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Structure of 64115-88-4 * Storage: {[proInfo.prStorage]}
* 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] Angewandte Chemie - International Edition, 2018, vol. 57, # 31, p. 9645 - 9649[2] Angew. Chem., 2018, vol. 130, p. 9793 - 9797,5
2
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6
3
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13795 - 13799[2] Angew. Chem., 2018, vol. 130, # 42, p. 13991 - 13995,5
4
[ 1035797-66-0 ]
[ 88284-48-4 ]
[ 64115-88-4 ]
Yield
Reaction Conditions
Operation in experiment
77%
With perhydrodibenzo-18-crown-6; potassium fluoride; bromopentafluorobenzene; 1-Bromo-2-phenylacetylene In ethyl acetate at 20℃; for 12 h; Glovebox; Sealed tube
General procedure: In the glove box, add KF (78.4mg, 1.35mmol, 4.5equiv) to cis- in 20mL plastic tube (PE).Dicyclohexano-18-crown-6 (503 mg, 1.35 mmol, 4.5 equiv) and 6 mL ethyl acetate.Then a phenylene precursor (0.3 mmol, 1.0 equiv), 1-bromophenylacetylene (218 mg, 1.2 mmol. 4.0 equiv) or perfluorohexyl bromide (479 mg,1.2 mmol. 4.0 equiv) or pentafluorophenyl bromide (296 mg, 1.2 mmol. 4.0 equiv) and trifluoromethyl benzoate (171 mg, 0.9 mmol, 3 equiv) were capped and allowed to react at room temperature for 12 hours.After the end of the reaction, the F-spectrum yield was first calculated by 19F NMR.After completion of the reaction, the mixture was filtered, dried, and directly subjected to column chromatography.
Reference：
[1] Patent: CN108516935, 2018, A, . Location in patent: Paragraph 0166; 0167; 0168; 0169; 0170; 0171
[2] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6801 - 6805
5
[ 456-55-3 ]
[ 64115-88-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695
6
[ 456-55-3 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Journal of the American Chemical Society, 1987, vol. 109, p. 3708
7
[ 1035797-66-0 ]
[ 88284-48-4 ]
[ 64115-88-4 ]
[ 456-55-3 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6801 - 6805
8
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 31, p. 9645 - 9649[2] Angew. Chem., 2018, vol. 130, p. 9793 - 9797,5
9
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6
10
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13795 - 13799[2] Angew. Chem., 2018, vol. 130, # 42, p. 13991 - 13995,5
11
[ 618-32-6 ]
[ 64115-88-4 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 22, p. 6801 - 6805
12
[ 334778-34-6 ]
[ 144584-66-7 ]
[ 125941-12-0 ]
[ 64115-88-4 ]
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 1, p. 222 - 229
13
[ 456-55-3 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Journal of the American Chemical Society, 1987, vol. 109, p. 3708
14
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 31, p. 9645 - 9649[2] Angew. Chem., 2018, vol. 130, p. 9793 - 9797,5
15
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6
16
[ 108-86-1 ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13795 - 13799[2] Angew. Chem., 2018, vol. 130, # 42, p. 13991 - 13995,5
17
[ 64115-88-4 ]
[ 175676-65-0 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.75 h; Stage #2: With Triisopropyl borate In tetrahydrofuran at -78 - 20℃; for 16 h;
n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-BROM-2- (trifluoromethoxy) benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ML) at-78°C and stirred for 45 minutes. Triisopropyl borate (2. 58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours. The reaction mixture was quenched with water, made basic with 2N NAOH and extracted with ethyl acetate. The aqueous solution was acidified with 2N HCI, stirred for 1 hour at room temperature and extracted into ethyl acetate. The organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65percent) as a white solid. No.x0;HNMR (CDCL3) ( 8, ppm): 7.96 (dd, J= 7.2, 1.6 Hz, 1 H), 7.53 (ddd, J = 9.1, 7.3, 1. 8 HZ, 1 H), 7.38 (td, J = 7.3, 0.7 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 5.25 (br s, 2H). MS: m/e 206.9 (M+1) +.
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.75 h; Stage #2: With Triisopropyl borate In tetrahydrofuran at 20℃; for 16 h;
n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-bromo-2- (trifluoromethoxy) benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ml) at -78°C and stirred for 45 minutes. Triisopropyl borate (2.58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours. The reaction mixture was quenched with water, made basic with 2N NaOH and extracted with ethyl acetate. The aqueous solution was acidified with 2N HCI, stirred for 1 hour at room temperature and extracted into ethyl acetate. The organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65percent) as a white solid. (at)HNMR (CDC13)(8, ppm) : 7.96 (dd, J= 7.2,1.6 Hz, 1 H), 7.53 (ddd, J = 9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J = 7.3, 0.7 Hz, I H), 7.28 (d, J = 8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H) : 206.9
n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-BROM-2- (trifluoromethoxy) benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ML) at-78C and stirred for 45 minutes. Triisopropyl borate (2. 58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours. The reaction mixture was quenched with water, made basic with 2N NAOH and extracted with ethyl acetate. The aqueous solution was acidified with 2N HCI, stirred for 1 hour at room temperature and extracted into ethyl acetate. The organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65%) as a white solid. &No.x0;HNMR (CDCL3) ( 8, ppm): 7.96 (dd, J= 7.2, 1.6 Hz, 1 H), 7.53 (ddd, J = 9.1, 7.3, 1. 8 HZ, 1 H), 7.38 (td, J = 7.3, 0.7 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 5.25 (br s, 2H). MS: m/e 206.9 (M+1) +.
65%
n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-bromo-2- (trifluoromethoxy) benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ml) at -78C and stirred for 45 minutes. Triisopropyl borate (2.58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours. The reaction mixture was quenched with water, made basic with 2N NaOH and extracted with ethyl acetate. The aqueous solution was acidified with 2N HCI, stirred for 1 hour at room temperature and extracted into ethyl acetate. The organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65%) as a white solid. (at)HNMR (CDC13)(8, ppm) : 7.96 (dd, J= 7.2,1.6 Hz, 1 H), 7.53 (ddd, J = 9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J = 7.3, 0.7 Hz, I H), 7.28 (d, J = 8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H) : 206.9
To a solution of 2-bromo (trifluoromethoxy) benzene (4.82g, 20 mmol) in n-propanol (35 mL) was added 3-acetylbenzeneboronic acid (3.61 g, 22 mmol) under N2. After 15 min. of stirring at room temperature, Ph3P (0.46g, 1.7 mmol) was added followed by 2M sodium carbonate (11 mL) and water (10 mL). To the well stirred solution, palladium acetate (50mg) was added quickly, and the mixture was refluxed for 4 hours. The reaction was cooled to room temperature and partitioned between EtOAc and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product obtained was purified by column chromatography on silica gel using 5% EtOAc in hexanes to yield the pure ketone as an oil. Yield: 4.45g (79%). IH R (CDC13) (6, PPM) : 8.09 (s, 1H), 8.06 (d, 1H), 7.71 (d, 2H), 7.58 (t, 1H), 7.50-7. 40 (m, 4H), 2.67 (s, 3H). MS (ESI): m/e 281 (M+1)+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 90℃; for 22h;
REFERENCE EXAMPLE 4 I- [3- ( (2- (2, 2, 2-Trifluoroethoxy)-phenyl)-phenyl]-1, 2, 4-triazole-3-carboxamide Step A. 3-((2-(2,2,2-Trifluoroethoxy)-phenyl)-aniline To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide (Example 2, Step A) in 39 mL of toluene was added 0.136 g (0.118 mmol) of tetrakis (triphenylphosphine) palladium (0), 0.56 g (4.31 mol) of 3-aminophenylboronic acid, 47 mL (94.1 mmol) of a 2M solution of sodium carbonate and 8 mL of ethanol and the reaction mixture was heated at 90 C for 22 hr. The reaction mixtur was colld to RT, and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc nd the combined organic fractions were washed with water and brine and dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4: 1 hexanes: EtOAc) to give the title compound. Mass Spectrum (ESI) m/e M+1 268.1.
With tert.-butyl lithium; In tetrahydrofuran; hexane; at -78 - 25℃; for 16h;
REFERENCE EXAMPLE 1 3- [3- (2-Trifluoromethoxyphenyl)-phenyl]-1, 2, 4-triazole Step A: 2-Trifluoromethoxvphenylboronic acid To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-trifluoromethoxy benzene in 28 mL of tetrahydrofuran (THF) at-78C, was carefully added 5.9 mL of a 1.7 M solution of t- butyl lithium in hexanes (9.5 mmol). This reaction mixture was stirred at-78C for 45 min. To this reaction mixture at-78C was added 2.58 mL (11. 1 mmol) of tri-isopropyl borate, followed by slow warming of the mixture to room temperature (RT) over a period of 16 h. The reaction mixture was diluted with water and made basic with 2N NaOH solution. The mixture was then washed with EtOAc. The aqueous fraction was acidified with 2N HCI solution and stirred for 1 h at RT. The reaction mixture was extracted with EtOAc and the organic fractions were washed with water and saturated NaCI solution (brine), dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a white soiid.'HNMR (CDC) 3) (o, ppm): 7.96 (dd, J= 7.2, 1.6 Hz, 1 H), 7. 53 (ddd, J = 9. 1, 7.3, 1.8 Hz, 1 H), 7. 38 (td, J = 7.3, 0.7 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H): 206.9.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran;
Step A: 2-Trifluoromethoxybenzeneboronic Acid. A solution of 2-bromo-trifluoromethoxybenzene (1.0 g, 4.15 mmol) in dry tetrahydrofuran (20 mL) was cooled to -70 C. A 2.5 M solution of n-butyllithium in hexanes (2.0 mL, 4.98 mmol) was slowly added over a 5 min period, keeping the temperature below -65 C. After stirring at -70 C. for 30 min, triisopropylborate (1.5 mL, 6.22 mmol) was added over a 5 min period. After stirring at -70 C. for 30 min, the solution was stirred at room temperature overnight. An aqueous solution of 2N HCl (10 mL) was added and the mixture stirred for 2 hr. The solution was diluted with ethyl acetate (100 mL). The layers were separated and the organic layer successively washed with 2N HCl (2*25 mL), water (1*25 mL), and saturated salt solution (1*25 mL). The solution was dried over anhydrous magnesium sulfate, filtered and concentrated by rotoevaporation to a pale crystalline solid which was triturated with a little hexanes and filtered. The filtrate was concentrated to a white solid. The two solids were combined to yield 434 mg of the title compound which was used without further purification in the subsequent reaction.
With chlorosulfonic acid; In dichloromethane; at 0 - 20℃; for 0.5h;
a.9 3-Bromo-4-trifluoromethoxy-benzenesulfonyl chloride2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-50C, 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound.1H-NMR (CDCI3, 400 MHz): delta [ppm] 8.3 (d, 1 H), 8.05 (dd, 1 H), 7.5 (dd, 1 H).
With chlorosulfonic acid; In dichloromethane; at 0 - 20℃; for 0.5h;
a.9 3-Bromo-4-trifluoromethoxy-benzenesulfonyl chloride; 2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-50C, 1.06 g of chlorosulfonic acid (9.13 mmol), dis- solved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chloro¬ sulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound.1H-NMR (CDCI3, 400 MHz): delta [ppm] 8.3 (d, 1H)1 8.05 (dd, 1H), 7.5 (dd, 1H).
With chlorosulfonic acid; In dichloromethane; at 0 - 20℃; for 0.5h;
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-50C, 1.06 g of chlorosulfonic acid (9.13 mmol), dis¬ solved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chloro¬ sulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound. 1H-NMR (CDCI3, 400 Hz): delta [ppm] 8.3 (d, 1H), 8.05 (dd, 1H), 7.5 (dd, 1H).
With chlorosulfonic acid; In dichloromethane; at 0 - 20℃;
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-50C, 1.06 g of chlorosulfonic acid (9.13 mmol), dis¬ solved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chloro- sulfonic in dichloromethane were added to drive the reaction to completion.Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound.1H-NMR (CDCl3, 400 MHz): delta [ppm] 8.3 (d, 1H), 8.05 (dd, 1H), 7.5 (dd, 1H).
With chlorosulfonic acid; In dichloromethane; at 0 - 20℃; for 0.5h;
2.0 g of 1~bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-50C, 1.06 g of chlorosulfonic acid (9.13 mmol), dis¬ solved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chloro¬ sulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound.1H-NMR (CDCI3, 400 MHz): delta [ppm] 8.3 (d, 1 H), 8.05 (dd, 1 H), 7.5 (dd, 1 H).
With chlorosulfonic acid; In dichloromethane; at 0 - 20℃; for 0.5h;
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-50C, 1.06 g of chlorosulfonic acid (9.13 mmol), dis- solved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chloro¬ sulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound.1H-NMR (CDCI3, 400 MHz): delta [ppm] 8.3 (d, 1 H), 8.05 (dd, 1 H), 7.5 (dd, 1 H).
With chlorosulfonic acid; In dichloromethane; at 20℃; for 0.5h;
I. Preparation of the intermediatesa. Preparation of sulfonyl chloridesa.1 3-Bromo-4-trifluoromethoxy-benzenesulfonyl chloride2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5C, 1.06 g of chlorosulfonic acid (9.13 mmol), dis- solved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane- dichloromethane (6:4) as eluent gave 2.19 g of the title compound.1H-NMR (CDCI3, 400 MHz): delta [ppm] 8.3 (d, 1 H), 8.05 (dd, 1 H), 7.5 (dd, 1 H).
To a solution of (commercially available) (<strong>[64115-88-4]1-bromo-2-trifluoromethoxy-benzene</strong>) in DME (first degased with argon) under argon was added 3 mol % Pd(PPh3)4, pyridyl-4-boronic acid and 2N Na2CO3, the resulting reaction mixture was vigorously stirred under reflux. After 5 h at reflux, reaction as monitored by TLC showed completion. Two phases were separated, evaporation of most of the DME, redissolution of the residue in EtOAc and washing with aq. NaOH followed by evaporation gave a yellow oil. Flash Chromatography on SiO2 gelwith a mixture of CH2Cl2/MeOH gave the title compound in 51% yield. ES-MS m/e (%): 239.9 (M+H+).
5 rnL microwave vial was charged 4-ethynyl-7H-pyrrolo[2,3-d]pyrimidine (143 mg, 1.0 mmol), l-bromo-2-(trifluoromethoxy)benzene (241 mg, 1.0 mmol), PdCl2(PPhS)2 (35 mg, 0.05 mmol) and CuI (10 mg, 0.05 mmol). 3 mL of anhydrous CH3CN were added, after 10 min of stirring followed by 1.4 mL of Et3N. The reaction mixture was purged with argon for 5 min. Then the vial was capped and placed in a heating block at 60 0C for 18 h. Then it was cooled down to ambient temperature and concentrated in vacuo. The resulting black residue was re-dissolved in 3 mL of DMF and purified by reverse-phase preparative HPLC in CH3CN/H2O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was washed with brine (1 x 30 mL), dried over anhydrous Na2SO4 and filtered through a short silica gel plug. The filtrate was concentrated in vacuo to give the title product as a yellow solid (43 mg, 14% yield).[0334] 1H NMR (500 MHz, DMSO-J6): delta 6.63 (d, J = 3.5 Hz, IH), 7.55 (dt, J = 7.5, 1.0 Hz, IH), 7.59 (d, J = 8.4 Hz, IH), 7.67 (dt, J = 8.4, 1.7 Hz, IH), 7.75 (d, J = 3.5 Hz, IH), 7.92 (dd, J = 7.7, 1.6 Hz, IH), 8.79 (s, IH), 12.42 (s, IH)[0335] MS (ES+): m/z 304 (M+H)+
Synthesis of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone To a flame-dried 100 ml round bottomed flask was added <strong>[64115-88-4]1-bromo-2-(trifluoromethoxy)benzene</strong> (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to -78 C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at -78 C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) delta=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79(br. s, 2H); MS m/z: 361 [MH]+.
A 10 mL round-bottomed flask was charged with l-bromo-2-(trifluoromethoxy)benzene (0.17 g, 0.70 mmol, Sigma-Aldrich, St. Louis, MO) and tetrahydrofuran (2.0 mL). The solution was cooled to -78 C, n-butyllithium (0.28 mL of a 2.5 M solution with hexane, 0.70 mmol, Sigma-Aldrich, St. Louis, MO) was added, and then the reaction mixture was stirred for 30 min. After that time, a solution of N-(l-benzofuran-2-ylmethylidene)-3,4-dihydro-2H-l,5- benzodioxepine-7-sulfonamide (intermediate A)(0.10 g, 0.28 mmol) and tetrahydrofuran (3.0 mL) was added. After stirring for 1 h, water (0.10 mL) was added, the reaction mixture was warmed to room temperature and concentrated. The residue was subjected to reversed-phase preparative HPLC (Phenomenex Gemini C18 column (Phenomenex, Inc., Torrance, CA)(150 x 30 mm, 5 muiotaeta) eluting with 0.10% trifluroacetic acid in acetonitrile-water, gradient of 10% to 90% over 10 min) to give N-(l-benzofuran-2-yl(2-(trifluoromethoxy)phenyl)methyl)-3 ,4-dihydro-2H- 1 ,5 -benzodioxepine-7- sulfonamide (0.11 g) as a yellow oil (racemic mixture).1H NMR (300 MHz, methanol-d4) delta 7.74 (dd, J= 3.0, 6.0 Hz, 1 H), 7.48 - 7.14 (m, 9 H), 6.85 (d, J= 6.0 Hz, 1 H), 6.37 (s, 1 H), 6.07 (s, 1 H), 4.11 (t, J = 6.0 Hz, 2 H), 4.01 (t, J= 6.0 Hz, 2 H), 2.12 (quin, J= 6.0 Hz, 2 H). m/z (ESI, +ve ion) 542.0 (M+Na)+. GK-GKRP EC50 (LCMS/MS) = 0.34 muMu. GK-GKRP IC (Binding) = 0.97 muMu.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation; Sealed tube;
Step 4: A mixture of <strong>[64115-88-4]2-bromophenyl trifluoromethyl ether</strong> (272 mg), 2-[4- (ethylsulfonyl)phenyl]-N-[7-(4,4,5J5-tetramethyl-l.3,2-dioxaborolan-2-yl)-lH-indol-4-yl]acetamide (480 mg), Pd(Pl¾P)4 (118 mg) and 2M aqueous Na2C03 (2.56 mL) in 1 ,4-dioxane (7.5 mL) was bubbled with N2. The mixture was sealed in a reaction vessel and heated in the microwave at 100C for 1 hour. The mixture was partitioned between water and EtOAc. The organic layer was washed with brine and dried over anhydrous Na2S04. After concentration, the residue was purified by flash chromatography (EA : PE = 0:1 to 7:3) to afford the crude product (214 mg) as a yellow solid. Part of this crude (110 mg) was dissolved in DMF (7 mL) and further purified by MDAP to afford pure 2-[4- (ethyIsulfonyl)phenyl]-N-(7-{2-[(trifluorome-liyl)oxy]phenyl}-lH-indol-4-yl)acetamide (20 mg) as a white solid. ?-NMR (400 MHz, MeOD-rf4) 5 ppm 1.22 (t, J= 7.4 Hz, 3H), 3.21 (q, J= 7.4 Hz, 2H), 3.99 (s, 2H), 6.64 (d, J= 3.2 Hz, 1H), 7.02 (d, J= 7.9 Hz, 1H), 7.22 (d, J= 3.2 Hz, 1H), 7.44-7.55 (m, 5H), 7.71 (d, J= 8.3 Hz, 2H), 7.91 (d, J= 8.3 Hz, 2H); 19F-NMR (376 MHz, DMSO-i/6) 5 ppm -60.53; MS(ES+) z 503 (MH+)
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tetrabutyl ammonium fluoride; triethylamine; In tetrahydrofuran; at 70℃; for 1h;Inert atmosphere;
To a solution of 4-chloro-2-trimethylsilanylethynyl-phenylamine (300 mg, 1.34 mmol) in THF (10 ml) was added triethylamine (0.6 ml, 4.02 mmol), and l-bromo-2- trifluoromethoxy-benzene (0.3 ml, 2.01 mmol). The mixture was purged with argon for 10 min and then PdCl2 (PPh3)2 (47 mg, 0.07 mmol) was added followed by Cul (7.7 mg, 0.04 mmol). The reaction mixture was then heated to 70C. TBAF (1M solution in THF) (1.54 ml, 1.54 mmol) was added and the reaction mixture was stirred for 1 h at 70C. After cooling, the mixture was filtered through celite bed, washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (2-3% ethyl acetate in hexane) to obtain 4-chloro-2-(2-trifluoromethoxy-phenylethynyl)- phenylamine (210 mg, 50% yield) as a brown solid. GC-MS: 311 (M).
50%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tetrabutyl ammonium fluoride; triethylamine; In tetrahydrofuran; at 70℃; for 1h;Inert atmosphere;
Step B: 4-Chloro-2-(2-trifluoromethoxy-phenylethynyl)-phenylamine To a solution of 4-chloro-2-trimethylsilanylethynyl-phenylamine (300 mg, 1.34 mmol) in THF (10 ml) was added triethylamine (0.6 ml, 4.02 mmol), and <strong>[64115-88-4]1-bromo-2-trifluoromethoxy-benzene</strong> (0.3 ml, 2.01 mmol). The mixture was purged with argon for 10 min and then PdCl2 (PPh3)2 (47 mg, 0.07 mmol) was added followed by CuI (7.7 mg, 0.04 mmol). The reaction mixture was then heated to 70 C. TBAF (1M solution in THF) (1.54 ml, 1.54 mmol) was added and the reaction mixture was stirred for 1 h at 70 C. After cooling, the mixture was filtered through celite bed, washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (2-3% ethyl acetate in hexane) to obtain 4-chloro-2-(2-trifluoromethoxy-phenylethynyl)-phenylamine (210 mg, 50% yield) as a brown solid. GC-MS: 311 (M).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 3h;
General procedure: To a microwave vial with stir bar was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3,4,5-trimethoxyphenyl)benzo[d]oxazol-2-amine (97 mg, 0.228 mmol), 4-bromo-1H-benzo[d]imidazole (30 mg, 0.152 mmol), DME (1.5 mL), Sodium carbonate (0.76 mL, 1.523 mmol) [2.0M (aq)] and PdCl2(dppf)-CH2Cl2 adduct (12.43 mg, 0.015 mmol). Vial capped and heated in an aluminum tray at 120 C for 3 hr. Reaction mixture was cooled to RT, diluted with water. Aqueous mixture was extracted with EtOAc. Organic phases combined, washed with brine, dried (Na2SO4), filtered and concentrated. Residue dissolved with DMSO and purified by RHPLC. Product fractions combined, frozen and lyophilized to afford a TFA salt of 7-(1H-benzo[d]imidazol-4-yl)-N-(3,4,5-trimethoxyphenyl) benzo[d]oxazol-2-amine (8.1 mg, 0.015 mmol, 9.93 % yield).
bromo[2-(trifluoromethoxy)phenyl]-magnesium[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With magnesium; In tetrahydrofuran; at 20℃;Schlenk technique;
Preparation of (2-[trifluoromethoxylphenyl)fphenyl)phosphine chloride To a flame dried Schlenk tube containing magnesium turnings (0.15 g, 6.22 mmo) in anhydrous THF (7 mi) was added 1-bromo-2- [trifluoromethoxy] benzene (1.0 g, 4.14 mmo). An exothermic reaction ensued. Stirring was continued at room temperature. Once the reaction exotherm had dissipated, the reaction mixture was used in the next step as described beiow: The Grignard reagent (separated from excess Mg) was incrementally added to a solution of PhPCI2 (0.74 g, 4.14 mmol) in anhydrous THF (10 ml) at -78C. Once addition was complete, the reaction was stirred at room temperature for a further 20 min after which the reaction was complete as judged by 3 P NMR ( 1P NMR (CDCIs): delta 72.27 (m); 61.81 (m)). The product was used in the next step without further purification.
With bis-triphenylphosphine-palladium(II) chloride; In toluene; at 100℃; for 4h;
Into a 300-ml glass reaction vessel equipped with a stirring apparatus were placed 10.0 g (42 mmol) of <strong>[64115-88-4]1-bromo-2-(trifluoromethoxy)benzene</strong>, 2.9 g (4.2 mmol) of dichlorobis(triphenylphosphine)palladium(II), 20.1 g (54 mmol) of 2-(tributyltin)thiophene, and 100 ml of toluene. The mixture was reacted at an internal temperature of about 100C for 4 hours. After the completion of the reaction, the solvent was concentrated, and then 300 ml of hexane was added to the reaction solution. Subsequently, the mixture was filtered through [silica gel: potassium carbonate = 90 : 10 (wt%)]. The filtrate was concentrated, and the concentrate was purified by column chromatography (hexane: 100 vol%), to provide 6.6 g of Compound (3-1) in the form of a pale yellow liquid. [0125] The properties of Compound (3-1) were as follows. 1H-NMR (400MHz; CDCl3); 7.09-7.14 (m, 1H), 7.27-7.37 (m, 3H), 7.37-7.41 (m, 1H), 7.41-7.44 (m, 1H), 7.63-7.70 (m, 1H)
6.6 g
With bis-triphenylphosphine-palladium(II) chloride; In toluene; at 100℃; for 4h;
Into a 300-mi glass reaction vessel equipped with a stirring apparatus were placed 10.0 g (42 mmol) of 1-bromo-2-(trif- luoromethoxy)benzene, 2.9 g (4.2 mmol) of dichiorobis (triphenylphosphine)palladium(II), 20.1 g (54 mmol) of 2-(tributyltin)thiophene, and 100 ml of toluene. The mixture was reacted at an internal temperature of about 100 C. for 4 hours. After the completion of the reaction, the solvent was concentrated, and then 300 ml of hexane was added to the reaction solution. Subsequently, the mixture was filtered through [silica gel:potassium carbonate=90: 10 (wt %)]. The filtrate was concentrated, and the concentrate was purified bycolumn chromatography (hexane: 100 vol %), to provide 6.6 g of Compound (3-1) in the form of a pale yellow liquid.The properties of Compound (3-1) were as follows.?H-NMR (400 MHz; CDC13); 7.09-7.14 (m, 1H), 7.27- 7.37 (m, 3H), 7.37-7.41 (m, 1H), 7.41-7.44 (m, 1H), 7.63-7.70 (m, 1H)
General procedure: Functionalized aryl bromide (2 mmol) was dissolved in Et2O (8 mL),and then a 1.6M n-BuLi solution (1.25 mL, 2 mmol) was added dropwiseat -78 C. After 1 h of stirring, N,N-diethylaminochlorophenylphosphine(1.8 mmol) in Et2O (2 mL) was added dropwise.The mixture was allowed to warm to ambient temperature and stirredfor another 3 h. The volatile solvent was removed in vacuo and thecrude mixture was slurried in n-hexane (10 mL). The slurry was filteredusing an activated alumina pad, and the filter cake was washed with nhexane(2×2 mL). The volatile solvent was removed in vacuo to affordpure (Et)2NPPh(ArR) in 75.8%-85.3% yield as colorless oil. Yields andcharacterization data are summarized in Table S2. The ClPPh(ArR)products were obtained in the same manner described above in 99.9%yield. Yields and characterization data are summarized in Table S3.
With perhydrodibenzo-18-crown-6; potassium fluoride; bromopentafluorobenzene; 1-Bromo-2-phenylacetylene; In ethyl acetate; at 20℃; for 12h;Glovebox; Sealed tube;
General procedure: In the glove box, add KF (78.4mg, 1.35mmol, 4.5equiv) to cis- in 20mL plastic tube (PE).Dicyclohexano-18-crown-6 (503 mg, 1.35 mmol, 4.5 equiv) and 6 mL ethyl acetate.Then a phenylene precursor (0.3 mmol, 1.0 equiv), 1-bromophenylacetylene (218 mg, 1.2 mmol. 4.0 equiv) or perfluorohexyl bromide (479 mg,1.2 mmol. 4.0 equiv) or pentafluorophenyl bromide (296 mg, 1.2 mmol. 4.0 equiv) and trifluoromethyl benzoate (171 mg, 0.9 mmol, 3 equiv) were capped and allowed to react at room temperature for 12 hours.After the end of the reaction, the F-spectrum yield was first calculated by 19F NMR.After completion of the reaction, the mixture was filtered, dried, and directly subjected to column chromatography.
(S)-(3-((tert-butyldimethylsilyloxy)methyl)-4-(pyridin-2-yl)piperazin-1-yl)(2,4-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylamino)phenyl)methanone[ No CAS ]
tert-butyl 1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32.6%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 16h;
Step 1: tert-butyl 1-(2-(trifluoromethoxy)phenyl)piperidin-4-ylcarbamate A mixture of <strong>[64115-88-4]1-bromo-2-(trifluoromethoxy)benzene</strong> (2.40 g, 9.96 mmol), tert-butyl N-(4-piperidyl)carbamate (1.99 g, 9.96 mmol), Pd2(dba)3 (546 mg, 597 umol), BINAP (744 mg, 1.20 mmol), t-BuONa (6.47 g, 69 mmol) in toluene (50 mL) was stirred at 90 C. for 16 h. Cooled to rt, filtered and concentrated, eluted with EtOAc (50 mL), washed with H2O (100 mL), then extracted with EtOAc (100 mL*3), washed with brine (50 mL*2), dried, concentrated to afford methyl 5-formyl-2,4-dimethylbenzoate (1.6 g, 32.6%) as brown gum. ESI-MS (EI+, m/z): 361 [M+H]+.
2-(3,5-bis(trifluoromethyl)phenyl)-4-nitro-1-(trifluoromethoxy)-6-(trifluoromethyl)-1H-benzo[d]imidazole[ No CAS ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Yield
Reaction Conditions
Operation in experiment
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 16h;Glovebox; Irradiation; Sealed tube; Inert atmosphere;
In a glovebox, to an oven-dried 20 mL screw cap vial was added 2- (3, 5-bis (trifluoromethyl) phenyl) -4-nitro-l- (trifluoromethoxy) -6- (trifluoromethyl) -lii-benzo [d] imidazole (1) (105 mg, 0.200 mmol, 1.00 equiv) , arene (2.00 mmol, 10.0 equiv) and Ru (bpy) 3 ( REe) 2, (0.0516 mg, 0.0600 pmol, 0.0300 moll) . Then MeCN (1.00 mL, 0.200 M) and a magnetic stir bar were added. The vial was capped and taken out of the glovebox. The reaction mixture was then stirred and irradiated with a 10 W LED (402 nm) at room temperature. After 16 h, an internal standard PhCF3 (5.84 mg, 4.95 pL, 0.04 mmol, 0.200 equiv) was added to the reaction vial, 0.200 mL of the resulting mixture was transferred to a 2 mL vial containing 0.500 mL of CDCI3. After the yield was determined using 19F NMR, the NMR sample was combined with the rest of the reaction mixture and the solvent was removed in vacuo. The crude material was purified by HPLC under noted conditions. The fractions containing the desired product were combined and extracted with CDCI3 (3 1 mL) , dried with magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to furnish the desired product of trifluoromethoxylation . For volatile compounds, after purification by HPLC, the desired product was extracted with 1 mL CDC13 and then directly characterized. The NMR peaks are referring to CH3CN residue signal ^H-NMR: d 1.94, 13C~NMR: 5 118.26, 1.32).2
With bis-triphenylphosphine-palladium(II) chloride; potassium hydroxide; In 2-methyltetrahydrofuran; water; at 80℃; for 24h;Inert atmosphere;
Step A: A solution of compound 12 (556.08mg, 1.18mmol, 1.00eq), 2-trifluoromethoxybromobenzene(281.98mg, 1.17mmol, 174.06uL, 1.00eq), aqueous potassium hydroxide solution (4M, 1.64mL, 5.60eq) and dichlorobis(triphenylphosphine)palladium (24.64mg, 35.10umol, 0.03eq) in 20mL 2-methyltetrahydrofuran was purged with nitrogenfor three times. The reaction solution was stirred at 80C under nitrogen atmosphere for 24 hours, then dilutedwith 20mL water. The mixture was extracted twice with 50mL ethyl acetate each time. The organic phase was combined,washed once with 100mL saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the compound 15 as a yellow oil (380.00mg), which was directly used in the next step.
4-methoxy-1-(R)-pyrrolidin-3-yl-3-(2-trifluoromethylbenzyl)-1,3-dihydrobenzoimidazol-2-one[ No CAS ]
4-methoxy-1-[(R)-1-(2-trifluoromethoxyphenyl)pyrrolidin-3-yl]-3-(2-trifluoromethylbenzyl)-1,3-dihydrobenzoimidazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃; for 20h;Inert atmosphere;
General procedure: Method A ( Buchwald-Hartwia ) To a mixture of C-1 (1 eq), BB-8 (1.3 eq) and sodium tert-butoxide (2 eq) in toluene (3 to 10 mL/mmol) under N2, was added BINAP (0.2 eq) and Pd2(dba)3 (0.1 eq). The rxn mixture was flushed with N2, heated at a given temperature and stirred for a given time (see Table 25). It was partitioned between water and EtOAc and the org. phase was washed with brine, dried over MgSC>4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc. When necessary an additional purification by prep. LC-MS was performed.
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 16h;Glovebox; Irradiation; Sealed tube; Inert atmosphere;
General procedure: In a glovebox, to an oven-dried 20 mL screw cap vial was added 3- methyl-4-nitro-l- ( trifluoromethoxy) -6- (trifluoromethyl ) -1H- benzo[d] [1, 2, 3] triazol-3-ium trifluoromethanesulfonate (lb) (98.0 mg, 0.200 mmol, 1.00 equiv), arene (2.00 mmol, 10.0 equiv) and Ru (bpy) 3 (PFe) 2, (1.72 mg, 2.00 pmol, 1.00 mol%). Then MeCN (1.00 mL, 0.200 M) and a magnetic stir bar were added. The vial was capped and taken out of the glovebox. The reaction mixture was then stirred and irradiated with 2 of 10 W LED (Xmax = 447 nm) at room temperature. After 16 h, an internal standard PhCF3 (24.6 pL, 0.200 mmol, 1.00 equiv) was added to the reaction vial, 0.200 mL of the resulting mixture was transferred to a 2 mL vial containing 0.500 mL of CDC13. After the yield was determined using 19F NMR, the NMR sample was combined with the rest of the reaction mixture and the solvent was removed in vacuo. The crude material was purified by HPLC under noted conditions. The fractions containing the desired product were combined and extracted with CDC13 (3 x 10.0 mL) , dried with magnesium sulfate, and filtered unless otherwise noted. The filtrate was concentrated in vacuo to furnish the desired product of trifluoromethoxylation . For volatile compounds, after purification by HPLC, the desired product was extracted with 1 mL CDCI3 and then directly characterized. The NMR peaks are referring to CCN residue signal (1H-NMR : d 1.94, 13C-NMR: d 118.26, 1.32).2
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