* 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 carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 20℃; for 4 h; Cooling with ice
4-hydroxymethylphenylboronic acid, pinacol ester (1.08 g, 4.61 mmol) was dissolved in THF (20 ml) together with triphenylphosphine (2.42 g, 9.23mmol). The reaction mixture was cooled in an ice-water bath, and carbon tetrabromide (3.06 g, 9.23 mmol) was added portion wise. After stirring for 4 hours at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was combined and dried by sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by flash chromatography to give the product as a white solid (1.72 g, 92percent). 1H NMR (300 MHz, CD2C12, δ): 7.62 (d, J = 6.0 Hz, 2H), 7.32 (d, J = 6.0 Hz, 2H), 4.58 (d, 2H), 1.34 (s, 9H); MS (ESI) m/z 297.0.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 85℃; Inert atmosphere
p-Bromobenzyl alcohol (Compound 1, 1.0 g, 5.35 mmol) was dissolved in 10 mL of dry 1,4-dioxane solution, and boranoic acid pinacol ester (247 mg, 5.88 mmol), potassium acetate and pdCl 2 ( Dppf), under N2 protection, heat to 85 ° C to stir the reaction. After the reaction was completed by thin layer chromatography, the solvent was evaporated under reduced pressure, and ethyl acetate (200 ml) was added and thenThe organic phase was dried over anhydrous sodium sulfate and concentrated under reduced vacuo.The crude product was purified by column chromatography (mobile phase ethyl acetate: petroleum ether = 1:8-1:4)Obtained 181 mg of a pale yellow oily liquid with a yield of 90percent.
1500 mg
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 16 h;
A mixture of (4-bromophenyl)methanol (1 g, 5.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.07 g, 16.04 mmol), KOAc (1.05 g, 10.69 mmol) and Pd(dppf)Cl2.CH2Cl2 (873.27 mg, 1.07 mmol) in 1,4-Dioxane (20 mL) was stirred at 90 C for 16 hours. After cooling to r.t., the mixture was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 to 50percent) to give the product (1500 mg) as oil. H NMR (400MHz DMSO-d6) __ = 7.63 (d, 2H), 7.32 (d, 2H), 5.23 (t, 1H), 4.51 (d, 2H), 1.29 (s, 12H).
Reference：
[1] Patent: CN108148098, 2018, A, . Location in patent: Paragraph 0058; 0059; 0060
[2] Journal of the American Chemical Society, 2018, vol. 140, # 19, p. 6109 - 6121
[3] Patent: US2012/184520, 2012, A1, . Location in patent: Page/Page column 17
[4] Patent: CN107445885, 2017, A, . Location in patent: Paragraph 0177; 0180
[5] Patent: WO2018/98499, 2018, A1, . Location in patent: Page/Page column 215
3
[ 76-09-5 ]
[ 59016-93-2 ]
[ 302348-51-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
for 22 h; Reflux
A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6. mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 mL) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2Cl2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2Cl2 / EtOAc (9/1, v/v) as eluent. Yield 1.4 g (92percent). Rf= 0.3 (silica, eluent - CH2Cl2 / EtOAc, 9/1, v/v). 1H NMR (200 MHz, CDCl3), δ in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz).
92%
for 22 h; Reflux
Synthesis4-(Hvdroxymethyl)phenylboronic acid pinacol ester:A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6 mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 ml_) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2CI2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2CI2 / EtOAc (9/1 , v/v) as eluent. Yield 1.4 g (92percent). Rf= 0.3 (silica, eluent - CH2CI2 / EtOAc, 9/1 , v/v). H NMR (200 MHz, CDCI3), δ in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz).
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 4, p. 756 - 758
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 924 - 934
[3] Patent: EP2497775, 2012, A1, . Location in patent: Page/Page column 11
[4] Patent: WO2012/123076, 2012, A1, . Location in patent: Page/Page column 21-22
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 45, p. 14025 - 14030[6] Angew. Chem., 2017, vol. 129, p. 14213 - 14218,6
[7] Organic Letters, 2013, vol. 15, # 18, p. 4850 - 4853
[8] Angewandte Chemie - International Edition, 2017, vol. 56, # 12, p. 3206 - 3210[9] Angew. Chem., 2017, vol. 129, # 12, p. 3254 - 3258,5
[10] Angewandte Chemie - International Edition, 2017, vol. 56, # 31, p. 9155 - 9159[11] Angew. Chem., 2017, vol. 129, # 31, p. 9283 - 9287,5
[12] Organic and Biomolecular Chemistry, 2017, vol. 15, # 11, p. 2459 - 2466
[13] Analytical Chemistry, 2016, vol. 88, # 21, p. 10728 - 10735
[14] Patent: WO2017/33163, 2017, A1, . Location in patent: Page/Page column 33; 34
4
[ 128376-64-7 ]
[ 302348-51-2 ]
Yield
Reaction Conditions
Operation in experiment
513 mg
at 20℃; for 5 h;
To a mixture of a4-formylbenzenboronic acid (1a, 375 mg, 2.50 mmol), pinacol (355 mg, 3.00 mmol) and anhydrous magnesium sulfate (625 mg, 5.00 mmol), methanol was added (12.50 mL). The mixture was stirred at room temperature for 6 h. After the reaction was completed, the crude solution was filtered, and then sodium borohydride (47 mg, 1.25 mmol) was added to the filtrate. Afterwards, the reaction mixture was stirred for an additional 5 h. Once the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the desired product 2a as a white solid (m.p. 75–77 °C) in88percent yield (513 mg). 1H-NMR (CD3OD-d4) δ ppm 7.71 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H),4.62 (s, 2H), 1.34 (s, 12H); 13C-NMR (CD3OD-d4) δ ppm 146.23, 135.93, 127.26, 85.19, 65.24, 25.34;11B-NMR (CDCl3) δ ppm 34.82.
Reference：
[1] Synthetic Communications, 2002, vol. 32, # 17, p. 2669 - 2676
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 9, p. 2487 - 2491
[3] Israel Journal of Chemistry, 2009, vol. 49, # 1, p. 1 - 8
[4] Molecules, 2013, vol. 18, # 10, p. 12346 - 12367
With chloro-trimethyl-silane; sodium iodide; In acetonitrile; at 0 - 20℃; for 1h;
To a stirred solution of <strong>[302348-51-2](4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol</strong> (1) (0.55 g, 2.35 mmol) in acetonitrile (20 mL), sodium iodide (1.1 g, 7.05 mmol) and Trimethylsilyl chloride (0.65 mL, 7.05 mmol) are added at about 0°C. The reaction mixture is allowed to stir at room temperature for about 1 hour. After completion of the reaction, solvent is evaporated under vacuum. The crude product is dissolved in saturated solution of Na2S203 to quench the unreacted iodide and the product is extracted with dichloromethane. The crude product is purified by column chromatography on silica gel using ethyl acetate\hexane (5:95) as an eluent to give product 2-(4-(iodomethyl)phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (2) in excellent yield (90percent). 1H NMR (400 MHz, ( 7X 7 ,· ) dppm 7.73 (d, J = 8 Hz, 21 1 ). 7.37 (d, J = 8 Hz, 2H), 4.45 (s, 2H), 1.34 (s, 12H) 1 C NMR (100 MHz, ( 7 ,·) 5ppm 142.3, 135.3, 128.0, 24.9, 5.4
4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
(ii) Synthesis of Compound (15); (4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methanesulfonate) (see Non-patent Literature 14); Under argon atmosphere, triethylamine (3.15 mL, 22.6 mmol) and methanesulfonyl chloride (1.40 mL, 18.1 mmol) were sequentially added to a CH2Cl2 (60 mL) solution of Compound (14) (3.48 g, 14.9 mmol), and the mixture was stirred at 0 °C for 2 hours. Water (150 mL) was added to the mixture, and the mixture was extracted with CH2Cl2 (100 mL .x. 3). All the organic phases were mixed, sequentially rinsed with water (70 mL .x. 3) and a saline solution (70 mL .x. 3), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (110 g of silica gel, n-hexane/EtOAc = 3/1) to obtain Compound (15) as a colorless solid. The Compound (15) was not purified furthermore and used in the next step. TLC 0.41 (n-hexane/EtOAc = 2/1).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 3h;Inert atmosphere;
2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3a). Compound 2a (585 mg, 2.50 mmol), and dichloromethane (25.00 mL) were added to a dry flask containing a magnetic stir bar under a nitrogen atmosphere. The flask was cooled to 0 °C, then methanesulfonyl chloroide (0.29 mL, 3.75 mmol) and N,N-diisopropylethylamine (DIPEA, 0.87 mL, 5.00 mmol) were slowly added to the flask. The reaction mixture was stirred at 0 °C for 3 h. After the reaction was completed, the reaction mixture was diluted with dichloromethane (25.00 mL) before H2O (25.00 mL)was added. The organic layer was then washed with brine and dried with MgSO4. The resulting organic layer was then filtered and the filtrate was concentrated in vacuo. The resulting crude material was re-dissolved in DMF (4.68 mL) after which both potassium phthalimide salt (695 mg, 3.75 mmol), and K2CO3 (1,036 mg, 7.50 mmol) were added to the solution. The reaction was then allowed to stir at room temperature for 3 days. After the reaction was completed, the distilled H2O (20.00 mL) was slowly added to the reaction mixture to afford the formation of a solid precipitate. The reaction mixture was then filtered and the filtered cake was collected. The filtered cake was re-dissolved in tertbutanol/H2O (4:1, v/v) (10.00 mL) before a freeze-drying process was applied to remove the remaining DMF. The desired product 3a was obtained as a white solid (m.p. 166?169 °C) in 96percent yield (872 mg);1H-NMR (CDCl3) delta ppm 7.84?7.82 (m, 2 H), 7.74 (d, J = 7.85 Hz, 2 H), 7.71?7.68 (m, 2H), 7.42 (d,J = 7.85 Hz, 2H), 4.85 (s, 2H), 1.34 (s, 12H); 13C-NMR (CDCl3) delta ppm 167.90, 139.26, 135.12,133.93, 132.04, 127.76, 123.29, 83.73, 41.60, 24.77; 11B-NMR (CDCl3) delta ppm 30.94.
To a solution of 4-nitrophenyl chloroformate (264 mg, 1.26 mmol) in 3 mL of DCM at 0 C was added dropwise Et3N (177 muL, 1.26 mmol). The mixture was stirred during 20 min under argon then a solution of 6a (100 mg, 0.42 mmol) in 4 mL of DCM was added dropwise to the first solution and the mixture was stirred during 3 h at r.t. The reaction was quenched with brine, extracted with DCM (3×20 mL), the organic layers were combined, dried with MgSO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography over silica gel with cyclohexane-EtOAc: 90- 10 to 60-40 to give the expected product (135 mg, yield: 80%). 1H NMR (300 MHz, CDCl3) delta 7.88-7.82 (m, 2H), 7.46-7.41 (m, 2H), 7.40-7.35 (m, 2H), 5.31 (m, 2H), 1.35 (s, 12H). 13C NMR (75 MHz, CDCl3) delta 155.47, 152.38, 145.36, 137.02, 135.15, 127.58, 127.23, 125.25, 121.74, 83.95, 70.75, 24.82. HRMS (ESI): m/z Calcd for C20H22BNO7Na, [M+Na]+:422.1387, found: 422.1367.
60%
With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Product distribution / selectivity;
4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5 g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL, 4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3 mmol) and the reaction was allowed to stir at room temperature for 1 h. The reaction was diluted with EtOAc and washed with 1.0 M HCl followed by saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Compound B2a was purified on a silica gel column eluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta=8.25 (d, J=9.2 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 5.31 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) delta=155.7, 152.7, 145.6, 137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1. ESI-MS(+): m/z 417.19 [M+NH4]+, 422.20 [M+Na]+.
In dichloromethane; at 0℃;
1) Preparation of active small molecules:Mixing 4-(hydroxymethyl)phenylboronic acid pinacol ester and p-nitrophenoxycarbonyl chloride as a molar ratio of 1:1The solution was dissolved in dichloromethane in that order, and the reaction was stirred well at 0 C.Synthesizing a small molecule capable of reversibly binding to methotrexate;
A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6. mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 mL) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2Cl2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2Cl2 / EtOAc (9/1, v/v) as eluent. Yield 1.4 g (92%). Rf= 0.3 (silica, eluent - CH2Cl2 / EtOAc, 9/1, v/v). 1H NMR (200 MHz, CDCl3), delta in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz).
92%
In tetrahydrofuran; for 22h;Reflux;
Synthesis4-(Hvdroxymethyl)phenylboronic acid pinacol ester:A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6 mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 ml_) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2CI2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2CI2 / EtOAc (9/1 , v/v) as eluent. Yield 1.4 g (92%). Rf= 0.3 (silica, eluent - CH2CI2 / EtOAc, 9/1 , v/v). H NMR (200 MHz, CDCI3), delta in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz).
With magnesium sulfate; In acetonitrile; for 24h;Reflux;
To a stirred solution of 4-(hydroxymethyl) phenylboronic acid (0.4 g, 2.63 mmol) in acetonitrile (15 mL), MgS04 (3 g) and pinacol (0.37 g, 3.15 mmol) are added. The reaction mixture is heated up to about 80C and allowed to reflux for about 24 hours. After completion of the reaction, solvent is evaporated under vacuum. The crude mixture is dissolved in dichloromethane and filtered. The obtained product (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanol (i.e. compound 1) is used for further reaction without purification.
Compound 2 (660 mg, 2.82 mmol) was dissolved in 10 mL of dry CH2Cl2.Then, N,N'-carbonyldiimidazole (915 mg, 5.64 mmol) was added, and the mixture was stirred at room temperature for 1-2 h under N2. After the reaction was completed, 40 ml of CH 2 Cl 2 was added, and the mixture was washed three times with an equal amount of 1 M HCl solution, and the organic phase was dried over anhydrous sodium sulfate.Concentrated under reduced pressure to give a white solid 787mg, yield 85%.
In dichloromethane; at 20℃; for 2h;
2.07 g of 1,1'-carbonyldiimidazole and 2.07 g of 4- (hydroxymethyl) phenylboronic pinicole ester(4- (hydroxymethyl) phenylboronic acid pinacol ester) was dissolved in 20 mL of dichloromethane (DCM)And allowed to react at room temperature for 2 hours. The product was named 1 and 1 was obtained by silica gel chromatography using an eluent of 1: 1 mixture of ethyl acetate and hexane.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 3h;
To a slurry of methyl 5-bromo-3-(4-methyl-benzylamino)-thiophene-2-carboxylate (154 mg, 0.45 mmol) and <strong>[302348-51-2][4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol</strong> (158 mg, 0.68 mmol) in DMF (4.5 mL) and sat'd. aq. Na2CO3 (1.9 mL) was added Pd(PPh3)4 (73 mg). The reaction mixture was heated to 100° C. for 3 h then cooled to RT. The solvent was removed and the crude product purified by SiO2 chromatography (Isco) eluting with an EtOAc/hexane gradient (0percent to 30percent EtOAc) to afford 255 mg of methyl 5-(4-hydroxymethyl-phenyl)-3-(4-methyl-benzylamino)-thiophene-2-carboxylate (72): MS calcd for C21H21NO3S [M+H]+ 368. Found, 368.
Add anhydrous sodium carbonate (1.59 g, 10 mmol) to a three-necked flask. After removing the water at high temperature, it is cooled to room temperature, and after three times of gas exchange, Anhydrous toluene (5 mL) was added thereto under argon gas, Ice bath to around 0 C, A solution of triphosgene (592 mg, 2 mmol) in toluene (10 mL) was added dropwise. After stirring at 0 C for 30 min, A solution of 4-(hydroxymethyl)phenylboronic acid pinacol ester (234 mg, 1 mmol) in toluene (10 mL) was added dropwise. After the addition was completed, the mixture was slowly warmed to room temperature for 5 hours. Use argon to drive away the remaining phosgene for 1 h. After filtration, the solvent was evaporated under reduced pressure to give Intermediate 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxycarbonyl chloride. After drying in vacuo, it was dissolved in anhydrous dichloromethane (10 mL). Temperature-controlled 0 C slowly added dropwise to 2-[2-[2-benzylamino-3-[(1,3-dihydro-1,3,3-trimethyl-2H-indole-2-ylidene) Ethylene]-1-cyclohexen-1-yl]vinyl]-1,3,3-trimethylphosphonium iodide (68 mg, 0.1 mmol) And N,N-diisopropylethylamine (132 muL, 0.8 mmol) In dichloromethane solution (20 mL), After the addition is completed, the reaction is slowly raised to room temperature for 12 to 18 hours.After the reaction was completed, it was washed twice with 0.1 N hydrochloric acid (20 mL). Wash once with saturated sodium carbonate solution (20 mL). Wash once with saturated sodium chloride solution (20 mL). The organic phase is dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give a crude material. Subsequent purification on a silica gel column (dichloromethane / 0-5% methanol). The green solid product is 2-[2-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-) Benzyloxycarbonyl]benzylamino]-3-[(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)ethylene]-1-cyclo Hexen-1-yl]vinyl]-1,3,3-trimethylphosphonium iodide, 10% yield.
With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; XPhos; In ethanol; at 20℃; for 0.5h;
General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%
94%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;
General procedure: Step 34b: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)[0334]To a solution of compound 0601-107 (2.5 g, 11.6 mmol) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was added potassium acetate (3.4 g, 35 mmol) and PdCl2(dppf)2 (0.95 g, 1.1 mmol). The mixture was degassed with nitrogen and heated at 85 C. for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product, which purified by column chromatography (ethyl acetate in petroleum ether, 15% v/v) to give the compound 0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s, 1H).
94%
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;
General procedure: Compound in dioxane (100mL) 0601-107 (2.5g, 11.6mmol) and a solution of bis (pinacolato) diboron (4.4 g, 17.5 mmol), potassium acetate (3.4 g, 35 mmol) and and PdCl2 (dppf) 2 ( 0.95g, 1.1mmol) was added. The mixture was degassed with nitrogen and heated overnight at 85 C.. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether in ethyl acetate, 15% v / v) to give the compound 0602-107 as a pink solid obtained (1.55 g, 51%).
With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; XPhos; In ethanol; at 20℃; for 0.5h;
General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
(IV) Synthesis of Compound (12); (4-[{4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl}(4H-1,2,4-triazol-4-yl)amino]benzonitrile); <Method A>; Compound (12) was synthesized according to the scheme below.; Here, Compound (16) was synthesized according to the scheme below.; (i) Synthesis of Compound (14) (4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl alcohol) (see Non-patent Literature 14 (Filippis, A.; Morin, C.; Thimon, C., Synth. Commun. 2002, 32, 2669-2676)); Under argon atmosphere, PdCl2(dppf)·CH2Cl2 (245 mg, 300 mumol), potassium acetate (2.94 g, 30.0 mmol) and bis(pinacolato)diboron (2.79 g, 11.0 mmol) were sequentially added to a DMSO (30 mL) solution of Compound (13) (2.34 g, 10.0 mmol) at room temperature, and the mixture was stirred at 85 C for 18 hours. The mixture was cooled to room temperature, and then water (250 mL) was added to the mixture and the mixture was extracted with ethyl acetate (100 mL × 3). All the organic phases were mixed, sequentially rinsed with water (100 mL × 3) and a saline solution (100 mL × 1), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (60 g of silica gel, n-hexane/EtOAc = 5/1) to obtain Compound (14) as a colorless solid. TLC Rf = 0.41 (n-hexane/EtOAc = 2/1) 1H NMR (300 MHz, CDCl3) delta 1.35 (s,12H,4CH3), 4.72 (s, 2H, benzylic CH2), 7.34-7.41 (AA'BB', 2H, aromatic), 7.78-7.84 (AA'BB', 2H, aromatic).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In water; dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
The compound 1(1 eq, 0.53 mmol) was dissolved in DMSO (2 mL) followed by the addition of potassium acetate (3 eq, 1.59 mmol), bis(pinacolato)diboron (1.1 eq, 0.59 mmol) and Pd(dppf)Cl2 (0.2 eq, 0.11 mmol). The mixture was deoxygenated by three successive argon bubbling/vaccum cycles. The reaction was then heated at 85C under argon for 18h. Water (5 mL) was added and the resulting black solution was extracted 3 times with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried, filtered and evaporated under vaccum. The resulting paste was purified using column chromatography (silica gel, 70/30 Hex/EtOAc) to afford the desired compound (Rf = 0.3) as a colourless oil (113 mg, 91%). 1H-NMR (CDCI3, 600 MHz) delta 7.79 (d, J = 7.7 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H), 4.71 (s, 2H), 1.35 (s, 12H); 13C-NMR (CDC13, 150 MHz) delta 144.1, 135.2, 126.2, 83.9, 65.4, 25.0.
90%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;
p-Bromobenzyl alcohol (Compound 1, 1.0 g, 5.35 mmol) was dissolved in 10 mL of dry 1,4-dioxane solution, and boranoic acid pinacol ester (247 mg, 5.88 mmol), potassium acetate and pdCl 2 ( Dppf), under N2 protection, heat to 85 C to stir the reaction. After the reaction was completed by thin layer chromatography, the solvent was evaporated under reduced pressure, and ethyl acetate (200 ml) was added and thenThe organic phase was dried over anhydrous sodium sulfate and concentrated under reduced vacuo.The crude product was purified by column chromatography (mobile phase ethyl acetate: petroleum ether = 1:8-1:4)Obtained 181 mg of a pale yellow oily liquid with a yield of 90%.
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
Under an argon atmosphere, (4-bromophenyl)methanol (3.0 g) and bis(pinacolato)diboron (4.5 g) was dissolved in dioxane (35 ml), and dichlorobis(triphenylphosphine)palladium(II) (567 mg) and potassium acetate (4.7 g) were added thereto, followed by stirring at 80 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in DME (35 ml) and water (18 ml), and tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (3.5 g) was added thereto under an argon atmosphere. In addition, sodium carbonate (3.1 g) and tetrakis(triphenylphosphine)palladium (339 mg) were added thereto, followed by stirring at 70 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl {2-[[4'-(hydroxymethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (2.8 g).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 6h;Inert atmosphere;
(3) 1 g of 1- (4-bromobenzene) ethanol was dissolved30 ml 1,4-dioxane solution,Two equivalents of bis (pinacolato) diboron,3 equivalents of potassium acetate,5% equivalent of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride Under argon atmosphere at 80 C,After 6 hours of reaction, the product was obtained by column chromatography.
1500 mg
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 16h;
A mixture of (4-bromophenyl)methanol (1 g, 5.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.07 g, 16.04 mmol), KOAc (1.05 g, 10.69 mmol) and Pd(dppf)Cl2.CH2Cl2 (873.27 mg, 1.07 mmol) in 1,4-Dioxane (20 mL) was stirred at 90 C for 16 hours. After cooling to r.t., the mixture was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 to 50%) to give the product (1500 mg) as oil. H NMR (400MHz DMSO-d6) _ = 7.63 (d, 2H), 7.32 (d, 2H), 5.23 (t, 1H), 4.51 (d, 2H), 1.29 (s, 12H).
16 g
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 85℃; for 3h;Inert atmosphere;
4-Bromobenzyl alcohol (15 g, 80.2 mmol), bis(pinacolato)diboron (30.6 g, 120.3 mmol), potassium acetate (23.6 g, 240 mmol) and Pd (PPh3)2Cl2 (5.6 g, 8 mmol) were added to 150 mL of dioxane, and the mixture was stirred at 85 C. for 3 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and then extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by column chromatography (eluent: petroleum ether:ethyl acetate 60:1-10:1) to give 16 g of title product.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 70℃; for 24h;Inert atmosphere;
Under an argon atmosphere, (4-bromophenyl)methanol (3.0 g) and bis(pinacolato)diboron (4.5 g) was dissolved in dioxane (35 ml), and dichlorobis(triphenylphosphine)palladium(II) (567 mg) and potassium acetate (4.7 g) were added thereto, followed by stirring at 80° C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in DME (35 ml) and water (18 ml), and tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (3.5 g) was added thereto under an argon atmosphere. In addition, sodium carbonate (3.1 g) and tetrakis(triphenylphosphine)palladium (339 mg) were added thereto, followed by stirring at 70° C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl {2-[[4'-(hydroxymethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (2.8 g).
Aminoferrocene (0.40 g, 1.98 mmol) and acetaldehyde (0.1 mL, 1.98 mmol) were dissolved on methanol (10 mL) and refluxed for 2 h.Then, Na[B(CN)H3] (0.12 g, 1.98 mmol) dissolved in MeOH (10 mL) was slowly added.The mixture obtained was acidified with HCl (2 mL, 1 M in water) and left stirring for 30 min.Afterwards, the solvent was removed in vacuum (0.01 mbar) and the rest was mixed with triphosgene (0.59 g, 1.98 mmol) in toluene (25 mL).The suspension obtained was refluxed for 1 h, cooled down to 22°C and then mixed with solution of 4-(hydroxymethyl)phenylboronic acid pinacol ester (0.46 g, 1.98 mmol) in toluene (10 mL).The resulting solution was heated to 120°C and stirred at these conditions for 6 h.Then, the solvent was removed in vacuum (0.01 mbar) and the crude product was purified by column chromatography on silica gel using hexane containing 5percent of acetone as eluent.Yield 0.20 g (20percent). Rf= 0.5 (silica, eluent - hexane / acetone, 5/1, v/v).1H NMR (400 MHz, acetone-d6), delta in ppm: 1.27 (t, 3H), 1.33 (s, 12H), 3.77 (q, 2H), 4.00 (s, 2H), 4.13 (s, 5H), 4.53 (m, 2H), 5.22 (s, 2H), 7.46 (d, 1 H), 7.77 (d, 2H).13C NMR (100.55 MHz, acetone-d6), delta in ppm: 14.4, 25.3, 45.8, 62.8, 65.1, 66.9, 67.5, 69.8, 84.6, 127.8, 128.1, 135.7 (two overlapping peaks), 139.1, 141.2. FAB MS: calculated for C26H32BNO4Fe 489.2, found 489.2 m/z. C, H, N analysis: calculated for C26H32BNO4Fe - C 63.8percent; H 6.6percent; N 2.9percent; found - C 63.8percent; H 6.8percent; N 2.9percent. IR spectra (in KBr), wave number in cm-1: 3101, 2973, 1696, 1623.
4-((N-Ethyl-N-Ferrocenylaminocarbonyl)oxymethyl)-2-phenylboronic acid pina- col ester (prodrug A):Aminoferrocene (0.40 g, 1.98 mmol) and acetaldehyde (0.1 mL, 1.98 mmol) were dissolved on methanol (10 mL) and refluxed for 2 h. Then, Na[B(CN)H3] (0.12 g, 1.98 mmol) dissolved in MeOH (10 mL) was slowly added. The mixture obtained was acidified with HCI (2 mL, 1 M in water) and left stirring for 30 min. Afterwards, the solvent was removed in vacuum (0.01 mbar) and the rest was mixed with triphosgene (0.59 g, 1.98 mmol) in toluene (25 mL). The suspension obtained was refluxed for 1 h, cooled down to 22°C and then mixed with solution of 4-(hydroxymethyl)phenylboronic acid pinacol ester (0.46 g, 1.98 mmol) in toluene (10 mL). The resulting solution was heated to 120°C and stirred at these conditions for 6 h. Then, the solvent was removed in vacuum (0.01 mbar) and the crude product was purified by column chromatography on silica gel using hexane containing 5percent of acetone as eluent. Yield 0.20 g (20percent). Rf= 0.5 (silica, eluent - hexane / acetone, 5/1 , v/v). 1H NMR (400 MHz, acetone- d6), delta in ppm: 1.27 (t, 3H), 1.33 (s, 12H), 3.77 (q, 2H), 4.00 (s, 2H), 4.13 (s, 5H), 4.53 (m, 2H), 5.22 (s, 2H), 7.46 (d, 1 H), 7.77 (d, 2H). 13C NMR (100.55 MHz, acetone-d6), delta in ppm: 14.4, 25.3, 45.8, 62.8, 65.1 , 66.9, 67.5, 69.8, 84.6, 127.8, 128.1 , 135.7 (two overlapping peaks), 139.1 , 141.2. FAB MS: calculated for C26H32BN04Fe 489.2, found 489.2 m/z. C, H, N analysis: calculated for C26H32BN04Fe - C 63.8percent; H 6.6percent; N 2.9percent; found - C 63.8percent; H 6.8percent; N 2.9percent. IR spectra (in KBr), wave number in cm'1: 3101 , 2973, 1696, 1623.
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 40℃; for 48h;Sealed vessel;
4-Bromo-5-iodo-l-(2-methylpropyl)-lH-benzotriazole (554 mg, 1.458 mmol), 4- (hydroxymethyl)benzeneboronic acid pinacol ester (325 mg, 1.388 mmol), PdCl2(dppf)- dichloromethane adduct (56.7 mg, 0.069 mmol) and cesium carbonate (1357 mg, 4.16 mmol) were combined in tetrahydrofuran (7 ml) and water (0.700 ml). The vessel was sealed and heated at 40 °C for 48 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound as white foam. LRMS m/z (M+H) 359.9 and 361.9 found, 360.06 and 362.06 required.
In tetrahydrofuran; toluene; at 20℃; for 24h;Inert atmosphere;
4-(Hydroxymethyl)phenylboronic acid pinacol ester, compound 42 (800 mg, 3.4 mmol, 1 .0 equiv.) was dissolved in THF (7 mL). The resulting solution was then added dropwise into a phosgene solution (15 wt% in toluene, 7.5 mL, 1 0.3 mmol, 3.0 equiv.) under an argon atmosphere at room temperature and was stirred for 24 h. The residual phosgene and solvent were then removed by high vacuum to yield chloroformate 45 (920 mg, 91 %) as a pale brown liquid. Phosgene collected in the liquid nitrogen-cooled trap was then quenched with methanol (20 mL) and saturated sodium hydroxide solution (20 mL). 1H NMR (400 MHz, CDCI3): delta 7.86 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 5.32 (s, 2H), 1 .36 (s, 12H). Spectral data are consistent with published values.33
In 1,4-dioxane; toluene; at 21℃; for 20h;Inert atmosphere;
A solution of (4-(4,4, 5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)methanol (2.0 g, 8.54 mmol) in anhydrous dioxane (25 m L) was treated with phosgene (20percent in toluene, 22.6 mL, 42.7 mmol) and the reaction was stirred under a N2 atmosphere at 21 °C for 20 h . The mixture was concentrated in vacuo, redissolved, and co-evaporated with toluene (2x) to afford the crude product 1 (2.5 g, quantitative yield) as a clear oil . The crude chloroformate was used in subsequent reactions within few hours after its isolation . 1H NMR (400 MHz, CDCI3) delta 7.84 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 5.31 (s, 2H), 1.35 (s, 12H) ; 13C N MR ( 101 MHz, CDCI3) delta 150.8, 136.2, 135.4, 128.0, 84.2, 73.4, 25.0.
With di-n-butyltin dilaurate; In toluene; at 100℃; for 4h;
[0445] To a solution of compound 13 (0.298 g, 0.41 mmol) and 14 (0.106 g, 0.45 mmol) in toluene (30 mL) was added di-n-butyltin dilaurate (12 muL, 0.002 mmol). The reaction was stirred at 100° C. for 4 h and concentrated under reduced pressure to a crude brown oil. Purification by column chromatography yielded 15 as a golden yellow oil (0.305 g, 0.33 mmol, 80percent).
With di-n-butyltin dilaurate; In toluene; at 100℃; for 3h;
To a solution of 28 (0.155 g, 0.35 mmol) in toluene (4 mL) was added 14 (0.090 g, 0.39 mmol) followed by di-n-butyltin dilaurate (12 muL, 0.002 mmol). The reaction was stirred at 100° C. for 3 h and concentrated under reduced pressure. Purification by column chromatograph yielded 29 as a yellow oil (0.169 g, 0.26 mmol, 74percent).
Triphosgen (0.26 g, 0.77 mmol) and 4-hydroxymethylphenylboronic acid, pinacol ester (0.5 g, 2.14 mmol) were dissolved in THF (20 ml) in an ice-water bath. Pyridine (0.35 ml, 4.28 mmol) was added dropwise, and the reaction mixture was stirred at 0°C until thin layer chromatography showed the disappearance of starting material. After bring the temperature to room temperature, the reaction mixture was extracted with dichloromethane/water. The organic layer was collected and dried over sodium sulfate. After filtration, solvent was removed and the residue was purified by flash chromatography to give the product as a white solid (0.1 g, 11percent). 1H NMR (300 MHz, CD2C12, delta): 8.43 (m, 1H), 8.10 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.26 (m, 1H), 5.25 (s, 2H), 1.32 (s, 12H); MS (ESI) m/z 436.1.
isopropyl-carbamic acid 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[302348-51-2][4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol</strong> (2.34 g,10 mmol) and pyridine (890 ul, 11 mmol) in THF (50 ml) at rt was added dropwise a solution of 4-nitrophenyl chloroformate (2.22 g, 11 mmol) in THF (10 ml). The reaction mixture was stirred at rt for overnight. The precipitate was removed by filtration. The filtrate was concentrated to give thedesired compound (4.2 g, may contain some pyridine HCI salt).To a solution of above product (400 mg, 1 mmol) in THF (3 ml) was added isopropyl amine(1.5 ml). The mixture was stirred at rt for 3h then concentrated to give the titled compound. LRMS5 (ESI) mjz 320.2 [(M+H)]+, calc'd for C17H26BN04: 319.21
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