18, p. 4750 - 4753
[5] Chemische Berichte, 1882, vol. 15, p. 1910
  • 31
  • [ 5332-25-2 ]
  • [ 65148-10-9 ]
Reference: [1] Patent: US2011/152246, 2011, A1,
  • 32
  • [ 5332-25-2 ]
  • [ 78593-41-6 ]
Reference: [1] Russian Journal of Organic Chemistry, 2003, vol. 39, # 6, p. 797 - 806
[2] Synthesis, 1981, # 5, p. 364 - 365
[3] Organic Letters, 2014, vol. 16, # 17, p. 4524 - 4527
[4] Organic Letters, 2014, vol. 16, # 24, p. 6302 - 6305
[5] Organic Letters, 2016, vol. 18, # 4, p. 860 - 863
  • 33
  • [ 5332-25-2 ]
  • [ 1810-66-8 ]
Reference: [1] Green Chemistry, 2018, vol. 20, # 3, p. 760 - 764
  • 34
  • [ 5332-25-2 ]
  • [ 73183-34-3 ]
  • [ 406463-06-7 ]
YieldReaction ConditionsOperation in experiment
100% With potassium acetate In tetrahydrofuran at 80℃; Inert atmosphere Step 2.
6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline
A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen.
Then a solution of 6-bromoquinoline (5 g, 23.92 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was added.
This was followed by the addition of KOAc (3.55 g, 1.50 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (18.23 g, 71.77 mmol, 3.00 equiv), and Pd(dppf)2Cl2 (1.95 g, 2.39 mmol, 0.10 equiv).
The reaction was stirred overnight at 80° C. in an oil bath.
The resulting solids were filtered off.
The filtrate was concentrated in vacuo and purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:50).
This resulted in 6.62 g (109percent) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline as red oil.
99% With potassium acetate In N,N-dimethyl-formamide at 100℃; for 0.5 h; Microwave irradiation A. 4,4,5,5-Tetramethyl-2-(6-quinolyl)-l,3,2-dioxaborolane. To a suspension of 6-bromo quinoline (0.9 g, 4.35 mmol), bis(pinacolato)diboron (8.85 g, 34.8 mmol) and potassium acetate (2.56 g, 5.22 mmol) in DMF (50 mL) was added [1,1 '- bis(diphenylphosphino) ferrocene]dichloro-palladium (II) dichloromethane adduct (355 mg, 0.435 mmol) and the reaction mixture was heated in the Emrys Optimizer microwave reactor at 100 0C for 30 minutes. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (SiO2, 20-50percent ethyl acetate in hexanes) to yield the title compound (1.1 g, 99percent yield). MS (ESI) m/z 256.5 [M+l]+.
93% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In tetrahydrofuranInert atmosphere; Reflux Compound A4-1 (210mg, 1.01mmol) was dissolved in tetrahydrofuran (10mL), was added bis (pinacolato) diboron (760mg, 2.99mmol),KOAc (150mg, 1.53mmol), Pd (dppf) 2Cl2 (80mg, 0.10mmol), purged with nitrogen, refluxed overnight, cooled to room temperature, CeliteFiltration, the filtrate was spin-dried, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give a colorless oil (240mg, 93percent).
82%
Stage #1: With potassium acetate In 1,4-dioxane for 0.333333 h; Sealed tube
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 100℃; for 2 h; Sealed tube
In a 30 mL sealed tube, 6-bromoquinoline (1.0 g, 4.8 mmol), BISPIN (1.8 g, 7.2 mmol), Potassium acetate (1.4 g, 14.4 mmol) and 1,4-dioxane (10 mL) were charged and the mixture was degassed for 20 min. To this, PdCi2(dppf) (0.14 g, 0.19 mmol) was added and the reaction was heated to 100 °C for 2 h. TLC showed complete conversion hence it was diluted with Ethyl acetate (50 mL), filtered, concentrated and purified by column chromatography to give desired titled compound (1.0 g, 82percent).

Reference: [1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 90
[2] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 104
[3] Patent: CN105254613, 2016, A, . Location in patent: Paragraph 0071; 0072; 0073
[4] Patent: WO2015/162538, 2015, A1, . Location in patent: Page/Page column 66
[5] Organic Letters, 2014, vol. 16, # 17, p. 4562 - 4565
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1724 - 1727
[7] Patent: CN108440588, 2018, A, . Location in patent: Paragraph 0062; 0064; 0065
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  • [ 1078160-86-7 ]
  • [ 927801-13-6 ]
  • [ 5332-25-2 ]
  • [ 650583-75-8 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 43, p. 10068 - 10074
  • 36
  • [ 5332-25-2 ]
  • [ 1022151-55-8 ]
  • [ 1022150-57-7 ]
YieldReaction ConditionsOperation in experiment
64% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 100℃; for 22 h; Method b; [0358] A solution of 6-bromoquinoline (550 mg, 2.64 mmol), diisopropylethylamine (1.13 niL, 6.46 mmol) in DMA (4 mL) under nitrogen was degassed by bubbling in nitrogen for 20 min. Tris(dibenzylideneacetone)dipalladium (105 mg, 0.108 mmol, Strem catalyst), Xantphos (125 mg, 0.216 mmol), and 6-(l-methyl-lH-pyrazol-4-yl)-[l,2,4]triazolo[4,3- ]pyridazine-3 -thiol (500 mg, 2.155 mmol) were added under a stream of nitrogen. The reaction mixture was stirred at 1000C for 22h, with disappearance of the solid suspension. The reaction mixture was cooled to room temperature and filtered through a plug of silica gel, using DMF as eluent. The organics were then directly poured onto ice/water mixture and left standing for 15 min. The precipitate was filtered and washed with water. The resulting cake was grinded in diethyl ether, filtered, and dried in vacuo to yield 770 mg of a yellow solid. The solid was stirred in refluxing isopropanol for Ih, filtered, washed with isopropanol, and dried in a vacuum oven at 7O0C for 3 days to provide 500 mg of 6-[6-(l- methyl-lH-pyrazol-4-yl)-[l,2,4]triazolo[4,3-6]pyridazin-3-ylsulfanyl]-quinoline as a yellow solid with 8percent impurity (64percent yield).
58% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 23 h; Example 4: 6-[6-(l-Methyl-lH-pyrazol-4-yl)-[l,2,4]triazoIo[4,3-^]pyridazin-3- ylsulfanyl]-quinoline (Compound 4); Method a; [0356] A solution of 6-bromoquinoline (45 mg, 0.215 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol) in DMF (1 mL) under nitrogen was degassed by bubbling in nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium (11 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol), and 6-(l-methyl-lH-pyrazol-4-yl)-[l,2,4]triazolo[4,3-]pyridazine-3- thiol (50 mg, 0.215 mmol) were added, and the mixture was degassed for another 5 min. The reaction mixture was stirred at 1000C for 23 h. More palladium catalyst (11 mg) and ligand (13 mg) were added after 6 h. The reaction mixture was cooled to room temperature, filtered through a 0.45 um filter, and the crude mixture was purified directly by mass- triggered HPLC (5 - 95percent CH&3CN/H2O, 0.1percent HCOOH modifier) to provide 45 mg of 6-[6- (1 -methyl-1 H-pyrazol-4-yl)-[l ,2,4]triazolo[4,3-]pyridazin-3-ylsulfanyl]-quinoline as a yellow solid (58percent yield).
Reference: [1] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 101
[2] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 99
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