* 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.
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 29, p. 10776 - 10782
2
[ 145691-59-4 ]
[ 56990-02-4 ]
Reference：
[1] Synlett, 2002, # 2, p. 251 - 254
3
[ 145691-59-4 ]
[ 56908-88-4 ]
Yield
Reaction Conditions
Operation in experiment
2.5 g
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 1 h;
General procedure: 3,5-Di-t-butylbenzoic acid (5.00 g, 0.021 mol) was dissolved in anhydrous THF (250 mL) under argon atmosphere and the solution cooled to 0 °C. Lithium aluminum hydride (1.62 g, 0.043 mol) was added in small portions and the solution stirred at room temperature overnight. The reaction was quenched with water, Et2O (100 mL) was added and the mixture acidified with concentrated HCl solution until the solid residue was dissolved. The medium was extracted with Et2O and the organic phase dried over MgSO4, filtered and concentrated to yield 4.31g of 5a. 1H NMR δ (CDCl3) 1.34 (s, 18H, di-t-butyl), 4.70 (s, 2H, PhCH2OH), 7.23 (d, 2H, J = 1.8 Hz, 2-CH and 6-CH), 7.38 (t, 1H, J = 1.8 Hz, 4-CH). Crude alcohol 5a (4.25 g) was dissolved in anhydrous CH2Cl2 (500 mL) and cooled at 0 °C. Triphenylphosphine (10.23 g, 0.039 mol) and carbon tetrabromide (12.93 g, 0.039 mol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel with hexanes to yield 4.62 g (86percent) of bromide 5b.
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7473 - 7485
[2] European Journal of Organic Chemistry, 2007, # 16, p. 2700 - 2712
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1215 - 1227
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4227 - 4237
4
[ 56990-02-4 ]
[ 145691-59-4 ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h;
Example 15 [4-[3,5-Bis-[(4-trifluoromethylphenyl)ethynyl]benzyloxy]-2-methylphenoxy]acetic acid 3,5-Dibromobenzaldehyde (1.7 g, 6.3 mmol) was dissolved in methanol (100 mL) and sodium borohydride (0.250 g, 6.3 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. and then at 20° C. for another 0.5 h. The reaction mixture was concentrated in vacuo, diluted with brine (250 mL), acidified with hydrochloric acid and extracted with dichloromethane (3*50 mL). Evaporation of the organic solution gave 3,5-dibromo-benzyl alcohol as a white crystalline compound. Yield: 1.4 g (84percent). RF (SiO2, hexanes/ethyl acetate 9:1) 0.25. 1H NMR spectrum (300 MHz, CDCl3, A) 7.59 (d, J=1.5 Hz, 1H); 7.47 (d, J=1.5 Hz, 2H); 4.36 (s, 2H); 1.55 (s, 1H).
84%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h;
Example 15; [4-[3,5-Bis-[(4-trifluoromethylphenyl)ethynyl]benzyloxy]-2-methylphenoxy]acetic acid; 3,5-Dibromobenzaldehyde (1.7 g, 6.3 mmol) was dissolved in methanol (100 mL) and sodium borohydride (0.250 g, 6.3 mmol) was added at 0 °C. The reaction mixture was stirred for 0.5 h at 0 °C and then at 20 °C for another 0.5 h. The reaction mixture was con- centrated in vacuo, diluted with brine (250 mL), acidified with hydrochloric acid and extracted with dichloromethane (3 x 50 mL). Evaporation of the organic solution gave 3,5-dibromo- benzyl alcohol as a white crystalline compound. Yield: 1.4 g (84 percent). RF (Si02, hexanes/ethyl acetate 9:1) 0.25. 1H NMR spectrum (300 MHz, CDCl3, No.H) : 7.59 (d, J=1.5 Hz, 1 H) ; 7.47 (d, J=1.5 Hz, 2 H); 4.36 (s, 2 H); 1.55 (s, 1 H).
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7473 - 7485
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 21, p. 3442 - 3452
[3] Organic Letters, 2004, vol. 6, # 16, p. 2765 - 2767
[4] Patent: US2009/209588, 2009, A1, . Location in patent: Page/Page column 25
[5] Patent: WO2005/105726, 2005, A1, . Location in patent: Page/Page column 62
[6] Chemical Communications, 2004, # 14, p. 1582 - 1583
[7] Patent: US5457118, 1995, A,
[8] Patent: WO2009/42694, 2009, A1, . Location in patent: Page/Page column 114
[9] Journal of Polymer Science, Part A: Polymer Chemistry, 2014, vol. 52, # 5, p. 707 - 718
5
[ 618-58-6 ]
[ 145691-59-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃;
Step 1 : To a stirred solution of 3,5-dibromobenzoic acid (2 g, 7.168 mmol) in tetrahydrofuran (20 mL) was added borane dimethylsulfide (3.4 mL, 35.842 mmol, 5 eq.) at 0 °C, and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched with methanol at 0 °C and concentrated under vacuo to obtain (3,5- dibromophenyl)methanol as an off white solid (1.8 g, 94percent). H NMR (400 MHz, DMSO-d6) δ ppm 4.47 (d, J = 6 Hz, 2H), 5.39 (t, J = 6 Hz, 1 H), 7.49 (s, 2H), 7.65 (s, 1 H).
Reference：
[1] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 60
[2] Patent: JP2005/120047, 2005, A, . Location in patent: Page/Page column 165
[3] Synlett, 2002, # 2, p. 251 - 254
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4227 - 4237
6
[ 67973-33-5 ]
[ 145691-59-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2009, # 18, p. 2953 - 2955
7
[ 626-39-1 ]
[ 145691-59-4 ]
Reference：
[1] Australian Journal of Chemistry, 1997, vol. 50, # 4, p. 425 - 434
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2014, vol. 52, # 5, p. 707 - 718
8
[ 56908-88-4 ]
[ 145691-59-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 303
9
[ 56990-02-4 ]
[ 145691-59-4 ]
[ 193408-02-5 ]
Reference：
[1] Australian Journal of Chemistry, 1997, vol. 50, # 4, p. 425 - 434
With 1H-imidazole; In DMF (N,N-dimethyl-formamide);
tert-Butyldimethylsilyl 3,5-dibromobenzyl ether. A mixture of 3,5-dibromobenzyl alcohol (9.77 g, 36.74 mmol), tert-butyldimethylchlorosilane (6.80 g, 45.1 mmol) and imidazole (6.08 g, 89.3 mmol) in DMF (100 mL) was stirred under argon over night. The reaction mixture was diluted with ether, washed with water three times, dried over magnesium sulfate, and concentrated under vacuum to provide the title compound. 1H NMR (400 MHz, CDCl3) delta 7.58 (s, 1H), 7.39 (s, 2H), 4.62 (s, 2H), 0.95 (s, 9H), 0.05 (s, 6H).
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;
Step 1 tert-Butyl-(3,5-dibromobenzyloxy)dimethyl silane (21A) A solution of 3,5-dibromobenzyl alcohol (16.5 g, 62.0 mmol), imidazole (10.8 g, 158.7 mmol) and tert-butyldimethylchlorosilane (11.5 g, 76.3 mmol) in DMF (100 mL) was stirred over weekend at ambient temperature. The solvent was removed under vacuum. The residue was dissolved in diethyl ether and washed with water four times and brine once. The organic phase was dried over magnesium sulfate and concentrated to give 21A.
With thionyl chloride; In DMF (N,N-dimethyl-formamide); for 0.5h;
3, [5-DIBROMOBENZYL ALCOHOL] (9.8 g, 36.9 [MMOL)] is dissolved in DMF (100 ml) and, while stirring, thionyl chloride (5 [ML)] is slowly added dropwise. [AFTER30 M IN,] the reaction mixture is concentrated in vacuo and the residue is taken up in EA (150 [ML). FORWORKUP,] the organic phase is washed with ice-water (50 ml) and then with half-saturated aqueous NaCi solution (50 [ML).] The organic phase is dried over [MGS04,] filtered and concentrated in vacuo. The title compound (10.4 g) is obtained as a yellow solid. TLC [PE/EA (95: [05)], RF=] 0.69.
1,3-Dibromo-benzyl alcohol (1) (20 g, 75.2 mmol) was dissolved in anhydrous DCM (200 mL) in a dried flask under nitrogen. The reaction mixture was cooled to 0 °C and stirred under nitrogen atmosphere. DIPEA (25.8 mL, 150.4 mmol) was added drop wise to the above solution, after 10 minutes of stirring at 0 °C, mesyl cholride (8.7 mL, 112.8 mmol) was added drop-wise to the above reaction mixture. Finally, the reaction mixture was allowed to stir at RT for 2 hrs. Reaction mixture was diluted with DCM, washed with water (100 mL) followed by NaHC03 solution and brine, dried over anhydrous Na2S04, filtered and evaporated to dryness to give 21 gm of crude product (2) as a brown liquid which was carried forward to the next step as such.
With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 26℃; for 2h;Inert atmosphere;
(3,5-Dibromophenyl)methanol (10 g, 37.60 mmol, 1 eq) was dissolved in anhydrous DCM (100 mL) in a dried flask under nitrogen. The reaction mixture was cooled to 0°C and stirred under nitrogen atmosphere. DIEA (9.72 g, 75.21 mmol, 13.10 mL, 2 eq) was added drop wise to the above solution, after 10 minutes of stirring at 0°C, MsCl (6.46 g, 56.41 mmol, 4.37 mL, 1.5 eq) was added drop-wise to the above reaction mixture. Finally, the reaction mixture was allowed to stir at 26°C for 2hrs. TLC (Petroleum ehter : EtOAc = 5:1, uv & stained by KMnO4) showed starting alcohol was consumed up and two new spots were formed. Reaction mixture was washed with water (80 mL) followed by NaHCO3 (80 mL) solution and brine (80 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness to give the desired product as a brown liquid (12.11g). The above liquid was used directly for the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.04 (s, 3 H) 4.49 (s, 2 H) 5.16 (s, 2 H) 7.48 (d, J=1.76 Hz, 2 H) 7.50 (d, J=1.76 Hz, 2 H) 7.63 (t, J=1.76 Hz, 1 H) 7.70 (t, J=1.76 Hz, 1 H).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 0 - 20℃;
The above benzyl alcohol (0.26 g, 1.0 mmol) and methyl (4-hydroxy-2-methylphenoxy)acetate (0.30 g, 1.5 mmol) and triphenylphosphine (0.50 g, 1.85 mmol) were dissolved in a mixture of anhydrous toluene (3-mL) and tetrahydrofuran (1 mL) and the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (0.22 g, 1.2 mmol) was added dropwise under nitrogen. The reaction mixture was stirred for 12 h at ambient temperature and the solvents were evaporated in vacuo. Column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-90:10) gave methyl [4-(3,5-dibromo)benzyloxy]-2-methylphenoxy]acetate. Yield: 0.25 g (56percent). RF (SiO2, hexanes/ethyl acetate 8:2) 0.45. 1H NMR spectrum (300 MHz, CDCl3, deltaH): 7.61 (s, 1H); 7.48 (s, 2H); 6.80 (s, 1H); 6.67 (s, 2H); 4.92 (s, 2H); 4.60 (s, 2H); 3.80 (s, 3H); 2.28 (s, 3H).
56%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 0 - 20℃; for 12h;
The above benzyl alcohol (0.26 g, 1.0 mmol) and methyl (4-hydroxy-2-methyl- phenoxy) acetate (0.30 g, 1.5 mmol) and triphenylphosphine (0.50 g, 1.85 mmol) were dis- solved in a mixture of anhydrous toluene (3 mL) and tetrahydrofuran (1 mL) and the mixture was cooled to 0 °C. Diisopropyl azodicarboxylate (0.22 g, 1.2 mmol) was added dropwise under nitrogen. The reaction mixture was stirred for 12 h at ambient temperature and the sol- vents were evaporated in vacuo. Column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 98: 2-90:10) gave methyl [4-(3,5-dibromo)benzyloxy]-2-methylphenoxy]acetate. Yield: 0.25 g (56 percent). RF (Si02, hexanes/ethyl acetate 8: 2) 0.45. 1H NMR spectrum (300 MHz, CDCI3, No.H) : 7.61 (s, 1 H) ; 7.48 (s, 2 H) ; 6.80 (s, 1 H) ; 6.67 (s, 2H) ; 4.92 (s, 2 H) ; 4.60 (s, 2 H) ; 3.80 (s, 3 H) ; 2.28 (s, 3 H).
STR13 Preparation of 3,5-dibromobenzylalcohol 1.14G(30 mM) of sodium borohydride was added slowly to a suspension of 3,5-dibromobenzaldehyde (7.92G; 30 mM), from step (a), in 50 mL of methanol at 0° under nitrogen. After stirring 30 mins., the reaction mixture was diluted with 150 mL of ethyl acetate and washed with 5*50 mL of saturated sodium chloride solution, dried over anhydrous magnesium sulfate. Solvent removal afforded a crude product, which was dissolved in minimum amount of CH2 Cl2 and applied on silica gel. Elution with 1:2 mixture of EtOAc:hexane gave 7.2G of the desired alcohol as white solid.
42
[ 145691-59-4 ]
[ 124-63-0 ]
[ 1096698-36-0 ]
[ 74337-30-7 ]
Yield
Reaction Conditions
Operation in experiment
35%; 73%
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 24.5h;
To a stirring cloudy solution of 2.41 g (9.04 mmol) of <strong>[145691-59-4](3,5-dibromophenyl)methanol</strong> in 40 mL of CH2Cl2 at r.t. was added 1.4 mL of Et3N and 62.7 mg of DMAP. The solution was cooled to 0 0C and 1.0 mL of MsCl was added, and the solution was gradually allowed to warm to r.t. After 24.5 h, the organic layer was washed with water (20 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 1.88 g of l,3-dibromo-5- (chloromethyl)benzene as a yellow oil in 73 % yield and 476 mg of the mesylate (35% EtOAc/hexanes) as a pale yellow solid.
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 20 - 45℃;
(3,5-Diethylphenyl)methanol. To a cooled (dry ice) mixture of 3,5-dibromobenzyl alcohol (1 g, 3.8 mmol) and PdCl2(dppf)[0.07 eq] in dry THF (10 mL) was added 1.1 M Et2Zn (15 mL, 16 mmol, 4.4 eq). The resulting mixture was allowed to warm to RT, stirred at 45° C. (programmed block temperature, overnight). To bring the reaction to completion (disappearance of both starting material and monoalkylated product) additional 1.1 M Et2Zn (10 mL, 11 mmol, 2.9 eq) was added with continued stirring at 45° C. (again overnight). After cooling, the reaction mixture was then added to a stirred mixture of dilute HCl and heptane/EtOAc (2:1; ~200 mL), and the organic layer was dried (Na2SO4), filtered, and evaporated. Chromatography (10percent EtOAc/heptane) gave 0.33 g (yield of 53percent) of title product. 1H NMR (300 MHz, CDCl3) delta 1.22 (t, 6H), 1.65 (br s, 1H), 2.61 (q, 4H), 4.66 (s, 2H), 6.95-7.05 (m, 3H). The following compounds were prepared by making the appropriate substitutions to the above procedure. (2,5-Diethylphenyl)methanol. 1H NMR (300 MHz, CDCl3) delta 1.22 (t, 6H), 1.50 (br s, 1H), 2.61 (q, 2H), 2.65 (q, 2H), 4.70 (br s, 1H), 7.0-7.2 (m, 3H). (3,4-Diethylphenyl)methanol. 1H NMR (300 MHz, DMSO-d6) delta 1.14 (t, 3H), 1.20 (t, 3H), 2.62-2.70 (m, 4H), 4.46 (d, 2H), 5.03 (t, 1H), 7.05-7.13 (m, 3H).
53%
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 45℃;Cooling with dry ice;
To a cooled (dry ice) mixture of 3, 5 -dibromobenzyl alcohol (1 g, 3.8 mmol) and PdCl2(dppf)[0.07 eq] in dry THF (10 mL) was added 1.1 M Et2Zn (15 mL, 16 mmol, 4.4 eq). The resulting mixture was allowed to warm to RT, stirred at 45°C (programmed block temperature, overnight). To bring the reaction to completion (disappearance of both starting material and monoalkylated product) additional 1.1 M Et2Zn (10 mL, 11 mmol, 2.9 eq) was added with continued stirring at 45°C (again overnight). After cooling, the reaction mixture was then added to a stirred mixture of dilute HCl and heptane/EtOAc (2: 1; -200 mL), and the organic layer was dried (Na2S04), filtered, and evaporated. Chromatography (10percent> EtO Ac/heptane) gave 0.33 g (yield of 53percent) of title product. 1H NMR (300 MHz, CDC13) delta 1.22 (t, 6 H), 1.65 (br s, 1 H), 2.61 (q, 4 H), 4.66 (s, 2 H), 6.95-7.05 (m, 3 H).
32%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; hexane; at -70 - 45℃;
Step 2: To a mixture of <strong>[145691-59-4](3,5-dibromophenyl)methanol</strong> (1 g, 3.759 mmol, 1 equiv) and PdCI2(dppf).CH2Cl2 complex (0.21 g, 0.263 mmol, 0.07 equiv) in 10 mL of dry THF at -70 °C was added 1 M diethyl zinc in hexane (15 mL). The resulting mixture was allowed to warm to room temperature, and stirred at 45 °C for overnight. To drive the reaction to completion, additional 11.3 mL of 1 M diethyl zinc in hexane was added with continued stirring at 45 °C for overnight. After cooling, the reaction mixture was added to a stirred mixture of dilute HCI and EtOAc. Organic layer was separated, washed with water, dried over Na2S04, filtered, and concentrated in vacuo to afford crude product. The crude product was purified by flash column chromatography with silica gel cartridge using gradient elution of 0 to 10percent EtOAc in Hexane. The collected fractions with pure product were combined and concentrated in vacuo to afford (3,5-diethylphenyl)methanol as colorless liquid (0.2 g, 32percent). LC-MS (ES) m/z = 147.2 [M+H]+. H NMR (400 MHz, DMSO-d6) delta ppm 1.14 (t, J = 7.2 Hz, 6H), 2.50 - 2.56 (m, 4H), 4.41 (d, J = 5.2 Hz, 2H), 5.01 (t, J = 5.6 Hz, 1 H), 6.87 (s, 1 H), 6.93 (s, 2H).
1,3-Dibromo-5-ethoxymethyl-benzene A solution of 3,5-dibromobenzyl alcohol (2.0 h, 8 mmol) in tetrahydrofuran (80 mL) was cooled to 5° C. and treated with sodium hydride (dispersion in oil 55percent; 316 mg, 8 mmol). The mixture was left to warm to room temperature and stirred for 15 min. Ethyliodide (2.35 g, 15 mmol) was added and the mixture stirred for 5 h. For the working-up, the reaction mixture was evaporated, then extracted with a mixture of ethyl acetate and saturated sodium hydrogencarbonate solution. After the aqueous layer was re-extracted twice with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. There were obtained 1.15 g of the title compound (yield: 52percent) as a yellow oil in sufficient purity to be engaged in the next step without further purification.
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