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The intermediate 1-1 (166 g, 655.6 mmol) was put and dissolved in methanol (1000 mE) in a reactor, and potassium carbonate (90.6 g, 655.6 mmol) was slowly added thereto in a dropwise fashion. The mixture is stirred for about 30 minutes and filtered. Afier removing all the solUsvents, the reactant was dissolved in ethylacetate and twice washed with distilled watet Then, an intermediate 1-2 (116 g, 98percent) was obtained by removing the solvent again.
50%
With potassium carbonate In methanolHeating / reflux
Step 1) 3-Bromophenylacetylene To each of 2 one-liter flasks were charged K2CO3 (68 g, 493 mmol), a large magnetic stirbar and MeOH (250 mL). Stirring was begun on both reaction mixtures and once it was satisfied that they were stirring without any problems, 3-bromophenyltrimethylsilylacetylene (12.5 g, 49.3 mmol, 10.5 mL) was added to each reaction vessel and the mixtures were refluxed overnight. The reaction mixtures were filtered and the filter cakes were washed with MeOH. The combined filtrate was concentrated in vacuo, diluted with hexanes, and washed with water twice. The organic layer was concentrated to give a yellow oil. Flash chromatography (SiO2, Hexanes), provided 9.1 g, 50percent, of the title compound as a colorless to light yellow oil. 1H NMR 500 MHz (CDCl3) δ 3.08 (s, 1H); 7.16 (t, 1H, J=7.89 Hz); 7.38 (dt, 1H, J=7.77 Hz, 2.44 Hz); 7.44-7.47 (m, 1H); 7.61 (t, 1H, J=1.68 Hz).
Reference：
[1] Patent: US2018/339967, 2018, A1, . Location in patent: Paragraph 0159; 0161
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 630 - 639
[3] European Journal of Organic Chemistry, 2010, # 33, p. 6323 - 6330
[4] Organic Letters, 2017, vol. 19, # 19, p. 5182 - 5185
[5] Patent: US2009/48320, 2009, A1, . Location in patent: Page/Page column 62; 82
[6] Tetrahedron Letters, 2003, vol. 44, # 41, p. 7611 - 7612
[7] Journal of Organic Chemistry, 2000, vol. 65, # 18, p. 5712 - 5719
[8] Chemical Communications, 2012, vol. 48, # 30, p. 3617 - 3619
[9] Organic Letters, 2013, vol. 15, # 4, p. 840 - 843
[10] Chemistry Letters, 2013, vol. 42, # 10, p. 1128 - 1130
[11] Organic Letters, 2015, vol. 17, # 10, p. 2522 - 2525
The intermediate 1-1 (166 g, 655.6 mmol) was put and dissolved in methanol (1000 mE) in a reactor, and potassium carbonate (90.6 g, 655.6 mmol) was slowly added thereto in a dropwise fashion. The mixture is stirred for about 30 minutes and filtered. Afier removing all the solUsvents, the reactant was dissolved in ethylacetate and twice washed with distilled watet Then, an intermediate 1-2 (116 g, 98%) was obtained by removing the solvent again.
50%
With potassium carbonate; In methanol;Heating / reflux;
Step 1) 3-Bromophenylacetylene To each of 2 one-liter flasks were charged K2CO3 (68 g, 493 mmol), a large magnetic stirbar and MeOH (250 mL). Stirring was begun on both reaction mixtures and once it was satisfied that they were stirring without any problems, 3-bromophenyltrimethylsilylacetylene (12.5 g, 49.3 mmol, 10.5 mL) was added to each reaction vessel and the mixtures were refluxed overnight. The reaction mixtures were filtered and the filter cakes were washed with MeOH. The combined filtrate was concentrated in vacuo, diluted with hexanes, and washed with water twice. The organic layer was concentrated to give a yellow oil. Flash chromatography (SiO2, Hexanes), provided 9.1 g, 50%, of the title compound as a colorless to light yellow oil. 1H NMR 500 MHz (CDCl3) delta 3.08 (s, 1H); 7.16 (t, 1H, J=7.89 Hz); 7.38 (dt, 1H, J=7.77 Hz, 2.44 Hz); 7.44-7.47 (m, 1H); 7.61 (t, 1H, J=1.68 Hz).
Example 2 . Synthesis of 3-TMS-ethynylphenyldimethyl silane (2') (C13H2OSi2) MW=232. The above-described 3-bromo-TMS protected phenyl acetylene (46.5 g, 0.18 mol) from Example 1 was dissolved in dry ethyl ether (300 mL) and cooled to 0C. A solution of n-butyl lithium (1.6 M in hexane, 130 mL, 0.21 mol) was added to the aryl bromide over a period of 30 minutes. The reaction mixture was stirred an additional hour, and then the metalated aryl halide was added to a solution of chlorodimethylsilane (29 g, 0.3 mol) in ether (100 mL) at 0C over a period of 1 hour via a double tipped stainless steel needle. The contents of the reaction flask were stirred at room temperature overnight and then filtered to remove the lithium chloride by-product. Concentration of the clear solution on a rotary evaporator, followed by distillation at reduced pressure, gave the product 3-TMS-ethynylphenyldimethyl silane (b.p. 78C/0.25 torr, 31.4 g, 0.14 mol, 78% yield). The compound had the following spectral characteristics: 1H-NMR (CDCl3) 7.65 (m, 1H), 7.47 (m, 2H), 7.31 (m, 1H), 4.43 (septet, J=3.7 Hz, 1H), 0.34 (d, J=3.7 Hz, 6H), 0.26 (s, 9H); 13C-NMR (CDCl3) 137.6, 137.4, 133.9, 132.6, 127.6, 122.8, 105.3, 94.0, 0.0, -3.9; 29Si-NMR (CDCl3) -16.67, -17.77.
With triethylamine;palladium; tetrakis(triphenylphosphine)palladium (0); In nitrogen; toluene;
Example 1 . Synthesis of 3-TMS-ethynylbromobenzene (1') (C11H13BrSi) MW=253. 1,3-Dibromobenzene (247 g, 1.05 mol), trimethylsilylacetylene (105 g, 1.07 mol), triethylamine (180 g, 1.78 mol), and toluene (200 mL) were dissolved with stirring in a dry nitrogen purged 1 L flask. Dry nitrogen was bubbled through this solution for 30 minutes. After removal of the bubbler, tetrakistriphenylphosphine palladium (1.0 g, 0.86 millimol) was added. The components of the reaction were heated to 90C. The reaction was monitored at intervals by capillary gas chromatography. Further addition of the palladium catalyst was made over 90 hours (total catalyst added: 4.6 g, 0.4 mol % based on dibromobenzene). The reaction mixture was cooled, and the contents filtered to remove the triethylamine hydrobromide by-product. The solution was concentrated on a rotary evaporator and then fractionally distilled through a ten inch Vigreux column to give dibromobenzene (b.p. 55C/0.20 torr, 110 g, 0.47 mol). The fractionating column was replaced with a short path distillation unit. The product, 3-TMS-ethynylbromobenzene (b.p. 75C/0.20 torr, 95 g., 0.38 mol), was collected. This corresponded to a 66% yield based on recovered dibromobenzene. The compound had the following spectral characteristics: 1H-NMR (CDCl3) 7.61 (m, 1H), 7.45-7.32 (m, 2H), 7.13 (t, 1H), 0.22 (s, 9H); 13C-NMR (CDCl3) 134.6, 131.5, 130.4, 129.6, 125.0, 121.9, 103.2, 95.8, -0.2; 29Si-NMR (CDCl3) -17.40; IR (thin film) 3064, 2960, 2163, 1588, 1559, 1471, 1404, 1250, 874, 843, 782, 760, 644 cmmin1.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃; for 3h;Heating / reflux;
EXAMPLE 60; Preparation of 3-(3-ethynylphenyl)-2-fluoropyridine; To a solution of <strong>[3989-13-7][(3-bromophenyl)ethynyl](trimethyl)silane</strong> (2.28 g, 9.0 mmol) in DME (150 mL) is added (2-fluoropyridin-3-yl)boronic acid (1.41 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.5 mmol) and a solution of sodium carbonate (3.8 g, 36.0 mmol) in H2O (15 mL) at room temperature. After refluxing for 3 h, the reaction mixture is cooled, quenched with saturated sodium carbonate, diluted with EtOAc. The two layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude mixture is purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give the 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.25 g, 91%) as an oil. MS(+) APPI: 270 (M+H)+.
A solution of n-Bu3MgLi (2.65 mL of 0.65 M, 1.725 mmol) in hexane - heptane - dibutylether (8:20:3) is added to 2-(3-bromophenyl)ethynyl-trimethyl-silane (1.248 g, 1.05 mL, 4.928 mmol) in toluene (2.4 mL) and dibutylether (1.4 mL) at 0 C and stirred in cold room for 25 h. A solution of ZnBr2-LiBr in dibutyl ether (2.6 mL of 1.05 M, 2.711 mmol) is added dropwise , cooling bath removed, stirred at room temperature for 1 h. A solution of [(2R,3R,4S,5S,6R)-6-bromo-3,4,5-tris(2,2-dimethylpropanoyloxy)tetrahydropyran-2- yl]methyl 2,2-dimethylpropanoate (2.38 g, 4.107 mmol) in toluene (4.3 mL) is added, it is placed on pre-heated oil bath at 90 C, stirred over weekend. The reaction mixture is cooled to room temperature, it is poured into aq. 1 N HC1 solution (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts are washed with brine, dried ( a2S04), concentrated, purified on Biotage 100 g SNAP silica gel cartridge using ethyl acetate in hexanes (0% to 10%, 12 CV, 10%, 5 CV) as eluent to afford the title compound.
765 mg
Step I: [(2R,3R,4R,5R,6R)-3,4,5-Tris(2,2-dimethylpropanoyloxy)-6-[3-(2- trimethylsilylethynyl)phenyl]tetrahydropyran-2-yl]methyl 2,2-dimethylpropanoate A solution of n-Bu3MgLi (2.65 mL of 0.65 M, 1.725 mmol) in Hex - heptane - dibutylether (8:20:3) is added to 2-(3-bromophenyl)ethynyl-trimethyl-silane (1.248 g, 1.05 mL, 4.928 mmol) in toluene (2.4 mL) and dibutylether (1.4 mL) at 0C and stirred in cold room for 25 h. A solution of ZnBr2-LiBr in dibutyl ether (2.6 mL of 1.05 M, 2.71 1 mmol) is added dropwise, cooling bath removed, stirred at RT for 1 h. A solution of [(2R,3R,4S,5S,6R)-6-bromo-3,4,5-tris(2,2-dimethylpropanoyloxy)tetrahydropyran-2- yl]methyl 2,2-dimethylpropanoate (2.38 g, 4.107 mmol) in toluene (4.3 mL) is added, it is placed on pre-heated oil bath at 90 C for weekend. The reaction mixture is cooled to RT, it is poured into aqueous 1 N HC1 solution (40 mL) and extracted with EtOAc (3 x 40 mL). The combined extracts are washed with brine, dried ( a2S04), concentrated, purified on Biotage SNAP 100 g silica gel cartridge using EtOAc in Hex (0% to 10%, 12 CV, 10%, 5 CV) as eluent to afford title product (765 mg) as an oil.
tert-butyl ((3'-ethynyl-[1,1'-biphenyl]-3-yl)methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of ((3-bromophenyl)ethynyl)trimethylsilane (CAS 3983-13-7) (500 mg, 1.975 mmol), (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (CAS 8321 14-05-3) (545 mg, 2.172 mmol), PdCI2(dppf).CH2CI2 adduct (CAS 95464-05-4) (81 mg, 0.099 mmol) and 2M aq. K3PO4 (1.975 ml_, 3.95 mmol) in CH3CN (10 mL) was heated at 1 10 C in the microwave for 1 hr. The reaction mixture was partitioned between EtOAc and sat. NH4CI. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried and concentrated. The crude mixture was dissolved in MeOH (5 mL) and K2C03 (84 mg, 0.606 mmol) was added. The resulting mixture was stirred at rt overnight then concentrated. The residue was purified by FCC (EtOAc-heptane 0-40%) to provide the title compound. 1H NMR (400 MHz, DICHLOROMETHANE-c 2) delta ppm 7.77 (t, J=1.64 Hz, 1 H) 7.64 (dt, J=7.71 , 1.52 Hz, 1 H) 7.50 - 7.57 (m, 3 H) 7.41 - 7.49 (m, 2 H) 7.33 (d, J=7.45 Hz, 1 H) 4.39 (br. s., 2 H) 3.21 (s, 1 H) 1.49 (s, 9 H).
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