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Lim, Taeho ; Ryoo, Jeong Yup ; Han, Min Su DOI: PubMed ID:

Abstract: In this study, we developed a simple transition-metal-free borylation reaction of aryl bromides. Bis-boronic acid (BBA), was used, and the borylation reaction was performed using a simple procedure at a mild temperature. Under mild conditions, aryl bromides were converted to arylboronic acids directly without any deprotection steps and purified by conversion to trifluoroborate salts. The functional group tolerance was considerably high. The mechanism study suggested that this borylation reaction proceeds via a radical pathway.

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Product Details of [ 52415-29-9 ]

CAS No. :52415-29-9 MDL No. :MFCD00238550
Formula : C8H6BrN Boiling Point : -
Linear Structure Formula :- InChI Key :MAWGHOPSCKCTPA-UHFFFAOYSA-N
M.W : 196.04 Pubchem ID :676493
Synonyms :

Calculated chemistry of [ 52415-29-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 0.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.0
TPSA : 15.79 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) : -5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.84
Log Po/w (XLOGP3) : 2.74
Log Po/w (WLOGP) : 2.93
Log Po/w (MLOGP) : 2.31
Log Po/w (SILICOS-IT) : 3.25
Consensus Log Po/w : 2.62

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.45
Solubility : 0.0699 mg/ml ; 0.000357 mol/l
Class : Soluble
Log S (Ali) : -2.73
Solubility : 0.368 mg/ml ; 0.00188 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.14
Solubility : 0.0142 mg/ml ; 0.0000726 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.43

Safety of [ 52415-29-9 ]

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

Application In Synthesis of [ 52415-29-9 ]

* 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 [ 52415-29-9 ]
  • Downstream synthetic route of [ 52415-29-9 ]

[ 52415-29-9 ] Synthesis Path-Upstream   1~56

  • 1
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YieldReaction ConditionsOperation in experiment
36%
Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 110℃; for 1.5 h;
Stage #2: With acetic acid; zinc In water at 75 - 85℃; for 5.5 h;
Step A: To a solution of 4-bromo-2-nitrotoluene (7.9 g, 36.6 mmol) in dimethylformamide (73 mL) were added N,N-dimethylformamide dimethylacetal (14.5 mL, 110 mmol) and pyrrolidine (4.7 mL), and the mixture was heated at 110° C. for 90 minutes. The cooled reaction mixture was diluted with diethyl ether, and washed with water. The aqueous layer was re-extracted with diethyl ether twice, and the combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in aqueous acetic acid (245 mL, 80percent), and heated to 75° C. Zinc powder (20.8 g, 318 mmol) was added to the hot solution in small portions over 2 hours. The reaction mixture was then heated at 85° C. for 3 hours and 30 minutes, cooled to room temperature and then to 0° C. The precipitate formed was removed by filtration, and the filtrate was diluted with ethyl acetate and washed with water twice. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate, then 90:10 hexanes/ethyl acetate) to give 6-bromoindole as a grey solid (2.61 g, 36percent): 1H NMR (500 MHz, CDCl3) δ 8.14 (br s, 1H), 7.53 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.15 (m, 1H), 6.53-6.51 (m, 1H).
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6812 - 6820
[2] RSC Advances, 2014, vol. 4, # 9, p. 4672 - 4675
[3] Patent: US2006/52378, 2006, A1, . Location in patent: Page/Page column 154
[4] Tetrahedron, 1999, vol. 55, # 4, p. 935 - 942
[5] Patent: US2011/46370, 2011, A1, . Location in patent: Page/Page column 10
[6] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 2
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  • [ 52415-29-9 ]
YieldReaction ConditionsOperation in experiment
27% With acetic acid; zinc In water at 75℃; for 1 h; Stirred Zinc granules (30 g, 459 mmol) were added over 30 minutes to a solution of crude Intermediate 10 (25 g, 93 mmol) in acetic acid (400 mL) and water (100 mL) at 75° C., after which the mixture was stirred for an additional 1 hour. The suspension was cooled, filtered, and extracted with ethyl acetate (2.x.2 L). The combined organic extracts were washed with water (2.x.2 L), saturated NaHCO3 solution (2.x.500 mL), and brine (2.x.500 mL), dried over magnesium sulfate (MgSO4), and filtered. The solvent was removed under reduced pressure to yield a purple residue which was purified by flash column chromatography, eluting with hexanes/methylene chloride (1:1), to provide 6-bromoindole (Intermediate 11) as a blue-white powder (4.9 g, 27percent over two steps): TLC Rf (1:9 ethyl acetate/chloroform)=0.81. The proton NMR spectrum (300 MHz, CDCl3) was identical to the known compound.
Reference: [1] Patent: US2003/225092, 2003, A1, . Location in patent: Page 12
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 1679 - 1680
[3] Chinese Chemical Letters, 2010, vol. 21, # 8, p. 889 - 891
  • 3
  • [ 99474-21-2 ]
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Reference: [1] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
[2] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5106 - 5110
[3] Organic and Biomolecular Chemistry, 2004, vol. 2, # 2, p. 160 - 167
[4] Tetrahedron, 2002, vol. 58, # 39, p. 7851 - 7861
  • 4
  • [ 123-75-1 ]
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  • [ 4637-24-5 ]
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Reference: [1] Tetrahedron, 1992, vol. 48, # 14, p. 2919 - 2924
[2] Patent: US5252732, 1993, A,
[3] Patent: US5310901, 1994, A,
[4] Patent: US5349061, 1994, A,
  • 5
  • [ 25408-61-1 ]
  • [ 60956-26-5 ]
  • [ 52415-29-9 ]
Reference: [1] Patent: EP1859798, 2015, B1, . Location in patent: Paragraph 0144
  • 6
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Reference: [1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 2, p. 160 - 167
[2] Tetrahedron, 2002, vol. 58, # 39, p. 7851 - 7861
[3] Journal of the American Chemical Society, 1987, vol. 109, p. 3378
[4] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5106 - 5110
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 1679 - 1680
[6] Chinese Chemical Letters, 2010, vol. 21, # 8, p. 889 - 891
[7] Chemistry of Heterocyclic Compounds, 2011, vol. 47, # 4, p. 425 - 434
  • 7
  • [ 16732-65-3 ]
  • [ 52415-29-9 ]
Reference: [1] Liebigs Annalen der Chemie, 1985, vol. 1985, # 4, p. 785 - 793
[2] Tetrahedron Letters, 1982, vol. 23, # 47, p. 4911 - 4914
[3] Chemische Berichte, 1955, vol. 88, p. 370,373
  • 8
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Reference: [1] Journal of the American Chemical Society, 1987, vol. 109, p. 3378
  • 9
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Reference: [1] Journal of the American Chemical Society, 1987, vol. 109, p. 3378
  • 10
  • [ 881-50-5 ]
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 11
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 12
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 13
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 14
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 15
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 16
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Reference: [1] Chemical & Pharmaceutical Bulletin, 1987, vol. 35, # 5, p. 1823 - 1828
  • 17
  • [ 61293-29-6 ]
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Reference: [1] Organic Preparations and Procedures International, 1995, vol. 27, # 5, p. 576 - 579
  • 18
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Reference: [1] Organic Preparations and Procedures International, 1995, vol. 27, # 5, p. 576 - 579
  • 19
  • [ 63839-24-7 ]
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 7, p. 1401 - 1404
  • 20
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Reference: [1] Chemische Berichte, 1955, vol. 88, p. 370,373
  • 21
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  • [ 6326-79-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 516 - 530
  • 22
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  • [ 101774-27-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7107 - 7112
[2] Patent: WO2011/50245, 2011, A1,
[3] Patent: EP2548864, 2013, A1,
[4] Patent: WO2013/14102, 2013, A1,
[5] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497
[6] Patent: US2014/200215, 2014, A1,
[7] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 8, p. 863 - 867
  • 23
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  • [ 114306-17-1 ]
Reference: [1] Dyes and Pigments, 2016, vol. 125, p. 54 - 63
[2] RSC Advances, 2018, vol. 8, # 27, p. 14747 - 14752
  • 24
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  • [ 31009-04-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 516 - 530
  • 25
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  • [ 145951-26-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 617 - 620
  • 26
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  • [ 20996-87-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 125 - 128
  • 27
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 125 - 128
  • 28
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  • [ 68-12-2 ]
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Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5106 - 5110
[2] Patent: EP1859798, 2015, B1, . Location in patent: Paragraph 0146
  • 29
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  • [ 1196-70-9 ]
Reference: [1] Patent: US6200978, 2001, B1,
  • 30
  • [ 52415-29-9 ]
  • [ 68-12-2 ]
  • [ 17826-04-9 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: for 0.333333 h; Cooling with ice
Stage #2: at 20℃; for 1.5 h;
General procedure: To a dried two-neck round-bottom flask containing DMF (0.7mL for 1.10mmol of starting material) chilled in an ice bath, POCl3 (1.95 equiv) was added slowly. After stirring for 20min, a solution of an indole derivative (1.0 equiv) in DMF (3mL for 1.10mmol of starting material) was added dropwise. The reaction was allowed to warm to room temperature and allowed to stir for 1.5h. The reaction was quenched by adding ice followed by 1N NaOH (40mL) dropwise in an ice bath. The crude mixture was allowed to stand at room temperature and the precipitate formed was filtered to afford the 3-formyl-indole derivative product.
47% at 0 - 20℃; for 2.5 h; At 0 , the POCl3(2.0mL) was added dropwise to DMF (8.0mL) and stirred for 30 minutes after the dropping Compound 1 (3.0g, 15.3mmol), DMF (2.0ml) mixed solution, the end of the dropwise addition, naturally warmed to room temperature and stirred for 2 hours .After completion of the reaction, the reaction solution was poured into ice water, saturated sodium bicarbonate solution was adjusted to about pH 8.By filtration, the filtrate was collected, concentrated under reduced pressure to give a pale yellow solid compound B(1.60g, 47percent).
25%
Stage #1: at 0 - 8℃; for 0.5 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 2 h;
13a) 6-Bromo-lH-indole-3-carbaldehydeThis compound was prepared according to the general procedure described by M. A. Wuonola et. al. (J. Org. Chem., (1994), 59_, 6823-6827). To ice-water cooled N,N-dimethylformamide (10 mL) was slowly added phosphorus oxychloride (3.2 mL, 34.6 mmol) with stirring under a nitrogen atmosphere while maintaining the temperature between 0 0C and 8 0C. The reaction mixture was stirred at 0 0C for 30 min. To the cold reaction mixture was slowly added a solution of 6-bromoindole (5.5 g, 28.1 mmol) in N,N-dimethylformamide (28 mL) while maintaining the temperature of the reaction mixture between 0 0C and 10 0C. The ice-water bath was removed and the reaction mixture was allowed to stir at room temperature for 2 hours. The viscous mixture was poured into ice-water (250 g) and the pη of the cold aqueous mixture was adjusted to ~7 (litmus paper) with 1 N sodium hydroxide. The mixture was allowed to stand at room temperature overnight. The mixture was filtered to give a pink solid which was washed with water and recrystallized from ethyl alcohol to give 1.6 g (25percent) of 6-bromo-l/f-indole-3-carbaldehyde as a pale tan solid. 1H NMR (dβ- DMSO, 400 MHz): δ 12.20 (br s, IH), 9.91 (s, IH), 8.31 (d, J = 3 Hz, IH), 8.00 (d, J = 9 Hz, IH), 7.69 (d, J = 2 Hz, IH), 7.34 (dd, J = 8, 2 Hz, IH).
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 27, p. 4621 - 4628
[2] Chinese Chemical Letters, 2010, vol. 21, # 8, p. 889 - 891
[3] Marine Drugs, 2013, vol. 11, # 5, p. 1427 - 1439
[4] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 344 - 367
[5] Angewandte Chemie - International Edition, 2014, vol. 53, # 22, p. 5600 - 5603[6] Angew. Chem., 2014, vol. 126, # 22, p. 5706 - 5709,4
[7] Journal of Chemical Crystallography, 2009, vol. 39, # 5, p. 329 - 336
[8] Patent: CN105440016, 2016, A, . Location in patent: Paragraph 0040; 0041
[9] Patent: WO2008/157270, 2008, A1, . Location in patent: Page/Page column 102
[10] Liebigs Annalen der Chemie, 1985, # 9, p. 1882 - 1894
[11] Journal of Organic Chemistry, 1994, vol. 59, # 22, p. 6823 - 6827
[12] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 4, p. 569 - 572
[13] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 2, p. 363 - 371
[14] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1301 - 1305
[15] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 13, p. 4783 - 4792
[16] Chemical Biology and Drug Design, 2011, vol. 77, # 3, p. 182 - 188
[17] Journal of Organic Chemistry, 2013, vol. 78, # 6, p. 2362 - 2372
[18] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497
[19] Organic Letters, 2013, vol. 15, # 24, p. 6262 - 6265
[20] Patent: WO2014/100695, 2014, A1, . Location in patent: Paragraph 00390
[21] Synthesis (Germany), 2017, vol. 49, # 11, p. 2562 - 2562
[22] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 184 - 194
[23] Organic Letters, 2017, vol. 19, # 10, p. 2502 - 2505
[24] Green Chemistry, 2017, vol. 19, # 13, p. 2952 - 2956
[25] Patent: WO2009/140769, 2009, A1, . Location in patent: Page/Page column 60
[26] Patent: WO2009/135299, 2009, A1, . Location in patent: Page/Page column 80-81
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YieldReaction ConditionsOperation in experiment
73% With iron(III) chloride; ammonia In water; N,N-dimethyl-formamide at 130℃; for 5 h; General procedure: A 50 mL round-bottomed flask equipped with a magnetic stirringbar was charged with the appropriate indole 1 (0.5 mmol,1.0 equiv), 37percent aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25percent aqNH3 (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl3 (0.01 mmol, 0.0016 g,2 molpercent), and DMF (2 mL). The flask was fitted with a reflux condenser,and the mixture was stirred at 130 °C under open air.When the reaction was complete (TLC), the mixture was cooledto r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL),and extracted with EtOAc (3 x 7 mL). The organic layers werecombined, washed with sat. aq NaHCO3 (10 mL) and sat. aq NaCl(10 mL), dried (Na2SO4), and concentrated under reduced pressure.The residue was purified by flash column chromatography(silica gel, hexane–EtOAc).
Reference: [1] Synlett, 2017, vol. 28, # 19, p. 2670 - 2674
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YieldReaction ConditionsOperation in experiment
73% With aluminum (III) chloride In N,N-dimethyl-formamide at 120℃; for 5 h; General procedure: A method for synthesizing compound III-1 wherein R1, R2 and R3 are simultaneously hydrogen in the formula III, the method comprising the steps of:(1) Add to a 50 mL round bottom flask1.0mmol indole(In the formula I, R1, R2, and R3 are both hydrogen) and1.0 mmol (0.140 g) of hexamethylenetetramine, then 2 mL of N,N-dimethylformamide (DMF), stirred in a magnetic stirrer to dissolve the solid, followed by the addition of 0.05 mmol (0.012 g) of crystalline trichloride Aluminum, connected to a reflux condenser, heated at 120 ° C, the reaction progress was monitored by TLC, and the reaction was cooled to room temperature after 1 h to prepare a suspension;(2) The suspension prepared in the step (1) is suction filtered with a funnel padded with diatomaceous earth.The filter cake was washed well with ethyl acetate, suction filtered, and the above operation was repeated until the filtrate had no product, and all the filtrates were combined.Dilute with 15 mL of saturated saline solution, disperse and separate the layers, and the aqueous layer was further extracted with ethyl acetate three times.Each time 10 mL, the ethyl acetate layer was combined and washed with 10 mL of 2 mol/L diluted hydrochloric acid.Wash with 10 mL of saturated sodium bicarbonate solution, and finally wash with 10 mL of saturated brine.The washed ethyl acetate layer was dried over anhydrous sodium sulfate, and after drying, the desiccant was filtered off.Then use a rotary evaporator to recover the solvent to concentrate the product, and finally,The residue is subjected to silica gel column chromatography using a mixture of n-hexane-ethyl acetate (V/V = 2:1) as an eluent to obtain a purified product.The mass of the compound III-indole-3-carbaldehyde is 0.137g,The product yield was 94percent.
Reference: [1] Patent: CN108329249, 2018, A, . Location in patent: Paragraph 0041-0044; 0116-0119
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Reference: [1] Patent: WO2010/151737, 2010, A2, . Location in patent: Page/Page column 142
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Reference: [1] Chemical Communications, 2012, vol. 48, # 42, p. 5187 - 5189
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 10, p. 1831 - 1839
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YieldReaction ConditionsOperation in experiment
Ca. 10 g With triethylsilane; trifluoroacetic acid In dichloromethane; trifluoroacetic acid at 20℃; for 16 h; Step 1: 6-Bromoindoline
To a solution of 6-bromo-lH-indole (11.0 g, 56.1 mmol) in dichloromethane (180 mL) and TFA (60 mL) was added triethylsilane (22.6 mL, 2.5 equiv.). The mixture was stirred at room temperature for 16 hrs, after which additional dichloromethane (180 mL), concentrated ammonium hydroxide (about 50 mL) and water (200 mL) were added. The mixture was then extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was re-dissolved in a 1: 1 mixture of ether and hexane (100 mL), to which was added 4N HC1 in dioxane (14 mL). A precipitation was formed instantly, which was collected by filtration. The obtained solid was treated with saturated sodium bicarbonate. The mixture was extracted with dichloromethane. The organic phase was combined, dried over sodium sulfate and evaporated to give the title compound as a brownish oil (approx. 10.0 g), which was used in the next step without further purification. LC-MS: 195.9/197.9 [M-H]+, RT 0.98 min.
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[2] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 373 - 377
[3] Patent: WO2016/25932, 2016, A1, . Location in patent: Page/Page column 144
[4] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2425 - 2437
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 32, p. 5889 - 5898
[6] Chemical Communications, 2018, vol. 54, # 20, p. 2494 - 2497
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YieldReaction ConditionsOperation in experiment
65% With copper(l) iodide; (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine; sodium iodide In 1,4-dioxane at 110℃; for 24 h; Schlenk technique; Inert atmosphere (According to the procedure described in J. Am. Chem. Soc. 2002, 124, 14844-14845). 6-Bromo-1H-indole (0.65 g,3.34 mmol), Nal (2.0 g, 13.34 mmol) and Cui (63.5 mg, 0.33 mmol) were charged in a Shlenk tube and degassedthree times back filling with argon each time. Dioxane (6.5 ml) and (1S,2S)-N,N-dimethyl-cyclohexane-1,2-diamine10 (0.11 ml, 0.67 mmol) were then added and the mixture was heated at 110 oc for 24 h. The reaction was quenchedwith NH3, poured in water and extracted with DCM (3 x 20 ml). The organic layer was dried over anhydrous Na2S04,filtered and concentrated to reduce volume. The product was purified by flash column chromatography (Hex/EtOAc98/2) and isolated as white solid (0.53 g, 65percent).1H NMR (600 MHz, DMSO-dG) o ppm 6.43 (t, J=2.01 Hz, 1 H) 7.25 (dd, J=8.24, 1.4 7Hz, 1 H) 7.31 (t, J=2.75 Hz, 1 H)15 7.38 (d, J=8.24 Hz, 1 H) 7.75 (s, 1 H) 11.15 (br. s., 1 H).
57% With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine In 1,4-dioxane at 110℃; Inert atmosphere NaI (4.59, 30.6 mmol), CuI (290 mg, 1.53 mmol) and N,N'-dimethylethylenediamine (0.35 mL) were added to a solution of 6-bromo-1H-indole (3.00 g, 15.3 mmol) in dioxane (30 mL) at the room temperature. The mixture was purged with nitrogen to remove oxygen for 5 minutes. The mixture was stirred at 110 °C in an oil bath overnight in a nitrogen atmosphere. After cooling, the organic solvent was removed by concentration under reduced pressure. EtOAc and water were added, and two phases were separated. The EtOAc phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: pure PE) to obtain the title compound 6-Iodo-1H-indole (2.1 g, 57percent). MS m/z (ESI): 244.0[M+H]+.
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 2, p. 650 - 654[2] Angew. Chem., 2013, vol. 125, # 2, p. 678 - 682,5
[3] Chemical Communications, 2016, vol. 52, # 60, p. 9442 - 9445
[4] Chemistry - A European Journal, 2017, vol. 23, # 72, p. 18216 - 18224
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 1, p. 263 - 266[6] Angew. Chem., 2015, vol. 127, # 01, p. 265 - 268,4
[7] Patent: WO2014/72220, 2014, A1, . Location in patent: Page/Page column 65
[8] Patent: EP3205650, 2017, A1, . Location in patent: Paragraph 0464; 0465
[9] Journal of the American Chemical Society, 2015, vol. 137, # 9, p. 3338 - 3351
[10] Patent: WO2015/131100, 2015, A1, . Location in patent: Page/Page column 163; 164
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  • [ 1189-71-5 ]
  • [ 224434-83-7 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 16, p. 4062 - 4072
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  • [ 224434-83-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 2, p. 363 - 371
[2] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 4, p. 569 - 572
[3] CrystEngComm, 2013, vol. 15, # 37, p. 7490 - 7497
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  • [ 52415-29-9 ]
  • [ 24424-99-5 ]
  • [ 182344-70-3 ]
YieldReaction ConditionsOperation in experiment
97% With dmap In dichloromethane at 20℃; 6-bromo-indole was protected with Boc and then converted to the corresponding boronic ester 19 using the same conditions as used for probe 10.
Reference: [1] Patent: WO2006/26368, 2006, A2, . Location in patent: Page/Page column 91-92
[2] Organic Letters, 2000, vol. 2, # 8, p. 1109 - 1112
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  • [ 74-88-4 ]
  • [ 125872-95-9 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil for 0.333333 h; Inert atmosphere
Stage #2: for 0.333333 h; Inert atmosphere
A 1 -round-bottom flask was charged with 6-bromo-lH-indole (14.88 g, 76 mmol) and THF (150 ml) to give a dark maroon solution. The flask was put under a 2 sweep, and sodium hydride (60 wtpercent) (3.64 g, 91 mmol) was added in several portions over 15 min. The resulting mixture was stirred for 20 min, then iodomethane (5.94 ml, 95 mmol) was added via syringe. Within a few minutes, an exotherm was observed. After stirring for 20 min, the mixture was concentrated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 40percent EtO Ac/Heptane) to afford 6-bromo-l -methyl- lH-indole (14.44 g, 68.7 mmol, 91 percent yield) as a lightly colored oil. .H NMR (400MHz, CDC13) δ = 7.51 - 7.46 (m, 2 H), 7.24 - 7.19 (m, 1 H), 7.03 (d, J = 3.1 Hz, 1 H), 6.47 (dd, J = 0.9, 3.1 Hz, 1 H), 3.77 (s, 3 H).
84%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.333333 h; Cooling with ice; Inert atmosphere
Stage #2: for 0.5 h; Cooling with ice
To a solution of 6-bromo-1H-indole (3.00 g, 15.3 mmol) in DMF (30 mL),NaH (60percent, 734 mg, 18.4 mmol) was added in an ice-water bath, and the mixture was stirred at this temperature for 20 minutes. Then a solution of MeI (1.14 mL, 18.4 mmol) in DMF (10 mL) was added dropwise, and the mixture was stirred at this temperature for 30 minutes. 100 mL of water was added, and the reaction solution was extracted with EtOAc. The EtOAc phase was washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: pure PE) to obtain the title compound 6-bromo-1-methyl-1H-indole (2.70 g, 84 percent).
79.1%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 7℃; for 3 h;
Stage #2: at 0 - 25℃; for 2 h;
To a suspension of 60percent NaH (3.61 g, 90.3 mmol) in dry DMF (150 mE) was added 6-bromoindole (11.8 g, 60.191 mmol) at 0° C. in portions. Caution: gas evolved. The inner temperature rose to 7° C. The mixture was re-cooled to 0° C. To the resulting red suspension was stirred at 0° C. for 3 h. CH3I (3.26 g, 23 mmol) was added dropwise at 0° C.-5° C. The reaction suspension was stirred at room temperature (25° C.) for 2 h. TEC (petroleum ether/EtOAc=8/i) showed most of the starting material was consumed and a good spot was formed. The mixture was poured into ice water (200 mE) and extracted with petroleum ether (100 mEx3). The extract was washed with brine (100 mE), dried over Na2 SO4 and concentrated in vacuo to dryness to afford crude (15 g). The crude was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 10percent to afford J-2 (10 g, 79.1percent) as a slight yellow oil. ‘H NMR (400 MHz, CDC13) ö ppm 7.49-7.47 (m, 2H), 7.22 (d, 1H), 7.03 (d, 1H), 6.46 (d, 1H),3.76 (s, 3H).
63% With potassium carbonate In acetone at 55℃; for 16 h; A mixture of 6-bromo-1H-indole (5 g, 25.50 mmol, 1.00 equiv), K2CO3 (7 g, 50.65 mmol, 2.00 equiv), and CH3I (7.3 g, 51.43 mmol, 2.00 equiv) in acetone (100 mL) was stirred for 16 h at 55° C., then cooled to rt, diluted with 100 mL H2O, and extracted with 2×200 mL of EtOAc. The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, concentrated under vacuum, and purified with silica gel chromatography using EtOAc/petroleum ether (1:10) to afford 3.4 g (63percent) of the title compound as a yellow oil. LC-MS: (ES, m/z): 208. 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dt, J=1.6, 0.7 Hz, 1H), 7.49 (dd, J=8.4, 0.6 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.4, 1.8 Hz, 1H), 6.43 (dd, J=3.1, 0.9 Hz, 1H), 3.77 (s, 3H).
62%
Stage #1: With potassium carbonate In dimethyl sulfoxide at 20℃; for 0.5 h;
Stage #2: at 20℃;
a) 6-bromo-l -methyl- lH-indoleA solution of 6-bromo-l H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with potassium carbonate (4.59 mmol) and was stirred at room temperature for 30 min. The solution was then treated with methyl iodide (1.683 mmol) and was stirred at room temperature overnight. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexanes) to provide the titlecompound as a yellow oil (62percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (s, 1 H) 7.50 (d, J=8.34 Hz, 1 H) 7.35 (d, J=3.03 Hz, 1 H) 7.14 (dd, J=8.34, 1.77 Hz, 1 H) 6.44 (d, J=3.03 Hz, 1 H) 3.78 (s, 3 H).

Reference: [1] European Journal of Organic Chemistry, 2011, # 20-21, p. 3781 - 3793
[2] Helvetica Chimica Acta, 2006, vol. 89, # 5, p. 936 - 946
[3] Patent: WO2013/25883, 2013, A1, . Location in patent: Page/Page column 41-42
[4] Journal of the American Chemical Society, 2013, vol. 135, # 30, p. 10978 - 10981
[5] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1062 - 1067
[6] Organic Process Research and Development, 2018, vol. 22, # 11, p. 1489 - 1499
[7] Patent: EP3205650, 2017, A1, . Location in patent: Paragraph 0106; 0249; 0250
[8] Patent: US2016/244475, 2016, A1, . Location in patent: Paragraph 0278; 0279
[9] Patent: US2018/162822, 2018, A1, . Location in patent: Paragraph 0500
[10] Patent: WO2011/103546, 2011, A1, . Location in patent: Page/Page column 141-142
[11] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 125 - 128
[12] Patent: US2003/125371, 2003, A1,
[13] Patent: US6017945, 2000, A,
[14] Journal of Organometallic Chemistry, 2011, vol. 696, # 5, p. 1072 - 1083
[15] Patent: WO2011/112995, 2011, A1, . Location in patent: Page/Page column 72
[16] Organic Letters, 2012, vol. 14, # 16, p. 4130 - 4133
[17] Chemical Communications, 2012, vol. 48, # 89, p. 11023 - 11025
[18] Patent: US2014/148430, 2014, A1, . Location in patent: Paragraph 0379
[19] Organic Letters, 2016, vol. 18, # 21, p. 5496 - 5499
[20] Chemical Communications, 2017, vol. 53, # 33, p. 4593 - 4596
[21] Organic Letters, 2018, vol. 20, # 16, p. 4898 - 4901
[22] Chemistry - An Asian Journal, 2018, vol. 13, # 18, p. 2664 - 2670
[23] European Journal of Medicinal Chemistry, 2018, vol. 160, p. 120 - 132
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Reference: [1] Patent: US6281356, 2001, B1,
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Reference: [1] European Journal of Medicinal Chemistry, 2019, vol. 161, p. 533 - 542
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  • [ 52415-29-9 ]
  • [ 98-09-9 ]
  • [ 679794-03-7 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 8, p. 1699 - 1707
[2] Journal of Antibiotics, 2002, vol. 55, # 11, p. 1009 - 1012
[3] Organic and Biomolecular Chemistry, 2018, vol. 16, # 43, p. 8169 - 8174
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Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 5, p. 1708 - 1725
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  • [ 214915-72-7 ]
Reference: [1] Journal of the American Chemical Society, 2004, vol. 126, # 16, p. 5068 - 5069
  • 47
  • [ 52415-29-9 ]
  • [ 73183-34-3 ]
  • [ 642494-36-8 ]
YieldReaction ConditionsOperation in experiment
65% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 130℃; for 12 h; Inert atmosphere Under a nitrogen stream, 6-bromo -1H- indole (25g, 0.128mol), 4,4,4 ', 4', 5,5,5 ', 5'- octamethyl-2,2'-bi (1, 3,2-dioxaborolane) (48.58g, 0.191mol), Pd (dppf) Cl2 (5.2g, 5molpercent), were mixed KOAc (37.55g, 0.383mol) and DMF with (500ml), 130 the mixture was stirred for 12 hours at . After completion of the reaction, and extracted with ethyl acetate, water was removed by MgSO4, column chromatography (hexane: EA = 10: 1 (v / v)) was purified by 6-4,4,5,5- tetramethyl to give the 1,3,2-dioxaborolan-2-yl)-lH-indole (20.15g, 65percent yield).
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[2] Synlett, 2003, # 8, p. 1204 - 1206
[3] Patent: JP2015/531758, 2015, A, . Location in patent: Paragraph 0045-0046
[4] Patent: US2007/112005, 2007, A1, . Location in patent: Page/Page column 82
[5] Patent: US2007/280928, 2007, A1, . Location in patent: Page/Page column 80
[6] Patent: KR101879905, 2018, B1, . Location in patent: Paragraph 0186; 0188; 0189; 0310-0313
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  • [ 52415-29-9 ]
  • [ 25015-63-8 ]
  • [ 120-72-9 ]
  • [ 642494-36-8 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 9, p. 2366 - 2369
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  • [ 642494-36-8 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6812 - 6820
[2] Journal of Organic Chemistry, 2004, vol. 69, # 20, p. 6812 - 6820
[3] Heterocycles, 2010, vol. 80, # 2, p. 1267 - 1274
[4] Patent: US2015/318483, 2015, A1,
[5] Patent: US2015/318483, 2015, A1,
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  • [ 152213-63-3 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 43, p. 14028 - 14029
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Reference: [1] Patent: US2014/200215, 2014, A1,
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 8, p. 863 - 867
[3] Patent: WO2008/157270, 2008, A1,
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  • [ 393553-57-6 ]
Reference: [1] Tetrahedron, 2018, vol. 74, # 12, p. 1199 - 1202
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  • [ 67-64-1 ]
  • [ 885271-72-7 ]
YieldReaction ConditionsOperation in experiment
22 g With hydrogenchloride; sodium nitrite In water; acetone at 20℃; for 0.333333 h; (1) to 70g is added in an aqueous solution of sodium nitrite of 20g compound 1 (6-bromo-indole) acetone: water (200 ml: 200 ml) solution; room temperature, in to the system by adding 2N HCl solution to pH to 2.5 the left and right; 20 min the rear, with a red brown gas desorbing, slabs system has; 10 min later, TLC detection material disappears, cessation of the reaction, adding to system 1.0L ethyl acetate (EA), two-phase separation, the organic phase with saturated sodium bicarbonate (500 ml * 2) washing, drying organic anhydrous magnesium sulfate, concentrated to obtain 22g compound 2, as a black solid.
450 g
Stage #1: With sodium nitrite In water at 10℃; for 0.5 h;
Stage #2: With hydrogenchloride In water; acetone at 10 - 25℃; for 3 h;
A solution of NaNO2 (704 g, 10.2 mol) in water (1 L) was added dropwise to a solution of 6-bromo-1H-indole (400 g, 2.0 mol) in acetone (7 L) at 10 °C. The reaction mixture was stirred at 10 °C for 30 mm, aqueous 3M HC1 (437 mL) was added slowly with vigorous stirring, keeping the internal temperature between 10 and 25 °C. Thesolution was stirred at 20 °C for 3 h, and concentrated while keeping the temperaturebelow 35 °C. The solid was collected by filtration. The filter cake was washed with 1:2petroleum ether:MTBE (800 mL). The solids were collected by filtration and dried undervacuum to afford the title intermediate (450 g) as a black brown solid. ‘H NMR (CH3OD,400 MHz) ö (ppm) 7.77 (d, J= 8.8 Hz, 1H), 7.69 (s, 1H), 7.22 (dd, J 8.4, 2.4 Hz, 1H),5.70 (s, 1H).
Reference: [1] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000263
[2] Patent: CN104098513, 2016, B, . Location in patent: Paragraph 0023; 0024; 0029
[3] Patent: WO2017/79205, 2017, A1, . Location in patent: Page/Page column 35
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YieldReaction ConditionsOperation in experiment
50% With hydrogenchloride; sodium nitrite In hexane; water; acetone 6-Bromo-1H-indazole-3-carbaldehyde (3)
Sodium nitrite (5.07 g, 73.4 mmol, 4.8 eq) was dissolved in water (270 mL) and highly concentrated HCl (6 mL).
6-Bromo-1H-indole (3.0 g, 15.3 mmol, 1.0 eq) dissolved in acetone (75 mL) was slowly added to the aqueous solution.
The reaction mixture was stirred for 19 hours.
Then, the aqueous layer was extracted using ether (50 mL) and hexane (500 mL).
The combined organic layer was washed with water and brine, dried with Mg2SO4, filtered, and then concentrated.
Purification by column chromatography (20percent BtOAc dissolved in hexane) yielded the aldehyde (3) as an orange solid substance (1.7 g; yield=50percent).
Reference: [1] Patent: US2011/245179, 2011, A1,
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Reference: [1] RSC Advances, 2018, vol. 8, # 24, p. 13121 - 13128
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 908 - 911
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1852 - 1856
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