* 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.
4.2 g (18 mmol) of 4-iodo-3-methylphenol are dissolved in 90 ml of anhydrous methanol and then placed in a steel reactor. 5 ml (35 mmol) of triethylamine and 400 mg (1.8 mmol) of palladium diacetate are added, the reaction medium is subjected to a carbon monoxide pressure of 3 bar and heated at 80° C. for 5 hours. The medium is then brought to ambient pressure and temperature and then dissolved in dichloromethane and filtered on celite. After evaporation, the residue is purified by chromatography on a silica column. An orange-coloured powder is obtained (m=1.8 g, Y=61 g).
Stage #1: With hydrogenchloride; sodium nitrite In tetrahydrofuran; water at 0℃; Stage #2: With potassium iodide In tetrahydrofuran; water at 0℃; for 0.25 h;
Example 25: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide Step-1: Synthesis of 4-iodo-3-methylphenol 3 M HCI/ J To a solution of 4-amino-3-methylphenol (10 g, 81 mmol) in THF (45 mL) was added 3M HC1 (35 mL) at 0 °C over a period of 10 min followed by NaN02 (6.1 g, 89 mmol). To the above reaction mixture, potassium iodide (53.89 g, 166 mmol) in water (140 mL) was added dropwise and stirred at 0 °C for 15 min. After completion of reaction, reaction mixture was extracted with EtOAc. Organic layer was washed water followed by brine, concentared under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230-400 mesh silica gel using 10percent EtOAc in n-hexane to give the title compound (9 g, 47percent).
15%
Stage #1: With sulfuric acid; sodium nitrite In water at 0℃; for 0.333333 h; Stage #2: With copper(l) iodide; sulfuric acid; potassium iodide In water at 0℃; for 3 h; Heating / reflux
15 g (122 mol) of 4-hydroxy-2-methylaniline are dissolved in 180 ml of 20percent sulphuric acid and then the reaction medium is cooled to 0° C. A solution of sodium nitrite (11.3 g, 163 mmol) in 60 ml of water is then added dropwise and then the medium is stirred for 20 minutes. This solution is then slowly added to a solution at 0° C. of CuI (32.5 g, 170 mmol) and KI (31.9 g, 193 mmol) in 180 ml of 20percent sulphuric acid. The reaction medium is heated under reflux for 3 hours, poured into 1 l of water and extracted with ethyl ether. The organic phases are washed with a saturated sodium thiosulphate solution, of water, dried over magnesium sulphate and concentrated under reduced pressure. After purification on a silica column (ethyl acetate 30-heptane 70), a brown oil is obtained (m 4.2 g; Y=15percent).
Reference:
[1] Patent: WO2016/196342, 2016, A1, . Location in patent: Page/Page column 129
[2] Patent: US6689922, 2004, B1, . Location in patent: Page column 85
[3] Journal of the Chemical Society, 1951, p. 1184,1186
[4] Patent: US6562823, 2003, B1,
3
[ 108-39-4 ]
[ 133921-27-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
With tetra-(n-butyl)ammonium iodide; isoquinolinium chlorochromate In water at 25 - 30℃; for 4 h;
General procedure: Phenol (1 mmol, 10 mL) dissolved in 1M PEG-600, isoquinolinium dichromate (IQDC) or isoquinolinium chlorochromate (IQCC) reagent, and tetrabutylammonium halide (TBAX) (1.1 mmol each) were taken in a reaction flask and refluxed with constant stirring at about 25 to 30 C, till the completion of reaction, as as certainedby thin layer chromatography. Then the contents of reaction were diluted with ethyl acetate (10 mL) and separated from aqueous layer. Organic layer was then washed two to three time swith 5 mL water and separated. Finally, the resultant mass is dried over sodium sulphate. The anhydrous ethyl acetate layerwas separated under reduced pressure to give crude product, which was further purified by column chromatography (silicagel, 100-200 mesh) using EtOAc-hexane (3:7). For the separation and recyclization of PEG, aqueous mother liquor (reaction mixture of PEG-600 and water) was treated with ether because PEG is insoluble in ether. The aqueous layer obtained after the removal of ether, was then distilled directly at 100 C to remove water and recover PEG-600. The recovered PEG-600 could be reused for consecutive runs.
70%
With potassium hydrogensulfate; potassium iodide; isoquinolinium chlorochromate In water at 50 - 60℃;
General procedure: A centimolar (0.01mol) organic substrate (phenols, anilines,or acetanilides), about 0.01 mol of potassium halide (KBr orKI), 0.001 mol hypervalent Cr (VI) reagent (IQCC orIQDC), and solvent (DCE or ACN) were taken in a previouslycleaned round-bottom flask. About 50 mg of KHSO4 isalso added to the reaction flask. The reaction mixture isrefluxed for about 4–5 h at 50–60C. Progress of the reactionwas monitored by TLC technique. After completion, thereaction mixture is treated with 5percent sodium thiosulfate solutionfollowed by the addition of ether. The aqueous layer wasseparated, dried, and evaporated under vacuum, and purifiedwith column chromatography using chloroform:n-hexane(9:1) as eluent to get pure product.General
Reference:
[1] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 261 - 264
[2] Synthetic Communications, 2008, vol. 38, # 17, p. 2881 - 2888
[3] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2011, vol. 41, # 3, p. 258 - 261
[4] Catalysis Communications, 2017, vol. 93, p. 1 - 4
[5] Asian Journal of Chemistry, 2018, vol. 30, # 8, p. 1892 - 1896
[6] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 6, p. 832 - 837
[7] Tetrahedron Letters, 2010, vol. 51, # 16, p. 2170 - 2173
[8] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 586 - 592
[10] Journal of Organic Chemistry, 1994, vol. 59, # 15, p. 4285 - 4296
[11] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1981, vol. 20, # 2, p. 133 - 135
[12] Tetrahedron Letters, 2007, vol. 48, # 35, p. 6124 - 6128
[13] International Journal of Chemical Kinetics, 2013, vol. 45, # 11, p. 693 - 702
Example 25: Synthesis of(E)-4-((2-(4-((Z)-l-(4-hydroxyphenyl)-2-phenylbut-l-en-l-yl)-3- methylphenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide Step-1: Synthesis of 4-iodo-3-methylphenol 3 M HCI/ J To a solution of 4-amino-3-methylphenol (10 g, 81 mmol) in THF (45 mL) was added 3M HC1 (35 mL) at 0 C over a period of 10 min followed by NaN02 (6.1 g, 89 mmol). To the above reaction mixture, potassium iodide (53.89 g, 166 mmol) in water (140 mL) was added dropwise and stirred at 0 C for 15 min. After completion of reaction, reaction mixture was extracted with EtOAc. Organic layer was washed water followed by brine, concentared under reduced pressure to obtain the crude compound. Crude material was purified by column chromatography over 230-400 mesh silica gel using 10% EtOAc in n-hexane to give the title compound (9 g, 47%).
15%
15 g (122 mol) of 4-hydroxy-2-methylaniline are dissolved in 180 ml of 20% sulphuric acid and then the reaction medium is cooled to 0 C. A solution of sodium nitrite (11.3 g, 163 mmol) in 60 ml of water is then added dropwise and then the medium is stirred for 20 minutes. This solution is then slowly added to a solution at 0 C. of CuI (32.5 g, 170 mmol) and KI (31.9 g, 193 mmol) in 180 ml of 20% sulphuric acid. The reaction medium is heated under reflux for 3 hours, poured into 1 l of water and extracted with ethyl ether. The organic phases are washed with a saturated sodium thiosulphate solution, of water, dried over magnesium sulphate and concentrated under reduced pressure. After purification on a silica column (ethyl acetate 30-heptane 70), a brown oil is obtained (m 4.2 g; Y=15%).
With hydrogenchloride; potassium iodide; sodium nitrite; In tetrahydrofuran; water;
Step A Preparation of 4-Iodo-3-methylphenol To a solution of 4-amino-meta-cresol (20.59 g, 167 mmol) in 90 mL of tetrahydrofuran and 280 mL of 3M HCl solution at 0 C. was added a solution of NaNO2 (12.73 g, 184 mmol) in 40 mL of water dropwise over 5 minutes. After 25 minutes, a solution of potassium iodide (112.5 g, 678 mmol) in 85 mL of water was added, and stirring was continued for 15 minutes. The solution was poured into EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (0-50% EtOAc/hexane) to provide the desired product as a dark crystalline solid.
With tetra-(n-butyl)ammonium iodide; isoquinolinium chlorochromate; In water; at 25 - 30℃; for 4h;
General procedure: Phenol (1 mmol, 10 mL) dissolved in 1M PEG-600, isoquinolinium dichromate (IQDC) or isoquinolinium chlorochromate (IQCC) reagent, and tetrabutylammonium halide (TBAX) (1.1 mmol each) were taken in a reaction flask and refluxed with constant stirring at about 25 to 30 C, till the completion of reaction, as as certainedby thin layer chromatography. Then the contents of reaction were diluted with ethyl acetate (10 mL) and separated from aqueous layer. Organic layer was then washed two to three time swith 5 mL water and separated. Finally, the resultant mass is dried over sodium sulphate. The anhydrous ethyl acetate layerwas separated under reduced pressure to give crude product, which was further purified by column chromatography (silicagel, 100-200 mesh) using EtOAc-hexane (3:7). For the separation and recyclization of PEG, aqueous mother liquor (reaction mixture of PEG-600 and water) was treated with ether because PEG is insoluble in ether. The aqueous layer obtained after the removal of ether, was then distilled directly at 100 C to remove water and recover PEG-600. The recovered PEG-600 could be reused for consecutive runs.
70%
With potassium hydrogensulfate; potassium iodide; isoquinolinium chlorochromate; In water; at 50 - 60℃;
General procedure: A centimolar (0.01mol) organic substrate (phenols, anilines,or acetanilides), about 0.01 mol of potassium halide (KBr orKI), 0.001 mol hypervalent Cr (VI) reagent (IQCC orIQDC), and solvent (DCE or ACN) were taken in a previouslycleaned round-bottom flask. About 50 mg of KHSO4 isalso added to the reaction flask. The reaction mixture isrefluxed for about 4-5 h at 50-60C. Progress of the reactionwas monitored by TLC technique. After completion, thereaction mixture is treated with 5% sodium thiosulfate solutionfollowed by the addition of ether. The aqueous layer wasseparated, dried, and evaporated under vacuum, and purifiedwith column chromatography using chloroform:n-hexane(9:1) as eluent to get pure product.General
With triethylamine;palladium diacetate; at 80℃; under 2250.23 Torr; for 5h;
4.2 g (18 mmol) of <strong>[133921-27-4]4-iodo-3-methylphenol</strong> are dissolved in 90 ml of anhydrous methanol and then placed in a steel reactor. 5 ml (35 mmol) of triethylamine and 400 mg (1.8 mmol) of palladium diacetate are added, the reaction medium is subjected to a carbon monoxide pressure of 3 bar and heated at 80° C. for 5 hours. The medium is then brought to ambient pressure and temperature and then dissolved in dichloromethane and filtered on celite. After evaporation, the residue is purified by chromatography on a silica column. An orange-coloured powder is obtained (m=1.8 g, Y=61 g).
tert-butyl (2-(4-iodo-3-methylphenoxy)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
Step-2: Synthesis of tert-butyl (2-(4-iodo-3-methylphenoxy)ethyl)carbamate To a solution of <strong>[133921-27-4]4-iodo-3-methylphenol</strong> (8 g, 34.3 mmol) in DMF (80 mL) was added potassium carbonate (28.4 g, 206 mmol) and tert-butyl (2-bromoethyl)carbamate (15.38 g, 68.6 mmol). The reaction mixture was stirred at 80 C for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford tert-butyl (2-(4-iodo-3- methylphenoxy)ethyl)carbamate (3.4 g, 28%).
With tetrabutyl ammonium fluoride In tetrahydrofuran; toluene at 90℃; for 4h;
4-5 Preparation of 4-(4-iodo-3-methylphenoxy)benzonitrile (Compound of Formula IV)
A flask was charged in turn with 46.8 g 4-iodo-3-methyl-phenol (0.2 mol) prepared according to the process described in Example 1, 29 g 4-fluorobenzonitrile (0.24 mol), 300 ml toluene and 300 ml of a solution of tetrabutylammonium fluoride in THF (1 mol/L). The system was heated to 90° C. and reacted at the temperature for 4 hours. When the reaction completed, the reaction solution was cooled to room temperature, added into 300 ml water, stirred for 1 hour, and then allowed to separate into layers. The aqueous layer was extracted with ethyl acetate twice (100 ml*2). The organic layers were combined, dried with anhydrous sodium sulfate, and then distilled to dry. 300 ml n-hexane was added into the residue, and the mixture was stirred in an ice-water bath for 2 hours to precipitate white solid. Filtration under reduced pressure and drying yielded target product (59 g, white solid) with purity of 99% and yield of 88%. Mass: m/z 333.9 [M-H]+; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 1H), 7.62-7.59 (m, 2H), 7.02-6.96 (m, 3H), 6.64 (dd, J1=2.8 Hz, J2=8.8 Hz, 1H), 2.42 (s, 3H).
80%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;
1
Put 66g 4-iodo-3-methylphenol (0.28mol), 46g 4-fluorobenzonitrile (0.38mol), 350mL DMF, and 50g potassium carbonate into the reaction flask successively; increase the temperature to 80, react for 8 hours, and decrease the temperature to 25 The reaction solution was added to 800mL of water, stirred for 1 hour, filtered, the filter cake was dissolved with 300mL of dichloromethane, concentrated under reduced pressure, the residue was recrystallized with a mixed solvent of 230mL of n-heptane and 30mL of ethyl acetate, filtered; dried to obtain the target product 75g of white solid d 4-(4-iodo-3-methylphenoxy)benzonitrile, purity 97%, yield 80%.