* 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 tetra-N-butylammonium tribromide In methanol; dichloromethane at 20℃; for 2 h;
4-Bromo-2-iodophenol (4). 2-Iodophenol (11 g, 50 mmol) was dissolved in DCM (200 mL) and MeOH (100 mL). Tetrabutylammonium tribromide (TBATB) (25.31 g, 52.5 mmol) was then added portionwise over 10 min. The solution was stirred at room temperature for 2 h and then quenched with 1 N HCl (200 mL). The DCM layer was extracted and the aqueous layer was extracted another two times with DCM. The organic layers were then combined, washed with brine, dried, and concentrated. Purification of the residue with flash chromatography (silica, 50percent-100percent DCM/Hexanes) yielded 4-bromo-2-iodophenol (10.2 g, 68percent).
Reference：
[1] Tetrahedron, 2015, vol. 71, # 35, p. 5946 - 5951
[2] Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8680 - 8688
[3] Organic Letters, 2015, vol. 17, # 22, p. 5666 - 5669
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1931, vol. 192, p. 1037
[5] Canadian Journal of Chemistry, 1965, vol. 43, p. 650 - 658
2
[ 106-41-2 ]
[ 207115-22-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-iodo-succinimide; sulfuric acid In acetic acid at 22℃;
4-Bromophenol (51.9 g, 0.30 mol) and N-iodosuccinimide (67.5 g, 0.30 mol) were combined in acetic acid (360 ML).The mixture was stirred briefly, treated with concentrated sulfuric acid (5 ML, 0.09 mol) and stirred at about 22° C. overnight.The mixture was poured into water (about 800 ML) with stirring to precipitate the product.The suspension was stirred for about 1 hour and filtered.The wet cake was washed with water (50 ML, 2*) and dried under reduced pressure at about 50° C. (80.9 g, 90percent). MS-DEI (M+H)+ m/z at 298; 1H NMR (CDCl3 at 400 MHz) δ5.28 (s, 1H), 6.86 (d, 1H), 7.33 (dd, 1H), 7.75 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ86.0, 112.8, 116.0, 132.7, 139.4, 153.7.
77%
With ammonia; iodine; potassium iodide In water at 20℃; for 2 h;
Step A: To a solution of 4-bromophenol (25 g, 144.5 mmol) in 25percent aqueous ammonia solution (350 mL) was added a solution of potassium iodide (72 g, 433.5 mmol) and iodine (36.7 g, 144.5 mmol) in water (288 mL). The reaction mixture was stirred at ambient temperature for 2 h and quenched with 250 mL of water. The reaction was acidified by addition of concentrated HCl (350 mL) and extracted with dichloromethane. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 9:1 hexanes/ethyl acetate) providing 4-bromo-2-iodophenol (33 g, 77percent) as a pink solid: 1H NMR (CDCl3, 300 MHz) δ 7.78-7.75 (m, 1H), 7.37-7.31 (m, 1H), 6.88 (d, J=8.7 Hz, 1H).
67%
With potassium hydrogensulfate; potassium iodide; isoquinolinium chlorochromate In water at 20℃; Sonication
General procedure: The general method for ultrasonically assisted brominationreaction is almost similar to conventional reaction as mentionedabove. A centimolar (0.01 mol) organic substrate (phenols,anilines, or acetanilides), 0.001 mol potassium halide(KBr), about 50 mg of dilute KHSO4, and hypervalent Cr(VI) reagent (IQCC or IQDC) were suspended in about30 mL solvent (DCE or ACN) in a previously cleaned roundbottom(R.B) flask placed in a sonicator. The reaction mixtureis sonicated at room temperature about 30–40 min. Progressof the reaction was monitored by TLC technique. Workupprocedure after completion of the reaction mixture is similarto the one described previously.
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 10634 - 10642
[2] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 1, p. 3 - 6
[3] Patent: US2004/54185, 2004, A1, . Location in patent: Page 10
[4] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 38 - 55
[5] Tetrahedron Letters, 2007, vol. 48, # 1, p. 81 - 83
[6] Synthetic Communications, 2010, vol. 40, # 23, p. 3506 - 3513
[7] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2011, vol. 41, # 3, p. 258 - 261
[8] Synthetic Communications, 2008, vol. 38, # 17, p. 2881 - 2888
[9] Patent: US2012/184531, 2012, A1, . Location in patent: Page/Page column 53
[10] Tetrahedron, 2008, vol. 64, # 37, p. 8992 - 8996
[11] Journal of Medicinal Chemistry, 2008, vol. 51, # 18, p. 5650 - 5662
[12] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 6, p. 832 - 837
[13] Journal of the American Chemical Society, 2014, vol. 136, # 12, p. 4740 - 4745
[14] Tetrahedron Letters, 2010, vol. 51, # 16, p. 2170 - 2173
[15] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1981, vol. 20, # 2, p. 133 - 135
[16] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2559 - 2563
[17] Tetrahedron Letters, 2007, vol. 48, # 35, p. 6124 - 6128
[18] Synthetic Communications, 2008, vol. 38, # 22, p. 3894 - 3902
[19] Patent: WO2005/100301, 2005, A1, . Location in patent: Page/Page column 61
[20] Patent: WO2010/92043, 2010, A1, . Location in patent: Page/Page column 140
3
[ 40925-68-6 ]
[ 207115-22-8 ]
Yield
Reaction Conditions
Operation in experiment
1.1 g
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With potassium iodide In water at 0 - 20℃;
To a solution of 2-amino-4-bromophenol (2 g, 8.9 mmol, 1.0 equiv) in HC1 (5 M, 12.5 mE, 7.0 equiv) was added drop-wise a solution of sodium nitrite (0.62 g, 8.9 mmol, 1.0 equiv) in water (5 mE) at 00 C. The mixture was stirred at this temperature for 30 mm afier which a cooled solution of KI (1.5 g, 8.9 mmol, 1.0 equiv) inH2O (14 mE) was slowly added at 00 C. The mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mE) and the separated aqueous phase was extracted with ethyl acetate (100 mEx3). The combined organic fraction was washed with Na2S2O3 (10percent, 40 mE), water (100 mEx2) and brine (40 mE), dried over Na2SO4 and concentrated to dryness.11219] The residue was purified by flash silica gel chromatography (ethyl acetate/hexanes) to afford 1.1 g 4-bromo-2- iodo-pheno as a yellow solid.
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 3911 - 3917
6
[ 108-95-2 ]
[ 207115-22-8 ]
Reference：
[1] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 6, p. 832 - 837
7
[ 207115-22-8 ]
[ 74-88-4 ]
[ 98273-59-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate In acetone at 20℃; for 16 h;
Iodomethane (103 μL, 1.65 mmol) was added to a solution of 4-bromo-2-iodophenol (450 mg, 1.51 mmol) and potassium carbonate (271 mg, 1.96 mmol) in acetone (10 mL). The resulting mixture was stirred at room temperature for 16 hours. After concentration in vacuo, the mixture was partitioned between water (20 mL) and EtOAc (20 mL), and the aqueous layer extracted with EtOAc (2*15 mL). The organics layers were combined and washed with brine (20 mL), dried over MgSO4 (s), and concentrated in vacuo, to afford the title compound as an orange oil in 93percent yield, 439 mg. 1H NMR (400 MHz, CDCl3): δ ppm 3.86 (s, 3H), 6.68 (d, 1H), 7.41 (dd, 1H), 7.88 (d, 1H).
With tetra-N-butylammonium tribromide; In methanol; dichloromethane; at 20℃; for 2h;
4-Bromo-2-iodophenol (4). 2-Iodophenol (11 g, 50 mmol) was dissolved in DCM (200 mL) and MeOH (100 mL). Tetrabutylammonium tribromide (TBATB) (25.31 g, 52.5 mmol) was then added portionwise over 10 min. The solution was stirred at room temperature for 2 h and then quenched with 1 N HCl (200 mL). The DCM layer was extracted and the aqueous layer was extracted another two times with DCM. The organic layers were then combined, washed with brine, dried, and concentrated. Purification of the residue with flash chromatography (silica, 50%-100% DCM/Hexanes) yielded 4-bromo-2-iodophenol (10.2 g, 68%).
With N-iodo-succinimide; sulfuric acid; In acetic acid; at 22℃;
4-Bromophenol (51.9 g, 0.30 mol) and N-iodosuccinimide (67.5 g, 0.30 mol) were combined in acetic acid (360 ML).The mixture was stirred briefly, treated with concentrated sulfuric acid (5 ML, 0.09 mol) and stirred at about 22 C. overnight.The mixture was poured into water (about 800 ML) with stirring to precipitate the product.The suspension was stirred for about 1 hour and filtered.The wet cake was washed with water (50 ML, 2*) and dried under reduced pressure at about 50 C. (80.9 g, 90%). MS-DEI (M+H)+ m/z at 298; 1H NMR (CDCl3 at 400 MHz) delta5.28 (s, 1H), 6.86 (d, 1H), 7.33 (dd, 1H), 7.75 (d, 1H); 13C NMR (CDCl3 at 100 MHz) delta86.0, 112.8, 116.0, 132.7, 139.4, 153.7.
77%
With ammonia; iodine; potassium iodide; In water; at 20℃; for 2h;
Step A: To a solution of 4-bromophenol (25 g, 144.5 mmol) in 25% aqueous ammonia solution (350 mL) was added a solution of potassium iodide (72 g, 433.5 mmol) and iodine (36.7 g, 144.5 mmol) in water (288 mL). The reaction mixture was stirred at ambient temperature for 2 h and quenched with 250 mL of water. The reaction was acidified by addition of concentrated HCl (350 mL) and extracted with dichloromethane. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 9:1 hexanes/ethyl acetate) providing 4-bromo-2-iodophenol (33 g, 77%) as a pink solid: 1H NMR (CDCl3, 300 MHz) delta 7.78-7.75 (m, 1H), 7.37-7.31 (m, 1H), 6.88 (d, J=8.7 Hz, 1H).
67%
With potassium hydrogensulfate; potassium iodide; isoquinolinium chlorochromate; In water; at 20℃;Sonication;
General procedure: The general method for ultrasonically assisted brominationreaction is almost similar to conventional reaction as mentionedabove. A centimolar (0.01 mol) organic substrate (phenols,anilines, or acetanilides), 0.001 mol potassium halide(KBr), about 50 mg of dilute KHSO4, and hypervalent Cr(VI) reagent (IQCC or IQDC) were suspended in about30 mL solvent (DCE or ACN) in a previously cleaned roundbottom(R.B) flask placed in a sonicator. The reaction mixtureis sonicated at room temperature about 30-40 min. Progressof the reaction was monitored by TLC technique. Workupprocedure after completion of the reaction mixture is similarto the one described previously.
With sodium hydroxide; sodium hypochlorite; sodium iodide; In methanol; water; at 0 - 2℃; for 0.333333h;
Dissolve 4-bromophenol (100 g, 0.578 mol), sodium iodide (86.6 g, 0.578 mol) and sodium hydroxide (23.1 g, 0.578 mol) in methanol (1500 mL) and cool to 0 C. Add aqueous sodium hypochlorite (5% active chlorine, 900 mL) dropwise keeping the temperature below 2 C and allow the reaction to stir for 20 min. Add 10% aqueous sodium thiosulphate solution (800 mL). Acidify to pH = 2 with 1 N hydrochloric acid. Extract the mixture with dichloromethane (3 x 1000 mL). Combine the organic phases, wash with saturated aqueous sodium chloride, dry (magnesium sulphate) and concentrate to give the crude title compound as a white solid which is used directly without further purification (171 g). ¹H NMR (300 MHz; CDCl3) 8 7.77 (1H, d, J=2.4 Hz), 7.35 (1H, dd, J=2.4,8.6 Hz), 6.87 (lH, d, J=8.6 Hz), 5.35 (1H, s)
With N-iodo-succinimide; In acetic acid; at 20℃; for 18h;
A solution of 4-bromophenol (35.0 g, 145 mmol) in acetic acid (250 ml) was treated with Lambda/-iodosuccinimide (32.5 g, 145 mmol) at RT. The reaction mixture was stirred at RT for 18 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica) eluting with 1 % methanol in chloroform to afford the title compound as a brown liquid.1H NMR (300MHz, DMSOd6) delta [ppm] 10.59 (1 H, s), 7.78 (1 H, s), 7.35 (1 H, d), 6.82 (1 H, d). MS (ESI+): 296.6. HPLC (Method D) Purity 99.3 %; Rt 3.81 min.
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; at 110℃; for 36h;
0.54 g (1.90 mmol) of <strong>[207115-22-8]4-bromoiodophenol</strong>, 1.24 g (3.80 mmol) of cesium carbonate, 68.0 mg (0.38 mmol) of 1,10-phenanthroline, and 36.0 mg (0.19 mmol) of Cul are added to a solution of 0.35 g (1.89 mmol) of (R)-3-methyl-2-(4-methylpiperidin-1-yl)butan-1-ol in 3.0 mL of toluene. The reaction mixture is shaken for 36 hours at 110 C. After cooling, it is diluted with 40 mL of EtOAc and washed twice with 30 mL of water. The organic phase is dried over magnesium sulfate and the solvent is eliminated in vacuo. Further purification is carried out by column chromatography on silica gel (DCM towards DCM/MeOH 9:1). Yield: 100 mg (16.0% of theoretical); C17H26BrNO (M=340.298); calc.: molpeak (M+H)+: 340/342 (Br); found: molpeak (M+H)+: 340/342 (Br); retention time HPLC: 4.93 min (method B).
Example 112A 4-bromo-2-iodophenol 4-Bromophenol was processed as described in Example 106C, except that after neutralization the mixture was partitioned between 20% EtOAc/hexanes (250 mL) and brine (50 mL) and the aqueous phase was separated and reextracted until nearly all the product was removed (TLC). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated to provide the (90% pure) title compound (100% yield). A portion was purified by chromatography on silica using a 25 to 80% gradient of CH2Cl2/hexanes. 1H-NMR (300 MHz, d6-DMSO) 6.83 (d, 1H), 7.36 (dd, 1H), 7.79 (d, 1H), 10.59 (s, 1H).
General procedure: The 2-iodophenol (0.5 mmol) and dichlorobis(triphenylphosphine)palladium (10.5 mg, 3 mol %) were placed in a 5 mL microwave vial and purged with argon. Dry THF (0.5 mL) was added and the reaction mixture was stirred until the iodophenol completely dissolved. Then dry triethylamine (1.0 mL) and a 3.8 M solution of CuI in dry triethylamine (0.5 mL) were added and the mixture allowed to stir for 10 min. Then 1.2 equiv of the corresponding alkyne was added; the vial was capped, purged with argon and placed in the microwave reactor for 30 min at 25 C. The corresponding aryl iodide (0.5 mmol) and dry acetonitrile (2 mL) were added and the reaction mixture was heated in the microwave reactor at 100 C for 25 min. After cooling, the solvents were evaporated and column chromatography using ethyl acetate/hexane as the eluent afforded the desired products.
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