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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 4-Trifluoromethylphenylboronic acid
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Wen Ren ; Yuling Deng ; Jacob D. Ward ; Rebecca Vairin ; Ruoli Bai b ; Hashini I. Wanniarachchi , et al.
Abstract: The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC50 values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents.
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Keywords: Inhibitors of tubulin polymerization ; Vascular disrupting agents ; Indole synthesis ; Molecular docking ; Antiproliferative agents ; Inhibitors of cell migration
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Purchased from AmBeed: 128796-39-4 ; 10365-98-7 ; 98-80-6 ; 98437-24-2 ; 5720-05-8 ; 64-86-8 ; 13331-27-6 ; 206551-43-1 ; 63139-21-9 ; 622864-48-6 ; 5720-07-0 ; 87199-18-6 ; 30418-59-8 ; 4521-61-3 ; 4521-61-3 ; 87199-18-6 ; 64-86-8 ; 64-86-8 ; 128796-39-4 ; 5720-05-8 ; 64-86-8
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Guo, Sheng ; Wu, Yifan ; Luo, Shao-Xiong Lennon ; Swager, Timothy M. ;
Abstract: Heterogenous catalysts with confined nanoporous catalytic sites are shown to have high activity and size selectivity. A solution-processable nanoporous organic polymer (1-BPy-Pd) catalyst displays high catalytic performance (TON > 200K) in the heterogeneous Suzuki–Miyaura coupling (SMC) reaction and can be used for the preparation of the intermediates in the synthesis of pharmaceutical agents. In comparison to the homogeneous catalyst analogue (2,2′-BPy)PdCl2, the heterogenous system offers size-dependent catalytic activity when bulkier substrates are used. Furthermore, the catalyst can be used to create catalytic impellers that simplify its use and recovery. We found that this system also works for applications in heterogenous Heck and nitroarenes reduction reactions. The metal-binding nanoporous polymer reported here represents a versatile platform for size-selective heterogeneous and recyclable catalysts.
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Keywords: nanoporous organic polymer ; heterogeneous catalyst ; Suzuki−Miyaura coupling reaction ; size-selective reaction ; catalyst processing
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Purchased from AmBeed: 128796-39-4 ; 10365-98-7 ; 98-80-6 ; 556-96-7 ; 171663-13-1 ; 71597-85-8 ; 402-43-7 ; 2042-37-7 ; 22385-77-9 ; 16419-60-6 ; 15862-18-7 ; 87199-15-3 ; 171408-84-7 ; 643-58-3 ; 591-50-4 ; 76911-73-4 ; 398-36-7 ; 14871-92-2 ; 5720-07-0 ; 945976-76-1 ; 366-18-7 ; 2920-38-9 ; 623-00-7 ; 24973-49-7 ; 588-59-0 ; 128796-39-4 ; 5723-93-3 ; 17057-88-4 ; 126485-55-0
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CAS No. : | 128796-39-4 |
Formula : | C7H6BF3O2 |
M.W : | 189.93 |
SMILES Code : | FC(C1=CC=C(B(O)O)C=C1)(F)F |
Synonyms : |
4-Trifluoromethylphenylboronic acid
|
MDL No. : | MFCD00151855 |
InChI Key : | ALMFIOZYDASRRC-UHFFFAOYSA-N |
Pubchem ID : | 2734389 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 130℃; for 0.25 - 0.333333h;Microwave irradiation;Product distribution / selectivity; | Description 6: 4-[4-(Trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (D6); A mixture of 4-trifluoromethylphenylboronic acid (644 mg, 3.39 mmol), 4-bromo-2- pyridinecarbaldehyde (D5) (420 mg, 2.26 mmol) and 2M Na2CO3 (4 mL, 7.91 mmol) in dimethoxyethane (12 mL) was degassed for 5-10 minutes in an ultrasonic bath <n="30"/>under a flow of argon. Pd(dppf)CI2 (92 mg, 0.113 mmol) was added and the resulting mixture was heated with stirring at 130 0C for 10 minutes in a microwave reactor. TLC (EtOAc/hexane 1:1) after 10 minutes showed the reaction went to completion . The mixture was filtered through a pad of celite, washed with EtOAc and concentrated to afford 1 g of crude material which was purified by flash chromatography (Biotage SP4, 40+S column) with a gradient 0 to 50percent of EtOAc in hexane to yield 340 mg (60percent) of desired product D6.1H-NMR (CDCI3): delta 7.76 (1 H, m), 7.81 (4H, s), 8.2 (1 H, s), 8.89 (1 H, d), 10.18 (1 H, s) |
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 90℃; for 18.25h;Product distribution / selectivity; | Description 6 - alternative procedure: 4-[4-(Trifluoromethyl)phenyl]-2- pyridinecarboxaldehyde. (D6); A mixture of <strong>[131747-63-2]4-bromo-2-pyridinecarboxaldehyde</strong> (D5) (18.33 g, 98.5 mmol), 4-trifluoromethylphenylboronic acid (20.6 g, 108.4 mmol) and sodium bicarbonate(41.4 g, 492.7 mmol) in toluene (550 ml_) and water (55 mL) was degassed with argon for 15 minutes. To this suspension under argon was added tetrakis(triphenylphosphine) palladium(O) (3.42 g, 2.96 mmol) in one portion and the reaction was heated to 90 0C for 18 h. After cooling the solvent was evaporated and the residue suspended in ethyl acetate (1 L). This was filtered and the filter cake washed with ethyl acetate (4 chi 100 mL). The combined organics were evaporated to afford a yellow solid which was purified by flash chromatography (Biotage Flash 75L, silica gel, 3:1 --> 2:1 40-60 petroleum ether / ethyl acetate) to afford the title compound as a yellow solid (22.46 g) (D6), with NMR data consistent with those previously obtained.LC-MS: [MH+] = 252, C13H8F3NO requires 251. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine;copper diacetate; In dichloromethane; at 20℃; for 48.0h;Molecular sieve; | (1) Production of 2-methoxy-3-[4-(trifluoromethyl)phenoxy]pyridine: [4-(Trifluoromethyl)phenyl]boronic acid (668 mg, 3.52 mmol), copper(II) acetate (480 mg, 2.64 mmol), triethylamine (0.74 mL, 5.28 mmol) and Molecular Sieve 4A (1.76 g) were added to a methylene chloride solution (20 mL) of <strong>[13472-83-8]2-methoxypyridin-3-ol</strong> (220 mg, 1.76 mmol), and stirred at room temperature for 2 days. The reaction liquid was filtered through Celite, then aqueous saturated sodium hydrogencarbonate solution was added to the filtrate, and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, then dried with anhydrous sodium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure, then the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 to 9:1) to obtain the entitled compound (298 mg, 63 %). Mass Spectrum (ESI): 270.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 19h;Heating / reflux; | Heat a degassed solution of ethyl 2-bromobenzothiazole-6- carboxylate (Step 1, 7.75 G, 27.1 mmol), tetrakis (TRIPHENYLPHOSPHINE) palladium (0) (1.7 g, 1.5 mmol), 4- (trifluoromethyl) phenylboronic acid (6.2 g, 32.6 mmol) and 2 M aqueous sodium carbonate solution (120 mL) in DME (90 mL) at reflux under nitrogen for 19 h. Dilute the cooled mixture with 1 N NAOH (1.2 L) and extract with methylene chloride (2 x 500 ML). Dry the combined organic extracts over MGS04, remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (98: 2), to afford ethyl 2- (4-trifluoromethylphenyl) benzothiazole-6-carboxylate as a white solid (2.62 g, 27%) : 1H NMR (CDC13) 5 1.40 (t, 3H), 4.40 (q, 2H), 7.80 (d, 2H), 8.10 (d, 1H), 8.20 (m, 3H), 8.60 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 80℃; for 3.5h; | A] 6-(4-Trifluoromethyl-phenyl)-pyridazine-3-carboxylic acid methyl ester 0.400 g (2.32 mmol) of the known <strong>[65202-50-8]6-chloro-pyridazine-3-carboxylic acid methyl ester</strong> was dissolved in 12 ml of abs. DMF and treated with 0.268 g (0.232 mmol) of Pd(Ph3P)4. After heating to 80° C., 0.572 g (3.01 mmol) of 4-(trifluoromethyl)benzeneborinic acid and 1.133 g (3.48 mmol) of Cs2CO3 was added and the reaction allowed to proceed for 3.5 h at the same temperature. After cooling, the mixture was poured onto crashed ice, extracted twice with AcOEt, washed with brine and water, and dried over sodium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=1/1) delivered 0.316 g of a reddish solid which was recrystallized from hexane/AcOEt to remove remaining impurities. Thereby, 0.230 g of the title compound was isolated. MS: 282.1 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
sodium carbonate; tetrakis(triphenylphosphine)palladium (0); In toluene; | Step (a) Preparation of 4-Oxo-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester In a manner similar to Example 12, Step (b), (4-trifluoromethyl-phenyl)boronic acid (1.285 g, 0.00676 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluding with chloroform to give 1.42 g of 4-oxo-4-(4'-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester as a white solid; mp 140-142 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | a) 4-(4-(Trifluoromethyl)phenyl)pyrimidin-2(1H)-one (CAS Registry Number 1159816-20-2) A suspension of <strong>[51421-99-9]4-chloro-2-methoxypyrimidine</strong> (500 mg, 3.47 mmol), 4-(trifluoromethyl)phenylboronic acid (788 mg, 4.17 mmol), PdCl2(dppf) (283 mg, 0.347 mmol) and K2CO3 (958 mg, 6.94 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 95 C. for 20 h. The suspension was cooled, H2O was added and the suspension was filtered to afford a light colored solid. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. The white solid was diluted with concentrated HCl solution (10 mL) and stirred at reflux for 4 h. The reaction was cooled, and the solution was neutralized with saturated NaHCO3 solution. The resulting suspension was filtered to afford 185 mg (22%) of the title compound as a white solid: ESI MS m/z 241 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(diphenylphosphin)ferrocene; In tetrahydrofuran; water; at 150.0℃; for 0.166667h;Microwave irradiation; | 5-Hydroxy-2-(4-trifluoromethyl-phenyI)-3H-pyrimidin-4-one (6)6To a mixture of 0.05 g (0.26 mmol) 4-trifluoromethylphenylboronic acid, 0.02 g (0.009 mmol Pd EN Cat 30, and 0.65 mL 1 M aq Cs2C03, was added a solution of 0.005 g (0.009 mmol) Iota ,Gamma- (bisdiphenylphosphino)ferrocene and 0.03 g (0.17 mmol) 2-chloro-4,5-dimethoxy-pyrirnidine in 1 mL THF, The resulting mixture was heated by microwave to 150 C for 10 minutes. After cooling, the aq layer was removed and the organic phase was filtered and concentrated, To the resulting residue was added 1 mL 33%> HBr in AcOH, and the resulting mixture was heated by microwave to 160 C for 5 min. The resulting solution was diluted with water (2 mL) and loaded onto an SCX column. After washing with MeOH (5 mL), the crude product was eluted off with 2 M ammonia in MeOH. Purification by automated mass-guided HPLC afforded 1 ,7 mg (4%) 5-hydroxy-2-(4-trifluoromethyl-phenyl)-3H- pyrimidin-4-one. 'H NMR (499 MHz, DMSO-de ): delta 9.85 (br s, 1 H); 8.22 (d, J = 7.93 Hz, 2 H); 7.85 (d, J = 8.12 Hz, 2 H); 7.63 (br s, 1 H). High resolution mass spec (FT/ICR) calc (M+H)+ - 257.0533 found 257.0532. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-(4-(trifluoromethyl)phenyl)pyrazin-2-amine A 100 mL round bottom flask was charged with <strong>[1445-39-2]2-amino-5-iodopyrimidine</strong> (3.66 g, 21.1 mmol), (4-(trifluoromethyl)phenyl)boronic acid (4.00 g, 21.1 mmol) and MeCN (84 mL). Stirred 15 minutes at room temperature until a nice clear solution is obtained. The resulting solution is then treated with 1,1'-Bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (508 mg, 695 mumol) was added followed by the sodium carbonate 1M aq. (52.7 mL, 52.7 mmol). Reaction refluxed for 2 hours. Reaction cooled down to room temperature and dissolved with ammonium chloride solution (aq. sat.). Aqueous layer extracted with ethyl acetate (3*). Combined organic layers washed with brine (1*), dried over sodium sulfate, filtered and concentrated to give the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/DCM) provide the title compound as a light yellow solid (4.4 g, 87%). 1H NMR (400 MHz, DMSO-d6) delta 6.76 (s, 2H) 7.76 (d, J=8.41 Hz, 2H) 7.99 (d, J=1.57 Hz, 1H) 8.14 (d, J=8.22 Hz, 2H) 8.62 (d, J=1.37 Hz, 1H). MS (M+1): 240.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 20.0h; | General procedure: Compound 3 (175 mg, 0.757 mmol) was mixed with phenylboronic acid (5a) (111 mg, 0.910 mmol, 1.2 equiv), finely powdered K2CO3 (230 mg, 1.67 mmol), Pd(PPh3)4 (44 mg, 0.04 mmol), 1,4-dioxane (2 mL) and water (2 mL). The reaction was then stirred at 110 C for 5 h. The solvent was removed and the crude product was suspended in saturated aq NH4Cl solution (30 mL), and extracted with EtOAc (4×50 mL). The combined organic fractions were dried over Na2SO4 and concentrated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 3h; | General procedure: Compound 4 (202 mg, 0.811 mmol) was mixed with phenylboronic acid (5a) (249 mg, 2.04 mmol, 2.5 equiv), finely powdered K2CO3 (341 mg, 2.47 mmol), Pd(PPh3)4 (47 mg, 0.040 mmol), 1,4-dioxane (2 mL) and water (2 mL). The reaction was then stirred at 110 C for 3 h. The solvent was removed and the residue was dissolved in EtOAc (25 mL) and washed with water (3×15 mL). The organic phase was dried over Na2SO4, filtered and evaporated onto silica gel. The obtained material was purified by silica gel column chromatography (n-pentane/EtOAc, 3/1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 6h;Inert atmosphere; | General procedure: A 1,4-dioxane solution (3 mL) of 1, arylboronic acid (1.2 equiv), aqueous K2CO3 (2.0 M, 1.0 mL) and Pd(PPh3)4 (3 mol percent) was heated at 80 °C for 6 h under argon atmosphere. After cooling to 20 °C, H2O was added and the reaction mixture was extracted with CH2Cl2 (3×25 mL). The organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc).#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere; | Compound number 289 was prepared as follows. To a solution of <strong>[335349-57-0]5-chloro-4-iodo-2-nitroaniline</strong> (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100 C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85 C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80 C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 14h;Inert atmosphere; Sealed tube; | A solution of 4-(trifluoromethyl)phenylboronic acid (519 mg, 2.73 mmol), <strong>[10386-27-3]2-bromo-isonicotinonitrile</strong> (500 mg, 2.73 mmol) and potassium carbonate (358 mg, 2.73 mmol) in DMF (5 mL) at 25°C was purged with nitrogen gas and evacuated three times. The solution was then treated with tetrakis(triphenylphosphine)palladium(0) (158 mg, 137 tmol) and then sealed and heated to 120°C for 14 h. The reaction mixture was cooled to 25°C, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 2-(4-trifluoromethyl-phenyl)- isonicotinonitrile (0.38 g, 56percent) as a white solid. MH+ = 248.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | Step A-6: Preparation of 3-chloro-5-[4-(trifluoromethyl)phenvnpyridine-2-carboxylic acid: A mixture of <strong>[1189513-51-6]5-bromo-3-chloro-pyridine-2-carboxylic acid</strong> (40 g, 169.2 mmol) , [4- (trifluoromethyl)phenyl]boronic acid (33.74 g, 177,6 mmol) and sodium carbonate (32.27 g, 304,5 mmol) were mixed in Dioxane (600 mL) and Water (200 mL). The resulting mixture was flushed with argon and then treated with dichloro-(chloromethylchloronio)- bis[cyclopentyl(diphenyl)phosphaniumyl]palladium(3-); iron (4.14g, 5.075 mmol, Pd(dppf)2CI) and the mixture was stirred at 90°C. After reaction completion,, the reaction mixture was cooled to room temperature, quenched with saturated NaHC03 solution to pH10-1 1 , and filtered. The aqueous layer was washed with diethylether, and the ether phase discarded. The separated aqueous layer was adjusted to pH 2-3 with HCI and extracted with ethyl acetate (three times). The combined organic phases was dried over MgS04, filtered and evaporated in vacuo. Crystallization from EtOAc/heptane gave the title compound as a white solid. LCMS ( Method 1 ) Rt: 1.34 min, [M+H] 302/300 H NMR (400 MHz, CHLOROFORM-c/) delta ppm 7.73 - 7.79 (m, 2 H) 7.80 - 7.86 (m, 2 H) 8.14 (d, J=1.47 Hz, 1 H) 8.77 (d, J=1 .47 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | With potassium phosphate; silver(I) acetate; palladium diacetate; trifluoroacetic acid; In 1,2-dichloro-ethane; at 80 - 90℃; | Embodiment of the 64 [...] -trifluoromethyl -2'-acetamido terphenyl synthesis ofTo 10 ml reaction flask by adding 3-bromo(acetylaniline) (0.2mmol, 42 . 81 mg), palladium acetate (0.002mmol, 0 . 45 mg), idodobenzene (0.22mmol, 44 . 88 mg), K3PO4(0.6mmol, silver acetate (0.3mmol, 50 . 07 mg), 127.36 mg), TFA (0.1mmol) and DCE (2 ml), for 90 C reaction under the conditions, the TLC reaction monitoring, when the temperature is reduced to the room temperature, by adding 4-trifluoromethylboronic acid (1.2mmol, 45 . 58 mg) with the ligand two phenol (0.004mmol, 1 . 07 mg), 80 C to continue reaction, the end point of the detection reaction TLC. When the reaction to room temperature, add 5 ml ethyl ether, the reaction solution is poured into the separatory funnel, using 5 ml ethyl ether washing reaction bottle, and then merged into the separatory funnel in ethyl ether, is added to the separatory funnel in 10 ml saturated NaCl solution, oscillating, liquid, so then to 10 ml × 2 of ethyl ether extraction, combined with the phase, adding anhydrous sodium sulfate for drying, filtering, vacuum screwed out of the solvent, with petroleum ether and ethyl acetate 4:1(v/v) as the mobile phase, rapid column separation, get the pure product white solid 4 the [...] -trifluoromethyl -2'-acetamide base three biphenyltetrazole, yield 90.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With potassium phosphate; silver(I) acetate; palladium diacetate; trifluoroacetic acid; In 1,2-dichloro-ethane; at 80 - 90℃; | Example 84-chloro -4 the [...] -trifluoromethyl -2'-acetamido terphenyl synthesis ofTo 10 ml reaction flask by adding 3-bromo(acetylaniline) (0.2mmol, 42 . 81 mg), palladium acetate (0.002mmol, 0 . 45 mg), 4-chloroiodobenzene (0.22mmol, 52 . 46 mg), K3PO4 (0.6mmol, 127 . 36 mg), silver acetate (0.3mmol, 50 . 07 mg), TFA (0.1mmol) and DCE (2 ml), for 90 C reaction under the conditions, the TLC reaction monitoring, when the temperature is reduced to the room temperature, by adding 4-trifluoromethylboronic acid (1.2mmol, 45 . 58 mg) with the ligand diphenol (0.004mmol, 1 . 07 mg), 80 C to continue reaction, the end point of the detection reaction TLC. When the reaction to room temperature, add 5 ml ethyl ether, the reaction solution is poured into the separatory funnel, using 5 ml ethyl ether washing reaction bottle, and then merged into the separatory funnel in ethyl ether, is added to the separatory funnel in 10 ml saturated NaCl solution, oscillating, liquid, so then to 10 ml × 2 of ethyl ether extraction, combined with the phase, adding anhydrous sodium sulfate for drying, filtering, vacuum screwed out of the solvent, with petroleum ether and ethyl acetate 4:1(v/v) as the mobile phase, rapid column separation, get the pure product white solid 4-chloro -4 the [...] -trifluoromethyl -2'-acetamide base three biphenyltetrazole, yield 84.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; copper diacetate; triethylamine; In dichloromethane; at 20℃; for 48h; | Dichloromethane (5.0 mL) in <strong>[4522-35-4]3-iodo-1H-pyrazole</strong> (1.03 mmol) solution, (4-(trifluoromethyl)phenyl)boronic acid (2.06 mmol), pyridine (5.15 mmol), copper (II)acetate (4.12 mmol) and triethylamine was added (3.09 mmol). The reaction mixturewas stirred at room temperature for two days. When the reaction is completed, afterremoving by filtration using Celite and the insoluble residue was filtered andconcentrated to a liquid. Purification of the crude residue by silica gel flash columnchromatography to produce a D1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: A mixture of N-boc-2-(4-bromophenyl)ethylamine, the desiredarylboronic acid (a-m) (1.2 equiv), tetrakis(triphenylphosphine)-palladium(0) (0.04 equiv), Na2CO3 (5 equiv) in degassed toluene/H2O (5/2) was refluxed for 18 h. The reaction mixture was filteredthrough Celite and concentrated in vacuo. The resulting residuewas dissolved in in EtOAc (200 mL), washed with H2O (200 mL 2) and brine (200 mL). The organic layer was dried with anhydrousNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on SiO2. Using Method E, 13 (0.50?g, 1.7?mmol), 4-(trifluoromethyl)phenylboronic acid (0.38?g, 2.0?mmol), tetrakis(triphenylphosphine)palladium(0) (0.08?g, 0.1?mmol), Na2CO3 (0.89?g, 8.3?mmol) in toluene/H2O (16?ml/6.6?ml), followed by 4.0?M HCl in dioxane (1.25?ml, 5.0?mmol) gave 14b as a white solid (0.28?g, 56%): Rf?=?0.00 (EtOAc 9: acetone 1): 1H NMR (DMSO-d6, 400?MHz) delta 3.01-3.11 (m, NH3CH2CH2), 7.44 (d, J?=?8.1?Hz, 2 ArH), 7.71-7.91 (m, 6 ArH), 8.37 (s, NH3); 13C NMR (DMSO-d6, 75?MHz) delta 33.0 (NCH2CH2), 124.8 (CF3, q, JC-F?=?270.1?Hz), 126.2 (q, JC-F?=?3.8?Hz), 127.6, 127.7, 128.2 (q, JC-F?=?31.7?Hz), 129.9, 137.4, 138.4, 144.3 (12 ArC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With copper diacetate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 72h; | To a solution of compound 116-1 (450 mg, 1.84 mmol, 1.0 eq), compound 116-la (420 mg, 2.21 mmol, 1.2 eq) and Cu(OAc)2 (402 mg, 2.21 mmol, 1.2 eq) in DCM (5 mL) was added DIPEA (477 mg, 3.69 mmol, 2.0 eq) under (. The reaction mixture was stirred at 25 C for 72 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel to afford the title compound 116-2 (180 mg, 25% yield). lH NMR (400MHz, CDC13) delta 7.84 (d, J= 2.0 Hz, 1H), 7.70 (dd, J= 2.0, 8.8 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.11 (d, J= 9.0 Hz, 1H), 6.46 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tetrabutylammomium bromide; palladium diacetate; sodium carbonate; In water; at 150℃; for 0.333333h;Sealed tube; | Compound 1 (1 eq, 5.35 mmol), 4-(Trifluoromethyl)phenylboronic acid (1 eq, 5.35 mmol), TBAB (1 eq, 5.35 mmol), Na2C03 (3 eq, 16.05 mmol) were dissolved in 11 mL of water. Palladium acetate (0.4 % eq, 0.021 mmol) was then added and the reaction was stirred in a scelled tube and heated at 150C. After 20 min, the tube is slowly cooled down to rt and opened with caution. The biphase mixture is poured onto 10 mL of EtOAc and extracted (3 x 10 mL). The combined organic phases were dried and filtered. After removal of the solvent under reduced pressure, the remaining black oil was purified using column chromatography (silica gel, 80/20 Hex/EtOAc) to afford the desired compound (Rf = 0.2) as a colourless solid (1.29 g, 96%). 1H-NMR (CDC13, 600 MHz) delta 7.69 (s, 4H), 7.60 (d, J = 8.1Hz, 2H), 7.47 (d, J = 8.1Hz, 2H), 4.77 (s, 2H); 13C-NMR (CDCI3, 150 MHz) delta: 144.5, 141.1, 139.3, 129.1, 127.7, 127.6, 127.5, 125.9, 124.4, 65.1;ESI-MS m/z for C14HnF30 [MH]+, [MNa]+; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; toluene;Inert atmosphere; Reflux; | General procedure: <strong>[1458-01-1]Methyl 3,5-diamino-6-chloropyrazine-2-carboxylate</strong> 2 (1 eq.) was combined with K2CO3 (10 eq.), the appropriate (het)aryl boronic acid (1.5 eq.) and Pd(PPh3)4 (5 mol%) in a two-neck round bottom flask. The flask was connected to a condenser and purged with nitrogen. A 4:1 mixture of anhydrous toluene: MeOH (60 mL) was added via syringe and the reaction mixture was heated at reflux for 0.5-18 h. The mixture was allowed to cool to room temperature and filtered through Celite (10 x 3 cm, eluting with 3 x 20 mL EtOAc). The filtrate was evaporated to dryness and the residue purified by silica gel flash column chromatography using EtOAc/pet spirit. |
Tags: 4-(Trifluoromethyl)phenylboronic acid | Boronic Acids | Organoboron | Benzene Compounds | Fluorinated Building Blocks | Trifluoromethyls | Aryls | Organometallic Reagents | Boronic Acids/Esters | Organic Building Blocks | 128796-39-4
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