* 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] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695
2
[ 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
3
[ 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
4
[ 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
5
[ 456-55-3 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Journal of the American Chemical Society, 1987, vol. 109, p. 3708
6
[ 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
7
[ 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
8
[ 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
9
[ 143582-87-0 ]
[ 407-14-7 ]
Yield
Reaction Conditions
Operation in experiment
71 %Spectr.
With Et3NHF*5HF; iodine pentafluoride-pyridine-hydrogen fluoride In 1,2-dichloro-ethane at 60℃; for 24 h;
General procedure: To IF5-pyridine-HF (321 mg, 1.0 mmol) in dichloroethane (2 mL), were added Et3N-6HF (553 mg, 2.5 mmol) and 2a (113 mg, 0.5 mmol) successively at room temperature. The mixture was stirred at 60 °C for 9 h. The resulting dark red solution was poured into water (20 mL) and extracted with CH2Cl2 (20 mL * 3). The combined organic layer was washed with aq NaHCO3 and aq Na2S2O3, and dried over MgSO4. The yield of 4a was determined to be 74percent by 19F NMR using fluorobenzene as an internal standard. Pure 4a was obtained by column chromatography (silica gel/hexane); IR (neat) 2963, 1256, 1212 cm-1; 1H NMR δ 7.23 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.95-2.85 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H); 19F NMR δ-58.53 (s, 3F); 13C NMR δ 147.7, 147.3, 127.8 (2C), 121.0 (2C), 120.7 (q, 1JC-F = 257.7 Hz), 33.7, 24.1 (2C); HRMS (EI) calcd for C10H11F3O 204.07620, found 204.07606.
70 %Spectr.
With Et3NHF*5HF; iodine pentafluoride-pyridine-hydrogen fluoride In 1,2-dichloro-ethane at 60℃; for 24 h;
Products were synthesized in the same manner as in Example 1, except that the substrate (compound 1a), reaction temperature, time, and solvent used in Example 1-1 were changed to those shown in Table 2.Regarding the “yield/percent” in Table 2, the 19F-NMR yield is based on the substrate. The value in parenthesis is an isolation yield. In air, IF5-pyridine-HF (321 mg, 1.00 mmol) and Et3N-6HF (553 mg, 2.50 mmol) were added to methylene chloride (1 mL) in a Teflon (trade name) container, and compound 1a (O-(4-isopropyl phenyl)S-methyl dithiocarbonate) (0.5 mmol) was added thereto at room temperature, followed by stirring at 60° C. for nine hours. The reaction mixture was added to water (30 mL), and extraction was performed using methylene chloride three times (20 mL×3). The organic layer was washed with a saturated sodium bicarbonate aqueous solution (20 mL) and a saturated sodium thiosulfate aqueous solution (20 mL), and then dried with magnesium sulfate. After condensation, product 2a (trifluoromethyl 4-isopropyl phenyl ether) was obtained by silica gel column chromatography (hexane ether) with a yield of 74percent.
Reference：
[1] Tetrahedron Letters, 1992, vol. 33, # 29, p. 4173 - 4176
[2] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 2, p. 471 - 484
[3] Journal of Fluorine Chemistry, 2015, vol. 179, p. 48 - 52
[4] Patent: US2015/315136, 2015, A1, . Location in patent: Paragraph 0132; 0137; 0138
10
[ 456-55-3 ]
[ 407-14-7 ]
Yield
Reaction Conditions
Operation in experiment
83.8%
at 100℃; for 16 h;
Step 2 1-bromo-4-(trifluoromethoxy)benzene Trifluoromethoxybenzene 6c (11.35 g, 70 mmol) was dissolved in 3.57 mL liquid bromine, followed by addition of iron (0.24 g). The reaction mixture was stirred for 16 hours at 100° C. 450 mL of dichloromethane were added and the organic extract was washed with 6 M hydrochloric acid (140 mL), 10percent sodium hydrogen sulfite solution (140 mL) and saturated sodium chloride solution (140 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-bromo-4-(trifluoromethoxy)benzene 6d (14.1 g, yellow solid), yield: 83.8percent. 1H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.11-7.09 (m, 2H).
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 34, p. 13308 - 13310
12
[ 106-41-2 ]
[ 407-14-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 2015, vol. 179, p. 48 - 52
[2] Organic Letters, 2016, vol. 18, # 18, p. 4570 - 4573
[3] Journal of Fluorine Chemistry, 2017, vol. 203, p. 130 - 135
13
[ 106-41-2 ]
[ 407-14-7 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 6905 - 6917
14
[ 456-55-3 ]
[ 107713-64-4 ]
[ 407-14-7 ]
Reference：
[1] Patent: US5225607, 1993, A,
[2] Patent: US4891450, 1990, A,
15
[ 456-55-3 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Reference：
[1] Journal of the American Chemical Society, 1987, vol. 109, p. 3708
16
[ 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
17
[ 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
18
[ 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
19
[ 106-41-2 ]
[ 353-50-4 ]
[ 407-14-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 22, p. 4238 - 4248
20
[ 407-14-7 ]
[ 461-82-5 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranInert atmosphere Stage #2: With C10H17NO In tetrahydrofuran; toluene at -20℃; for 2 h; Inert atmosphere
General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH4Cl. (The actual temperature/reaction time is listed for each substrate.)
Reference：
[1] New Journal of Chemistry, 2012, vol. 36, # 11, p. 2334 - 2339
22
[ 407-14-7 ]
[ 544-92-3 ]
[ 332-25-2 ]
Yield
Reaction Conditions
Operation in experiment
21%
Heating / reflux
4-(Trifluoromethoxy)benzonitrile: To a solution of 1-bromo-4-(trifluoromethoxy)benzene (24 g, 99.6 mmol) in DMF (120 mL) was added CuCN (19.7 g, 200.0 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was quenched by adding H2O/ice (200 mL) and the resulting solution was extracted from EtOAc (3.x.200 mL). The combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (1:20 EtOAc/hexanes) to give the title compound (4 g, 21percent) as a colorless oil.
Reference：
[1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695
24
[ 773837-37-9 ]
[ 407-14-7 ]
[ 332-25-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2345 - 2351
25
[ 407-14-7 ]
[ 103962-05-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695
26
[ 407-14-7 ]
[ 160542-02-9 ]
Reference：
[1] Canadian Journal of Chemistry, 1995, vol. 73, # 2, p. 191 - 203
27
[ 75-21-8 ]
[ 407-14-7 ]
[ 196811-90-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695
28
[ 407-14-7 ]
[ 139301-27-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695
29
[ 5419-55-6 ]
[ 407-14-7 ]
[ 139301-27-2 ]
Yield
Reaction Conditions
Operation in experiment
90.4%
With hydrogenchloride; n-butyllithium; sodium chloride In tetrahydrofuran; n-heptane
EXAMPLE 1E 4-(trifluoromethoxy)phenylboronic Acid A solution of 1-bromo-4-(trifluoromethoxy)benzene (1.69 kg) and triisopropyl borate (1.46 kg) in THF (6.75 L) at -70° C. was treated with 2.25 M butyllithium in hexanes (3.27 L) over 2.3 hours, stirred for 10 minutes, treated with 6M HCl (1.52 L) over 50 minutes, stirred for 18 hours at room temperature, and poured into a mixture of heptane (8.43 L) and 20percent (w/w) sodium chloride (8.44 kg). This mixture was stirred for 10 minutes and separated into an aqueous fraction and an organic fraction. The organic fraction was concentrated to provide a white paste. The paste was dried under vacuum (100 mmHg) at ambient temperature with a nitrogen bleed for 2 days then at 40-50° C. for 18 hours to provide 1.306 kg (90.4percent) of the desired product as a solid. 1H NMR (CDCl3, 300 MHz) δ 7.24-7.19 (m, 2H), 8.14-8.10 (m, 2H) with additional absorptions at 7.19-7.15 (m, 2H) and 8.04-8.00 (m, 2H) corresponding to the cyclic boronic acid trimer.
With Et3NHF*5HF; iodine pentafluoride-pyridine-hydrogen fluoride; In 1,2-dichloro-ethane; at 60℃; for 24h;
General procedure: To IF5-pyridine-HF (321 mg, 1.0 mmol) in dichloroethane (2 mL), were added Et3N-6HF (553 mg, 2.5 mmol) and 2a (113 mg, 0.5 mmol) successively at room temperature. The mixture was stirred at 60 C for 9 h. The resulting dark red solution was poured into water (20 mL) and extracted with CH2Cl2 (20 mL * 3). The combined organic layer was washed with aq NaHCO3 and aq Na2S2O3, and dried over MgSO4. The yield of 4a was determined to be 74% by 19F NMR using fluorobenzene as an internal standard. Pure 4a was obtained by column chromatography (silica gel/hexane); IR (neat) 2963, 1256, 1212 cm-1; 1H NMR delta 7.23 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.95-2.85 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H); 19F NMR delta-58.53 (s, 3F); 13C NMR delta 147.7, 147.3, 127.8 (2C), 121.0 (2C), 120.7 (q, 1JC-F = 257.7 Hz), 33.7, 24.1 (2C); HRMS (EI) calcd for C10H11F3O 204.07620, found 204.07606.
70%Spectr.
With Et3NHF*5HF; iodine pentafluoride-pyridine-hydrogen fluoride; In 1,2-dichloro-ethane; at 60℃; for 24h;
Products were synthesized in the same manner as in Example 1, except that the substrate (compound 1a), reaction temperature, time, and solvent used in Example 1-1 were changed to those shown in Table 2.Regarding the ?yield/%? in Table 2, the 19F-NMR yield is based on the substrate. The value in parenthesis is an isolation yield. In air, IF5-pyridine-HF (321 mg, 1.00 mmol) and Et3N-6HF (553 mg, 2.50 mmol) were added to methylene chloride (1 mL) in a Teflon (trade name) container, and compound 1a (O-(4-isopropyl phenyl)S-methyl dithiocarbonate) (0.5 mmol) was added thereto at room temperature, followed by stirring at 60 C. for nine hours. The reaction mixture was added to water (30 mL), and extraction was performed using methylene chloride three times (20 mL×3). The organic layer was washed with a saturated sodium bicarbonate aqueous solution (20 mL) and a saturated sodium thiosulfate aqueous solution (20 mL), and then dried with magnesium sulfate. After condensation, product 2a (trifluoromethyl 4-isopropyl phenyl ether) was obtained by silica gel column chromatography (hexane ether) with a yield of 74%.
ethyl 2-oxo-2-[4-(trifluoromethoxy)phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A) ethyl amino (4-(trifluoromethoxy)phenyl)acetate To a solution of <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> (10 g) in tetrahydrofuran (200 mL) was added 1.6 M n-butyllithium/hexane solution (31.1 mL) at -78C, and the mixture was stirred at the same temperature for 50 min under nitrogen atmosphere. Ethyl 2-chloro-2-oxoacetate (6.23 g) was added thereto at the same temperature, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was added to 1 M hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product (2.50 g) of ethyl oxo-(4-(trifluoromethoxy)phenyl)acetate.
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 2h;
Under argon a solution of LDA (12.45 ml, 2M in THF) was cooled to -78C and a solution of 1-Bromo-4-trifluoromethoxy-benzene (3.7 ml) in THF (50 ml) was added slowly. The reaction mixture was stirred at -78C for two hours and dry ice was added in excess. The solvent was distilled off and the crude product was dissolved in aqueous NaOH (1N), extracted with dichloromethane, then acidified with HCl and again extracted with dichloromethane. The organic layers were dried over sodium sulphate and the solvent was removed in vacuum. The title compound was obtained in 49% yield. 1H-NMR (DMSO-d6): 13.78 s (1H); 8.05 d (J = 2.6 Hz, 1H); 7.92 dd (J = 2.6 Hz / 8.9 Hz, 1H); 7.47 dd (J = 1.3 Hz / 8.9, 1H).
49%
2b) 5-Bromo-2-trifluoromethoxy-benzoic acid Under argon a solution of LDA (12.45 ml, 2M in THF) was cooled to -78C and a solution of 1-Bromo-4-trifluoromethoxy-benzene (3.7 ml) in THF (50 ml) was added slowly. The reaction mixture was stirred at -78C for two hours and dry ice was added in excess. The solvent was distilled off and the crude product was dissolved in aqueous NaOH (1 N), extracted with dichloromethane, then acidified with HCl and again extracted with dichloromethane. The organic layers were dried over sodium sulphate and the solvent was removed in vacuum. The title compound was obtained in 49% yield. 1H-NMR (DMSO-d6): 13.78 s (1 H); 8.05 d (J = 2.6 Hz, 1 H); 7.92 dd (J = 2.6 Hz / 8.9 Hz, 1 H); 7.47 dd (J = 1.3 Hz / 8.9, 1 H).
With C31H28ClN4Pd; potassium carbonate; In ethanol; water; at 20℃;
General procedure: In a reaction tube, bromobenzene (0.5mmol, 1equiv), (4-methoxyl phenyl)boronic acid (0.75mmol, 1.5equiv) and K2CO3 (1mmol, 2equiv) were dissolved in 3mL mixed solvent (EtOH:H2O, 2:1). The reaction mixture was stirred at ambient temperature and monitored by TLC. After completion, 10mL water was added to the resulting mixture, then it was extracted with ethyl acetate (3×10mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether as the eluent) to obtain the desired product.
tert-butyl 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To toluene 3.0mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10g were added <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> 0.13mL, cesium carbonate 0.23g, tris(dibenzylideneacetone)dipalladium(0) 3.2mg and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 8.3mg at room temperature, and it was stirred at 110C for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6mg, tris(dibenzylideneacetone)dipalladium(0) 3.2mg and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 8.3mg were added at room temperature, and it was stirred at 110C for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoate. Trifluoroacetic acid 10mL was added to the obtained tert-butyl 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-phenethyl-2-(4-(trifluoromethoxy)anilino)benzoic acid 20mg of white solid. 1H-NMR(DMSO-d6) delta value: 2.85(4H,s),6.72-6.78(1H,m),6.97(1H,s),7.11-7.30(9H,m),7.83(1H,d,J=8.0Hz),9.62(1H,s),13.00(1H,s).
4-(Trifluoromethoxy)benzonitrile: To a solution of 1-bromo-4-(trifluoromethoxy)benzene (24 g, 99.6 mmol) in DMF (120 mL) was added CuCN (19.7 g, 200.0 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was quenched by adding H2O/ice (200 mL) and the resulting solution was extracted from EtOAc (3.x.200 mL). The combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (1:20 EtOAc/hexanes) to give the title compound (4 g, 21percent) as a colorless oil.
2,2-dimethyl-3-(4-trifluoromethoxyphenyl)propanal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.1%
With sodium hydroxide; tetra-(n-butyl)ammonium iodide; In water; benzene; at 70℃; for 2h;
6-chloro-N-[2,2-dimethyl-3-(4-trifluoromethoxyphe nyl)propyl]-3-pyridylmethylamine (I-45) was synthesized by the method described by the aforementioned reaction scheme (A). Sodium hydroxide of 0. 4 g was first dissolved in water of 0.4 ml, benzene of 0.4 ml and tetrabutylammonium iodide of 15 mg (0.04 mmol) were added and the solution was heated at 70 C. A solution where isobutylaldehyde of 720 mg (10.0 mmol) and 4-trifluoromethoxybenzylbromide of 1.05 g (4.0 mmol) were dissolved with benzene of 0.4 ml was dropped to the solution and the solution was heated at 70 C for 2 hours. After the solution was naturally cooled down, the reaction solution was added to water and the solution was extracted with benzene. The obtained benzene layer was washed with a saturated saline solution followed by drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue thus obtained was refined with the silica gel (Silica Gel 60,230-400 mesh, made by Merck Inc.). column [the composition of the eluate: n-Hex (n-hexane)/AcOEt (ethyl acetate) = 20/1], and 2,2-dimethyl-3-(4-trifluoromethoxyphenyl)propanal (IV-45) of 700 mg was obtained as a colorless oily matter. The yield was 71.1 %. Next, the compound (IV-45) of 600 mg (2.44 mmol) obtained in the aforementioned reaction was dissolved in 1,2-dichloroethane of 12 ml, and then 6-chloro-N-methyl-3-pyridylmethylamine of 458 mg (2.93 mmol) was added. Further, sodium triacetoxyborohydride of 620 mg (2.93 mmol) and acetic acid of 0.14 ml (0.24 mmol) were added, and the solution was stirred at a room temperature for 2 hours. Thereafter, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution and the solution was extracted with methylene chloride. The obtained methylene chloride layer was washed with a saturated saline solution followed by drying with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was refined with the silica gel (Silica Gel 60, 230-400 mesh, made by Merck Inc.) column [the composition of the eluate: n-Hex (n-hexane)/AcOEt (ethyl acetate) = 20/1], and the object compound (I-45) of 300 mg was obtained as a light-yellow oily matter. The yield was 31.8 %.
2-methyl-3-(4-trifluoromethoxyphenyl)propanal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.0%
With sodium hydrogencarbonate;triphenylphosphine; palladium dichloride; In DMF (N,N-dimethyl-formamide); at 50 - 125℃; for 1h;
2-methyl-3-(4-trifluoromethoxyphenyl)propanal [in the formula (II), W represents 4-trifluoromethoxyphenyl group] was prepared using the procedure described by the reaction formula (D). 16 mg (0.09mmol) of palladium chloride (II) and 46 mg (0.18 mmol) of triphenylphosphine were dissolved in 4 ml of N,N-dimethylformamide at 120C under nitrogen atmosphere, and allowed to cool to 50C. The solution was admixed with 2.0 g (8.3 mmol) of 4-trifluoromethoxybromobenzene, 900 mg (12.5 mmol) of methallyl alcohol (equivalent of 2-methyl-2-propene-1-ol) and 840 mg (10 mmol) of sodium hydrogencarbonate and stirred at 125C for 1 hour. After standing to cool, the resultant solution was admixed with water and extracted with benzene. The separated benzene phase was washed with water and saturated brine successively and dried over sodium sulfate anhydride. After solvent removal by distillation under a reduced pressure, 1.7 g of an oily substance was obtained. The oily substance was purified by using silica gel column (Merck Silica gel 60, 230-400 mesh, Merck Co., eluent composition: Hexane/AcOEt=10/1). This gave 1.27 g of 2-methyl-3-(4-trifluoromethoxyphenyl)propanal as an oily substance. The yield was 66.0%.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; at 20 - 65℃; for 18h;
A mixture of 4-(trifluromethoxy)bromobenzene (4.54 g, 18.8 mmole), thiophene-2-boronic acid (4.82 g, 37.6 mmol) and Na2CO3 (12 g, 112.8 mmol) in EtOH (150 mL) is stirred at room temperature. Then, [1,1'-bis (diphenylphosphnio)-ferrocene]dichloropalladium(ii) complex with dichloromethane (1:1) (1.1 g, 0.94 mmol) is added and the reaction mixture is heated at 65 C. for 18 hours. The reaction mixture is cooled to room temperature, filtered through celite and concentrated in vacuo. The residue is dissolved in EtOAc and silica gel is added. The EtOAc is evaporated in vacuo and the gel is placed on a column of silica gel and eluted with hexane, then EtOAc/Hexane (1:9) to give 2-(4-trifluromethoxyphenyl)-thiophene as a solid. [0223] A solution of 2-(4-trifluoromethoxyphenyl)-thiophene (2.15 g, 8.8 mmol) in THF (110 mL) is stirred at -78 C. and n-BuLi (6.06 mL, 1.6 M in hexane) is added. The mixture is stirred at -78 C. for 45 minutes, then SO2 gas is bubbled through the solution for 15 minutes, stirred at -78 C. for 1 hour, warmed to room temperature and stirred for another 15 minutes. Hexane is added to the mixture and the product is filtered. The precipitate is washed with hexane to give lithium 5-(4-trifluromethoxyphenyl)-thiophene-2-sulfinate. [0224] To a suspension of lithium 5-(4-trifluromethoxyphenyl)-thiophene-2-sulfinate (960 mg, 3.06 mmol) in CH2Cl2 (30 mL) is added N-chlorosuccinimide (408 mg, 3.06 mmol) and the mixture is stirred at 0 C. for 15 minutes, then warmed to room temperature and stirred for an additional 15 minutes. The reaction mixture is filtered, rinsed with CH2Cl2, and concentrated in vacuo. Flash chromatography using EtOAc/Hexane (1:1) yields 5-(4-trifluromethoxyphenyl)-thiophene-2-sulfonyl chloride.
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; for 19h;Heating / reflux;
To a solution of 1-BROMO-4-(TRIFLUOROMETHOXY) BENZENE (0.90 g, 3.7 mmol) in tetrahydrofuran (20 ml) was added a solution of 2- (4-methoxyphenyl)-4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolane (0.36 g, 1.54 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0 mmol), [1, 1-BIS (diphenylphosphino) FERROCENE] dichloropalladium (II) (40 mg, 0.077 mmol) and water (0.20 ml) and the mixture refluxed under nitrogen for 19 h. The reaction mixture was tipped into water (150 ml) and extracted with ether (2x50 ML), the ether extract then dried (MgSO4) and evaporated to give a tan semi-solid (0.801 g). Purification by column chromatography (silica gel, 4: 1 hexane/chloroform) afforded 4- METHOXY-4 -(TRIFLUOROMETHOXY)-1, 1 -BIPHENYL (36) as a white solid (0.33 g, 80%). LH NMR (CDCl3, 300 MHz) 3. 86, s, 4-OME ; 6.99, d (8. 7 Hz), H3,5 ; 7.26, d (8.1 Hz), H3', 5 ; 7.49, d (8. 7 Hz), H2,6 or H2', 6 ; 7. 55, d (8.7 Hz), H2', 6' or H2,6. APCI (+ve) MS M/Z268 (M+, 80%).
2,6-bis(methyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine[ No CAS ]
[ 407-14-7 ]
[ 777063-42-0 ]
Yield
Reaction Conditions
Operation in experiment
53%
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; for 43h;Heating / reflux;
To a solution of 1-BROMO-4- (TRIFLUOROMETHOXY) benzene (0.92 g, 3. 86 mmol) in tetrahydrofuran (20 ml) was added A solution of 2, 6-DIMETHOXY-3- (4, 4, 5, 5-TETRAMETHYL-1, 3, 2-DIOXABOROLAN-2-YL) pyridine (0.40 g, 1.50 mmol) in tetrahydrofuran (10 ml), potassium carbonate (0.42 g, 3.0 MMOL), [L, L-BIS (DIPHENYLPHOSPHINO) FERROCENE] DICHLOROPALLADIUM (II) (40 mg, 0.077 mmol) and water (40 mul) and the mixture refluxed under nitrogen for 43 h. Water (50 ml) was added to the reaction mixture and stirring continued at RT for 10 min followed by extraction with ether (2X50 ML). THE ether extract was then dried (MGSO4) and evaporated to give a dark mobile oil (0.504 G). Purification by column chromatography (silica gel, 3: 1 hexane/dichloromethane) afforded 2, 6-DIMETHOXY-3- [4- (TRIFLUOROMETHOXY) PHENYL] PYRIDINE (14) as a clear, colourless oil (0. 372 g, 83%). 1H nmr (CDCL3, 300 MHz) 3.97, s, 2x OMe; 6.40, d (8.1 Hz), H5; 7.24, d (8.4 Hz), H3 , 5 ; 7.55, m, H2,2', 6'. ESI (+ve) MS m/z300 (M+H, 100%).
A mixture of 4- (trifluoromethoxy) bromobenzene (2. 41 g, 10. 0 mmol), 4-hydroxypiperidine (1. 21 g, 12. 0 mmol), tris (dibenzylideneacetone) dipalladium (O) (137 mg, 0. 15 mmol), and 2- (DI-T- butylphosphino) biphenyl (107 mg, 0. 36 mmol) under N2 was combined with lithium bis (trimethylsilyl) amide (1. 0 M in THF, 22 ML, 22 mmol). The reaction mixture was heated at 65C for 2 h, and then was cooled to ambient temperature and quenched with 1 N HCl (35 mL) to pH 7. The resulting mixture was extracted with EtOAc (20 mL), and the organic extract was rinsed with brine, dried over MgS04, and the solvent was removed. The residue was subjected to flash chromatography (2% 7N methanol ammonia in CH2C12), and a waxy, amber solid was obtained upon solvent removal (1. 4 g, 54% yield) : H NMR (CDC13) 5 7. 02 (d, 2 H, J= 8. 7 Hz), 6. 83 (d, 2 H, J= 8. 4 Hz), 3. 79 (m, 1 H), 3. 45 (m, 2 H), 2. 86 (m, 2 H), 1. 94 (m, 2 H), 1. 62 (m, 2 H), 1. 49 (s, 1 H) ; MS LNLZ 261. 9 (M+).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere;
To a suspension of <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> (20.0 g, 83.0 mmol), compound tert-butyl piperazine-1-carboxylate (18.6 g, 99.6 mmol) in dioxane (100 mL) was added Cs2CO3 (37.8 g, 166 mmol) and Pd2(dba)3 (1.20 g), Xantphos (1.20 g) under nitrogen. The reaction mixture was stirred at 120 C under nitrogen for 16 hours. TLC and LCMS showed the reaction was finished. Water (200 mL) was added and the mixture was extracted with EtOAc (100 mLx3 ). The combined organic layers were washed with brine (100 mLx2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with MTBE (50 mL) to afford compound c1 (18.8 g, 65% yield) as a red solid.
13%
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 100℃; for 4h;
To a mixture of cesium carbonate (1.88 g, 5.7 mmol), palladium (II) acetate (46.1 mg, 0.205 mmol), rac-2,2'-Bis (diphenylphosphino)-l, 1 -BINAPHTHYL (192 mg, 0.31 mmol), TERT-BUTYL-1-PIPERAZINE carboxylate (928mg, 4.93 mmol) and 1-BROMO-4- (TRIFLUOROMETHOXY) benzene (lg, 4.11 mmol) was added degazed toluene (10 ML). The mixture was heated to 100C for 4 hours. The mixture was cool to room temperature, diluted with ethylacetate, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silica gel: eluent: heptane/ethylacetate 0-10% over 20 minutes to provide the title compound (180 mg, 13%) as a yellow solid, MS (M/E) : 347.4 (M+H, 100%)
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene;Inert atmosphere; Reflux;
The starting material reagent 1 (p-trifluoromethoxy- bromobenzene ; l-Bromo-4- (trifluoromethoxy) benzene) was used. To a solution of reagent 1 (2.41 g, 10 mmol) in toluene (50 mL) were consecutively added the following compounds: reagent 2 (1- Boc-piperazine ; tert-butyl piperazine-l-carboxylate) (1.68 g, 9 mmol), Pd2(dba) 3 (tris- (dibenzylidenacetone) dipalladium) (290 mg, 0.5 mmol), 2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (BINAP) (311 mg, 0.5 mmol) and sodium t-butoxide (1.92 g, 20 mmol) . The mixture was refluxed under N2 atmosphere overnight. The solvent was evaporated to provide crude reagent 3 (tert-butyl 4- (4- (trifluoromethyl) -phenyl) -piperazine-l-carboxylate) as a residue .
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene;Reflux; Inert atmosphere;
The starting material reagent 1 (p-trifluoromethoxy-bromobenzene; 1 -Bromo-4-(trifluoromethoxy) benzene) was used. To a solution of reagent 1 (2.41 g, 10 mmol) in toluene (50 mL) were consecutively added the following compounds: reagent 2 (1-Boc-piperazine; tertbutyl piperazine-1-carboxylate) (1.68 g, 9 mmol), Pd2(dba)3 (tris-(dibenzylidenacetone)dipalladium) (290 mg, 0.5 mmol), 2,2?-bis(diphenylphosphino)-l , 1 ?-binaphthyl (BINAP) (311 mg, 0.5 mmol) and sodium t-butoxide (1.92 g, 20 mmol). The mixture was refluxed under N2 atmosphere overnight. The solvent was evaporated to provide crude reagent 3 (tert-butyl 4-(4-(trifluoromethyl)-phenyl)-pipera- zine-1-carboxylate) as a residue.
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃; for 8h;Inert atmosphere;
A mixture of 1 -bromo-4-(trifluoromethoxy)benzene (4000 mg, 16.60 mmol), tert-butyl piperazine-1 -carboxylate (3400 mg, 18.26 mmol), BINAP (3100 mg, 4.98 mmol), Pd2(dba)3 (1520 mg, 1 .660 mmol) and NaOtBu (1914 mg, 19.92 mmol) in toluene (5 mL) was degassed for a couple of times and refilled with N2. Then the mixture was heated at 110 C for 8 h, followed by aqueous work up and extracted with EtOAc. Organic layer was dried over Na2S04 and concentrated to give a crude, which was purified by ISCO with 0-50% EtOAc in hexanes to give the desired product. M/Z (M+H) = 347.1 .
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 16h;Heating / reflux;
Intermediate 2: (3i?)-3-methyl-l-(4-trifluoromethoxyphenyl)-piperazine; To a mixture of (R)-2-methylpiperazine (3.0 g, 30 mmol), 4-trifluoromethoxy bromo benzene (6.6 g, 27.5 mmol) and sodium tert-butoxide (3.56 g, 37.5 mmol) in dry toluene (50 mL) under nitrogen atmosphere, were added Pd(OAc)2 (0.28 g, 12.5 mmol) followed by BINAP (0.62 g, 1 mmol) and refluxed for 16 h. Then the reaction mixture was concentrated and the crude compound was purified by clolumn chromatography on silica gel using chloroform and methanol as eluent to give the title compound as a dark brown liquid (3 g, 38 %).
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20℃; for 1h;Heating / reflux;
Intermediate 23;: l-[4-(trifluoromethoxy)phenyl]piperazine, dihydrochloride; HCI HCI ^ nFA solution of piperazine (2.0 g, 23.2 mmol), l-bromo-4-(trifluoromethoxy)benzene (5.6 g, 23.2 mmol) and sodium tert-butoxide (3.3 g, 34.8 mmol) was prepared in anhydrous toluene (50 mL). The solution was degassed by argon bubbling for 10 min. Then palladium(II) acetate (260 mg, 1.16 mmol) and (+/-)-BINAP (580 mg, 0.93 mmol) were added. The resulting mixture was slowly heated from RT to reflux and maintained at reflux for 1 hour. Then the reaction mixture was cooled to RT and concentrated under reducedpressure. The residue was taken up with Et2O (200 mL), filtrated on Celite and washed with brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure to give a dark brown oil. Purification by flash chromatography (DCM/MeOH/25% aq. ammonia 80/20/2) gave a brown oil. This oil was taken up with DCM/Et2O and treated with activated charcoal at RT for 10 min. After filtration on Celite, the solution was concentrated under reduced pressure. Then a solution of HC1 1M in Et2O (25 mL) was added dropwise. Filtration of the precipitate, washing with Et2O and drying under reduced pressure gave 2.87 g (39%) of the title compound as a white powder. M+(ESI): 247.2. HPLC (Condition A), Rt: 2.4 min (HPLC purity: 98.6 %).
[0104] Piperazine [(0.] 588g, 6. [84MMOL),] Pd (II) acetate [(0.] 027g, 0. [123MMOL),] sodium t- butoxide (0.837g, 10. [06MMOL)] and BINAP (0.154g, 0. [286MMOL)] were stirred at room temperature in 10 mL dry toluene for 15 min. 4-trifluoromethoxy bromo benzene (1.5 g, 6. [22MMOL)] in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at [110C] for 20 hrs. The reaction mixture was filtered through a celite bed, washed with toluene, concentrated, ethyl acetate added and then extracted with 1.5 (N) aqueous [HCL] solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated to afford the product.
diisopropyl (2S,3R)-2-hydroxy-3-{(2E)-3-[4-(trifluoromethoxy)phenyl]-2-propenyl}butanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.2%
With triethylamine;palladium diacetate; tris-(o-tolyl)phosphine; In acetonitrile; at 80℃; for 14h;
Intermediate 10: (2R)-2-[(4S)-2,2-dimethyl-5-oxo-l,3-dioxolan^-yl]-5-[4-(trifluoromethoxy)phenyl]pentanoic acid; o ^-o oStep a); Formation ofdiisopropyl (2S,3R)-2-hydroxy-3-{(2E)-3-[4-(trifluoromethoxy)phenyl]-2-propenyl}butanedioate; OH OTo a solution ofdiisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (Intermediate 2a, 5.0 g; 19.4 mmol; 1.0 eq.), TEA (6.23 mL; 46.5 mmol; 2.4 eq.) in CH3CN (50.0 mL) was added l-bromo^-(trifluoromethoxy)benzene (5.13 g; 21.3 mmol; 1.1 eq.). To this solution was added a sonicated mixture of tri-o-tolylphosphine (0.59 g; 1.94 mmol; 0.10 eq.) and palladium(II) acetate (43.46 mg; 0.19 mmol; 0.01 eq.) in CH3CN (4 mL). The reaction was stirred at 80C for 14 h, cooled to RT and the solvents were evaporated (rotavap). The residue was taken up in EtOAc and washed with an aqueous saturated solution of NEUCl, an aqueous saturated solution of NaHCOs and then with an aqueous saturated solution of NaCl and dried over MgSC>4. Evaporation of the solvent gave an oil. Purification by chromatography (SiO2, gradient from 10/90 EtOAc/c-hex to 100/0 EtOAc/c-hex in 30 min.) gave a colorless oil (6.98 g, 86.2%). M+(ESI): 419.2; M'(ESI): 417.0.
trifluoromethoxy-4-(4-pentylphenyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With magnesium; In tetrahydrofuran;
EXAMPLE 13 A Grignard compound is prepared from 1.2 g of magnesium, 50 ml of THF and 11.4 g of 4-pentyl-bromobenzene in 25 ml of THF. When the addition is complete, the mixture is refluxed for a further I hour and cooled to 10°, and 14 g of 4-trifluoromethoxy-bromobenzene in 25 ml of THF and 0.73 g of PdCl2 (dppf) are added. The cooling is removed, but the reaction mixture should not climb above 20°. The mixture is subsequently stirred at room temperature for 16 hours, poured into 100 ml of saturated NH4 Cl solution a nd stirred for a further 15 minutes, and the organic phase is then worked up. After purification by crystallization, trifluoromethoxy-4-(4-pentylphenyl)benzene having C 67° I is obtained.
trifluoromethoxy-4-(4-pentylphenyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With magnesium; In tetrahydrofuran;
Example 13 A Grignard compound is prepared from 1.2 g of magnesium, 50 ml of THF and 11.4 g of 4-pentyl-bromobenzene in 25 ml of THF. When the addition is complete, the mixture is refluxed for a further 1 hour and cooled to 10° and 14 g of 4-trifluoromethoxy-bromobenzene in 25 ml of THF and 0.73 g of PdCl2 (dppf) are added. The cooling is removed, but the reaction mixture should not climb above 20°. The mixture is subsequently stirred at room temperature for 16 hours, poured into 100 ml of saturated NH4 Cl solution and stirred for a further 15 minutes, and the organic phase is then worked up. After purification by crystallization, trifluoromethoxy-4-(4-pentylphenyl)benzene having C 67° I is obtained.
Trans-4-(4-(4-trifluoromethoxyphenyl)phenyl)-1-n-pentyl-1-silacyclohexane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With magnesium;tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran;
[Example 11] (Preparation of 4'-(trans-4-n-pentyl-4-silacyclohexyl)-4-trifluoromethoxybiphenyl) 6.5 g (20 mmol) of p-(trans-4-n-pentyl-4-silacyclohexyl) bromobenzene was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a THF solution of 2.1 g trimethyl borate, and a boric acid derivative was obtained by means of hydrolysis by acid. This solution was then dripped into a 50 ml THF solution of 4.8 g (20 mmol) of p-trifluoromethoxybromobenzene and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-4-trifluoromethoxybiphenyl. This was then purified by means of chromatography to obtain 7.4 g of the target product (yield 91%). The results of its analysis are shown below.
4-(trans-4-n-propyl-1-methyl-1-silacyclohexyl)-1-bromobenzene[ No CAS ]
[ 407-14-7 ]
4'-(trans-4-propyl-1-methyl-1-silacyclohexyl)-4-trifluoromethoxybiphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With magnesium;tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran;
[Example 37] (Preparation of 4'-(trans-4-propyl-1-methyl-1-silacyclohexyl)-4-trifluoromethoxybiphenyl) 6.2 g (20 mmol) of 4'-(trans-4-propyl-1-methyl-1-silacyclohexyl) bromobenzene was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 4.8 g (20 mmol) of p-trifluoromethoxybromobenzene and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) to obtain 4'-(trans-4-propyl-1-methyl-1-silacyclohexyl)-4-trifluoromethoxybiphenyl. This was then purified by means of chromatography to obtain 6.8 g of the target product (yield 87%). IR (liquid film) numax: 2956, 2910, 2848, 1518, 1489, 1259, 1221, 1167, 1115 and 804 cm-1
4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)]-piperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine hydrochloride; A mixture of 200 g cis-2,6-dimethylpiperazine (1.75 mol), 421 g 1-bromo-4-trifluoromethoxybezene (1.74 mol), 200 g sodium-t-butoxide (2.08 mol), 10 g tris(dibenzylideneacetone)dipalladium (0.011 mol), 20 g 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (0.047 mol), and 4 L toluene was degassed through 5 vacuum-nitrogen cycles (Firestone valve) and heated to 100 C under nitrogen for 2 hours. The reaction was allowed to cool and was filtered through celite. The filtrate was concentrated under vacuum and the residue was diluted with hexanes (2 L). The mixture was filtered and the filtrate diluted with diethyl ether (2 L). To this was added concentrated HCl (150 ml, 1.8 mol) and the resulting mixture agitated briefly resulting in precipitation of the product which was collected by filtration and dried under vacuum (2 mm Hg, 14 hr) to give 467 g tan solid (86%).
To a suspension of Rieke Magnesium [(LOLMG,] 4.15mmols) in anhydrous THF [(8ML)] was added a solution of 1-bromo-4- (trifluoromethoxy) benzene in anhydrous THF [(4ML).] The reaction was left to stand for 5 minutes then stirred for a further 5 minutes. To the resulting solution was added a solution of [1-(T-BUTOXYCARBONYL)-4-(N-METHYL-N-METHOXYCARBAMOYL)] piperidine (J. [MED.] Chem. 2000,43, 21,3895-3905 ; 282mg, 1.04mmols) in anhydrous THF [(4ML).] The resulting reaction was stirred at room temperature for 30 minutes then quenched with sat [NH4CI] solution [(20ML).] The reaction mixture was partitioned between water [(20ML)] and EtOAc [(20ML),] the layers were separated and the aqueous layer was reextracted with EtOAc [(10ML).] The combined organics were washed with brine [(10ML)] and dried [(MGS04),] filtered and evaporated to yield a solid. This solid was dissolved in DCM [(10ML)] and treated with TFA [(1.] 5ml), the resulting reaction was stirred at room temperature for 1 hour then diluted [TO"20ML] and washed with 1M [NAOH] [(20ML)] and brine (lOml). The DCM was evaporated under reduced pressure to yield an orange oil. This oil was loaded onto an Isolute SCX-2 column which was then flushed through with MeOH, when all impurities had eluted the product was eluted off with [1% NH3/MEOH] solution. The product was dissolved in [ETOH] [(20ML)] and treated with [1.] 1eq of [1M HCI] in ether. The solvent was then evaporated to yield the title compound (80mg, [25%).] M/z 274.
5-bromo-4-methoxy-2-methoxymethoxybenzaldehyde[ No CAS ]
[ 407-14-7 ]
[ 75-36-5 ]
[ 1153673-91-6 ]
Yield
Reaction Conditions
Operation in experiment
78%
To a solution of <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> (0.14 mL, 0.91 mmol) in THF (8 mL) was added t-BuLi (1.7 M in pentane, 1.07 mL, 1.83 mmol) via syringe and the reaction mixture was stirred for 1 h at -78 C. At that time, a solution of 5-bromo-4-methoxy-2-(methoxymethoxy)benzaldehyde (0.25 g, 0.91 mmol) in THF (2 mL) was added via syringe. The resulting mixture was warmed up and stirred at room temperature for 2 h. At that time, the reaction mixture was cooled in an ice bath for 10 min. Acetyl chloride (0.13 mL, 1.83 mmol) was added slowly via syringe and then the resulting mixture was warmed to room temperature and stirred for 2 h. Water (10 mL) and EtOAc (10 mL) were added and the two phases were separated. The aqueous layer was extracted with EtOAc (2 x 15 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica (15% EtOAc/hexanes) to furnish the desired product (0.34 g, 0.71 mmol, 78%) as a colorless oil.
With potassium carbonate; XPhos;bis(dibenzylideneacetone)-palladium(0); In tert-butyl alcohol; at 90℃;Inert atmosphere;
A compound obtained in Reference Example 3 was dissolved in t-BuOH under nitrogen atmosphere, l-bromo-4-(trifluoromethoxy)benzene, potassium carbonate,2-dicyclohexyl-2',4',6'-triisopropylbiphenyl (X-Phos) and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) were added to the mixture, and the mixture was subjected to a deaeration operation, followed by stirring the reaction liquid overnight at 900C. The reaction liquid was cooled to room temperature, thereafter poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate twice. The extract was washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. Sodium sulfate was filtered off, and the filtrate was removed under reduced pressure. The residue was purified through silica gel chromatography (hexane:ethyl acetate = 100:0-40:60) to yield the compound of interest as a white solid.The analytical data of the title compound are shown below.1 H-NMR(CDCl3 )delta:1.69(6H,s),3.39(3H,s),3.56(lH,dd,J=12.0,8Hz),4.24(lH,dd,J=12.0,8Hz),4.74(lH,d t,J=12.0,8Hz),6.67(2H,d,J=8Hz),6.76(lH,s),6.95-7.22(8H,m),7.79(2H,dd,J=12.0,8Hz). ESI-MS(m/e):557[M+H]+
Intermediate 10 1,1-dimethylethyl 4-hydroxy-4-{4-[(trifluoromethyl)oxy]phenyl}-1-piperidinecarboxylate A solution of 0.893 ml of 1-bromo-4-[(trifluoromethyl)oxy]benzene in 6.0 ml of dry THF under argon atmosphere was cooled to -780C and 3.6 ml of n-BuLi 2.0 M were added. The reaction mixture was stirred at -780C for 45 min and then was added a solution of 1.437 g of 1 ,1-dimethylethyl-4-oxo-1-piperidinecarboxylate in 6.0 ml of THF. The reaction mixture was stirred at -780C for 1 h, then was quenched with 10 ml of mixture 1 :1 of sat. NH4CI and H2O. This mixture was stirred at room temperature and extracted with EtOAc three times (3 x 20 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel eluting with Et2O-HeX 10:90 to 50:50 to afford 1.802 mg (83%) of the title compound as a white solid.1H NMR (delta, ppm, CDCI3): 7.50 (d, 2H); 7.21 (d, 2H); 4.05 (br d, 2H); 3.23 (td, 2H); 1.98 (td, 2H); 1.71 (d, 2H); 1.48 (s, 9H). [ES MS] m/z: 262 (MH+).
40%
(1) 4-hydroxy-4-(4-(trifluoromethoxy)phenyl)piperidine-1-formic acid tert-butyl ester[0074] 4-trifluoromethoxy bromobenzene (2.41 g, 10 mmol) was dissolved in dry tetrahydrofuran (30 ml), cooled to -78 C, to which slowly added dropwise n-butyllithium (1.6 M n-hexane solution, 6.5 ml), kept the temperature below -70 C during the dropwise adding procedure, after adding, kept stirring this system for 20 min, added 4-carbonyl piperidine-1-formic acid tert-butyl ester (1.99 g, 10 mmol) in tetrahydrofuran solution, kept the temperature below -70 C during the dropwise adding procedure, after adding, the temperature can be increased to room temperature while stirring for 15 h. After the reaction was finished, added saturated ammonium chloride aqueous solution to quench reaction, partitioned, organic phases were washed by saturated saline, followed by anhydrous sodium sulphate drying, concentration, column chromatography (PE : EA = 15:1) to give 1.6 g light yellow gel-like substance, yield: 40 %.MS (ESI/LR): 362.2 [M+1]+.
With potassium phosphate; palladium diacetate; In N,N-dimethyl acetamide; at 140℃; for 12h;Inert atmosphere;
Step 1. 4-[(E)-2-(4-Trifluoromethoxyphenyl)-vinyl]-benzonitrile. To a round bottom flask flushed with nitrogen was added potassium phosphate, tribasic (617 mg, 2.9 mmol) in dimethyl acetamide (DMA; 2 mL), 4-trifluoromethoxy bromobenzene (500 mg, 2.1 mmol) and 4-cyanovinylbenzene (322 mg, 2.5 mmol), followed by palladium acetate (23 mg, 5 mol %). The solution was heated to 140 C. with stiffing for 12 h. The solution was then allowed to cool to room temperature, poured into H2O, extracted with EtOAc, and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (EtOAc in hexanes, 0-75%) to furnish a yellow solid (543 mg, 90%) that was pure by gas chromatography/mass spectral (GC-MS) analysis. This material was used directly in next reaction without further purification. Step 2. 4-[(E)-2-(4-Trifluoromethoxyphenyl)-vinyl]-benzaldehyde. The cyano diphenyl styrene (543 mg, 1.88 mmol) was dissolved in dry CH2Cl2 (10 mL) and cooled to -78 C. in a dry ice/acetone bath. To this solution was added dropwise diisobutylaluminum hydride in hexanes (3.7 mL, 3.7 mmol). The reaction was allowed to stir 4 h while warming to room temperature. The desired aldehyde was formed exclusively by GC-MS. Water and methanol were added to the reaction mixture, which caused bubbling and gel formation. The heterogeneous mixture was diluted with CH2Cl2 and filtered through a Biotage phase separator frit. The organic layer was collected and concentrated to give a yellow solid (450 mg, 81%) that was pure product by GC-MS. The product was used directly in the next reaction without further purification. Step 3.
With caesium carbonate; XPhos;palladium diacetate; In toluene; for 6h;Reflux;
To degassed toluene (200 mL) was added palladium acetate (0.21 g, 0.9 mmol) and x-phos (0.89 g, 1.9 mmol) and the mixture degassed a further 5 minutes. To the reaction mixture was then added cesium carbonate (24.3 g, 74.6 mmol), beta alanine ethyl ester hydrochloride (4.3 g, 28 mmol) and 1-bromo-4-trifluoromethoxybenzene (4.5 g, 18.7 mmol). The reaction mixture was heated at reflux for 6 hours, cooled and filtered through a pad of celite. Filtrate concentrated and the residue purified on silica gel eluding with a gradient from 10% to 15% ethyl acetate in heptane to give ethyl 2-(4-(trifluoromethoxy)phenylamino)acetate (3.35 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3): delta ppm 1.26 (t, 3H), 2.60 (t, 2H), 3.42 (t, 2H), 4.16 (q, 2H), 6.57 (dd, 2H), 7.03 (dd, 2H).
Reference Example 8; 3' -formyl-4' - (trifluoromethoxy) biphenyl-4-carbonitrile; To a solution of diisopropylamine (3.5 mL) in THF (50 mL) was added a 1.6 mol/L n-butyllithium in hexane solution (15 mL) at 00C. After cooling the reaction mixture to -78C, 1- bromo-4- (trifluoromethoxy) benzene (6.0 g) was added, and the mixture was stirred for 2 hr. Then, morpholine-4-carbaldehyde (8.6 g) was added to the reaction mixture, and the mixture was concentrated to dryness under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent EPO <DP n="86"/>gradient; 0-»30% ethyl acetate/hexane) to give 5-bromo-2- (trifluoromethoxy) benzaldehyde (5.04 g, 75%) as a colorless oil.
a) A solution of <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> (62) (23.4 g, 97.0 mmol, WACO) in diethyl ether (30 ml) was added dropwise over 30 minutes to a suspension of magnesium (2.60 g, 107 mmol) and catalytic amount of iodine in diethyl ether (8 ml) and the whole was stirred at room temperature for 1 hour. Trifluoroacetic anhydride (TFAA) (17.8 ml, 126 mmol) was added dropwise to the reaction mixture at 0 C. and stirred at room temperature for 1 hour. The reaction was quenched with aqueous HCl solution, extracted with ethyl acetate, washed with NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 1/99 to 20/80) to give 2,2,2-trifluoro-1-(4-trifluoromethoxyphenyl)ethanone (63) (599 mg, yield 2%) as colorless oil.
With palladium diacetate; silver nitrate; at 150℃; for 48h;Inert atmosphere;
General procedure: Aryl bromides (0.5 mmol) and AgNO3 (85 mg, 0.5 mmol) and Pd(OAc)2 (11.2 mg, 0.05 mmol) were added to Schlenk tubes. Benzene (4 ml) was added to the tubes using a syringe. The mixture was then stirred in a sealed tube under argon atmosphere. Then the mixture was stirred at 150 C until complete consumption of the starting material was monitored by TLC. After completion of the reaction, the mixture was diluted with ethyl acetate, passed through a fritted glass filter to remove the inorganic salts and the solvent was removed with the aid of an rotary evaporator. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to provide the desired product.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 120℃; for 2h;
To a solution of l-bromo-4-(trifluoromethoxy)benzene (0.50 g, 2.07 mmol) in DME (6 mL) were added 3-cyanophenyl boronic acid (0.37 g, 2.49 mmol), 1,1 '- bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.046 g, 0.062 mmol) and Na2C03 (2 mL of aqueous solution, 0.44 g, 4.14 mmol). The resulting mixture was stirred at 120 C for 2h. After removal of organic solvent, the resulting residue was dilited with water (10 mL) and extracted with methylene chloride (10 mL x 2). The organic layer was dried over MgS04 and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography (n-hexane : ethyl acetate = 10 : 1 ratio) to give a Jl.
With tetrabutylammomium bromide; palladium diacetate; sodium carbonate; In water; at 150℃;Microwave irradiation; Sealed vessel;
General procedure: Method A. A solution of Pd(OAc)2 (25.2 mg, 0.112 mmol) and triphenylphosphine (147 mg, 0.560 mmol) in absolute ethanol (4 mL) and anhydrous toluene (4 mL) was stirred at RT under nitrogen for 10 min. After that period, commercially available 5-chloro-2-nitrotoluene 4 (646 mg, 3.76 mmol), 4 mL of 2M aqueous Na2CO3, and the appropriate boronic acid R1B(OH)2 (6.03 mmol) were sequentially added. The resulting mixture was heated at 100 C in a sealed vial under nitrogen overnight. After being cooled to RT, the mixture was diluted with water and extracted with EtOAc. The combined organic phase were dried and concentrated. The crude product was purified by flash chromatography over silica gel column using n-Hex/EtOAc or CHCl3/MeOH mixtures as the eluent.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; for 48h;Inert atmosphere; Reflux;
To a solution of 1-bromo-4-trifluoromethoxybenzene 19a (345.5 mg, 1.43 mmol) in DMF (3 mL), tributyl(vinyl)tin (500 mg, 1.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (82.8 mg, 0.072 mmol) were added. The reaction mixture was then refluxed for 2 days and then evaporated to dryness. The residue was diluted with DCM and washed with saturated aqueous sodium chloride. The aqueous layer was extracted with DCM three times. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated. The crude compound was purified by column chromatography to give 20a. Yield 60%. 1H NMR (400 MHz, CDCl3) delta 7.37 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 6.65 (dd, J=17.6, 10.9 Hz, 1H), 5.68 (d, J=17.6 Hz, 1H), 5.24 (d, J=10.4 Hz, 1H).
1 -bromo-4-(trifluronnethoxy)benzene (1 .95 g, 8.10 mmol) was dissolved in anhydrous tetrahydrofuran (8 ml_). To a stirred mixture of magnesium (194.4 mg, 8.10 mmol) and iodine (5 mg) in anhydrous tetrahydrofuran (2 ml_) under nitrogen was added the solution of 1 -bromo-4-(trifluromethoxy)benzene (2 ml_) under N2 at 0 C and then the solution was warmed to 40 C and the remainder of the 1 -bromo-4-(trifluromethoxy)benzene solution (6 ml_) was added dropwise. The reaction was heated to reflux for 1 hour and then cooled to -78 C prior to the addition of the product of Example 1 b (250 mg, 1 .62 mmol). The reaction was stirred at this temperature for 2 hours. The mixture was quenched by the addition of saturated aqueous ammonium chloride (20 ml_) at 0 C. The solution was warmed to room temperature and then extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 80/1 -> 60/1 ) to afford the title compound as a white solid (190 mg, Yield: 39 %). Mp = 29-33 C; Rf = 0.4 (10:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCI3) delta 7.42 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 5.10 (d, J = 5.2 Hz, 1 H), 1 .87-1 .80 (m, 1 H), 1 .77 (d, J = 5.6 Hz, 1 H), 1 .62 (d, J = 13.2 Hz, 1 H), 1 .50-1 .38 (m, 4 H), 1 .31 -1 .23 (m, 1 H), 1 .14 (s, 3 H), 1 .06 (s, 3 H), 1 .00-0.89 (m, 1 H), 0.58 (d, J = 6.4 Hz, 3 H) ppm; Mass spectrum (El +ve) m/z 316 (M+); [a]D25 = -1 .00 (c = 0.20, dichloromethane).
4-carbonyl piperidine-1-formic acid tert-butyl ester[ No CAS ]
[ 1236000-59-1 ]
Yield
Reaction Conditions
Operation in experiment
40%
(1) 4-hydroxy-4-(4-(trifluoromethoxy)phenyl)piperidine-1-formic acid tert-butyl ester 4-trifluoromethoxy bromobenzene (2.41 g, 10 mmol) was dissolved in dry tetrahydrofuran (30 mL), cooled to -78 C., to which slowly added dropwise n-butyllithium (1.6M n-hexane solution, 6.5 mL), kept the temperature below -70 C. during the dropwise adding procedure, after adding, kept stirring this system for 20 min, added 4-carbonyl piperidine-1-formic acid tert-butyl ester (1.99 g, 10 mmol) in tetrahydrofuran solution, kept the temperature below -70 C. during the dropwise adding procedure, after adding, the temperature can be increased to room temperature while stirring for 15 h. After the reaction was finished, added saturated ammonium chloride aqueous solution to quench reaction, partitioned, organic phases were washed by saturated saline, followed by anhydrous sodium sulphate drying, concentration, column chromatography (PE: EA=15:1) to give 1.6 g light yellow gel-like substance, yield: 40%. MS (ESI/LR): 362.2 [M+1]+.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;
Example 270C. N-(4-(3,4-dichlorophenyl)butan-2-yl)-4-hydroxy-5-oxo-l-(3-(4- (trifluoromethoxy)phenyl)prop-2-ynyl)-2,5-dihydro-lH-pyrrole-3-carboxamide[00285] The mixture of l-Bromo-4-(trifluoromethoxy)benzene (37 mg, 0.15 mmol), Example 270B (60 mg, 0.15 mmol), (copper (I) iodide (6 mg, 0.03 mmol), triphenylphosphine (8 mg, 0.03 mmol) and bis(triphenylphosphine)palladium chloride (1 1 mg, 0.015 mmol) in dimethylformamide (1.0 niL) and diethylamine (1.0 niL) was filled with nitrogen and evacuated with vacuum three times. The reaction mixture was subject to microwave irradiation at 120C for 20 min. After cooling to rt, the solvents were evaporated to afford a dark brown residue which was dissolved in methanol and purified by reverse phase preparative HPLC (Method U) to afford Example 270C (15 mg, 18%) as a clear oil. LC/MS (HPLC Method L): RT = 2.38 min, [M+l]+ 541.0.
Step 2 1-bromo-4-(trifluoromethoxy)benzene Trifluoromethoxybenzene 6c (11.35 g, 70 mmol) was dissolved in 3.57 mL liquid bromine, followed by addition of iron (0.24 g). The reaction mixture was stirred for 16 hours at 100 C. 450 mL of dichloromethane were added and the organic extract was washed with 6 M hydrochloric acid (140 mL), 10% sodium hydrogen sulfite solution (140 mL) and saturated sodium chloride solution (140 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 1-bromo-4-(trifluoromethoxy)benzene 6d (14.1 g, yellow solid), yield: 83.8%. 1H NMR (400 MHz, CDCl3): delta 7.54-7.50 (m, 2H), 7.11-7.09 (m, 2H).
Step 3 1-bromo-magnesium-4-(trifluoromethoxy)benzene Magnesium (0.12 g, 5 mmol) and iodine (I2, catalytic) were added into the reaction flask, followed by dropwise addition of a solution (5 mL) of <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> 6d (1.2 g, 5 mmol) in THF. The reaction mixture was refluxed for 1 hour to obtain the title compound 1-bromo-magnesium-4-(trifluoromethoxy)benzene 6e (1.32 g), which was used directly in the next step without purification.
With lithium chloride; In tetrahydrofuran; at 0 - 25℃; for 0.5h;Inert atmosphere; Schlenk technique;
General procedure: A dry and argon-flushed Schlenk tube, equipped with a magnetic stirring bar and a rubber septum, was charged with LiCl (0.42 g, 10.0 mmol, 1.20 equiv) and heated at 450 C under high vacuum for 5 min. After cooling to r.t. under vigorous stirring, Mg turnings (0.47 g, 19.2 mmol, 2.40 equiv) and freshly distilled THF (8 mL) were added. The mixture was cooled to 0 C, the corresponding aryl bromide (8.00 mmol, 1.00 equiv) was added and the reaction mixture was allowed to warm to r.t. The completion of the metalation was monitored by GC analysis of hydrolyzed and iodolyzed aliquots. When the oxidative insertion was complete, the solution was transferred to another predried and argon-flushed Schlenk tube, before titrating against I2. The remaining arylmagnesium halide was cooled to 0 C and transmetalated with a solution of MnCl2·2LiCl (0.55 equiv, 1.0 M in THF). The resulting bis-(aryl)manganese reagent was titrated with an iodine solution one more time before use.
General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH4Cl. (The actual temperature/reaction time is listed for each substrate.)
A solution of l-bromo-4-(trifluoromethoxy)benzene (1.0 g, 4.18 mrnol) in CISO3H (10 mL) was stirred at room temperature overnight. TLC showed the starting material was consumed completely. The reaction mixture was poured into ice water (10 mL) and extracted with DCM (15 x3). The combined organic layer was wash with brine (10 mL), dried over Na2S04 and concentrated in vacuum to give 1 g (yield: 70%) of 5-bromo-2- (trifluoromethoxy)benzene-l-sulfonyl chloride as colorless oil.
tetrahydro-2H-pyran-4-yl(4-(trifluoromethoxy)phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
812 mg
B) tetrahydro-2H-pyran-4-yl(4-(trifluoromethoxy)phenyl)methanone To a solution of 1-bromo-4-(trifluoromethoxy)benzene (2.78 g) in tetrahydrofuran (76.8 mL) was slowly added 1.6 M n-butyllithium/hexane solution (7.20 mL) at -78C. The reaction mixture was stirred at -78C for 30 min under nitrogen atmosphere, a solution of <strong>[156353-01-4]N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide</strong> (665 mg) in tetrahydrofuran (1.00 mL) was added thereto at -78C. The reaction mixture was stirred at room temperature for 2 hr under nitrogen atmosphere, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (812 mg). MS (API+): [M+H]+275.1.
[000456] To a solution of Compound 37A (2 g, 8.3 mmol) in THF (30 mL) was added n-BuLi (4 mL, 2.5 M) under N2 at -60 C. The mixture was stirred for 1 h, Compound 8C (2.2 g, 8.3 mmol) in THF (10 mL) was added. Stirred at rt for 15 min, the mixture was diluted with aq NH4C1 (40 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL x 2), and evaporated to dryness. The crude product was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 37B (1.4 g, yield 40%) as colorless oil. LC-MS (m/z): 426 [M+l]+.
2-(4-trifluoromethoxy)phenyl-2H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 120℃; for 24h;Inert atmosphere;
Compound 8 was prepared by adapting a procedure described. 13 A degased solution of Pd2(dba)3 (20 mg, 90 mumol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (104 mg, 0.22 mmol) in toluene (6 mL) was heated at 120 C for 5 min and transferred to a degased mixture of K3PO4 (5.1 g, 24 mmol), 1,2,3-triazole (0.83 mL, 14 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (1.8 mL, 12 mmol) in toluene (6 mL). The resulting mixture was heated under argon at 120 C for 24 h. CH2Cl2 (30 mL) was added, the organic phase was washed with NH4Cl-saturated water (10 mL) and brine (10 mL), and the solvent was evaporated. The crude product was purified by chromatography over silica gel (eluent: heptane/AcOEt 95:5) to afford the pure compound in 96% yield as a beige powder: mp <50 C; IR (ATR): 1606, 1511, 1411, 1386, 1251, 1207, 1193, 1152, 1100, 1084, 1056, 962, 949, 921, 852, 821, 731, 664 cm-1; 1H NMR (CDCl3, 300 MHz) 7.32-7.36 (m, 2H), 7.82 (s, 2H), 8.11-8.15 (m, 2H); 13C NMR (CDCl3, 75 MHz) 120.4 (2CH), 120.6 (q, C, J = 256 Hz), 122.0 (2CH), 136.0 (2CH), 138.4 (C), 148.3 (C); 19F NMR (CDCl3, 282 MHz) -58.0.
4-([4-(trifluoromethoxy)phenyl]carbonyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With n-butyllithium; In tetrahydrofuran; at -70℃; for 2h;
4-([4-(Truoromethoxy)phenylJ carbonyl}benzonitrile (6i). To a solution of n-butyllithium(8.87 ml, 12.5 mmol) in THF (30 ml) at -70C 4-bromotrifluoromethoxybenzene (3.00 g, 12.5mmol) in THF (10 ml) was added without allowing the temperature to exceed -70C. To thegrey-brown solution 1,4-dicyanobenzene (1.60 g, 12.5 mmol) was added as a suspension inTHF (10 ml). After 2 h at -70C the red suspension was quenched with aq. 2NHC1 (75 ml)and ice (about 25 g) and TBME (150 ml) was added. After separation of the organic layer theinorganic phase was extracted with TBME (2 x 30 ml). The organic phases were combined,dried over Na2SO4 and concentrated at reduced pressure. The crude product (2 g) was purifiedby silica gel flash chromatography (TBME/hept 1:8) to afford a white solid 6i (1.2 g, 33%).?H-NMR (400 MHz, CDC13): 7.35 (m, 2 H), 7.78-7.9 1 (m, 6 H).HPLC retention time: 4.95 mm
pyridin-4-yl[4-(trifluoromethoxy)phenyl]methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Pyridin-4-yl[4-(trzjluoromethoxy)phenyl] methanol (lOw, Q1=OCF3, Z=N). To an iPrMgCl LiC1 complex solution 1.3 M in THF (17 ml, 13 mmol) 1 -bromo-4-trifluoromethoxybenzene(3 g, 12.4 mmol) was added dropwise over 15 mm between -15C and -5C. The brown suspension was stirred for 1 h at 0C, for 2 h at 10C and overnight (about 16 h) at it. To this brown solution 4-pyridinecarboxaldehyde (1.2 ml, 12.4 mmol) was added dropwise over 30 mm between -15C and 0C and THF (10 ml) was added. The orange solution was allowed to warm up to it and was added to a solution of aq. sat. NH4C1 (25 ml) and water (25m1) at 0C.The inorganic layer was extracted with EtOAc (100 ml + 2 x 50 ml). The organic layers were combined, washed with aq. sat. NaC1, dried over Na2SO4 and concentrated at reduced pressure to afford a yellow oil (3.6 g). The crude product was purified by silica gel flash chromatography (EtOAc/hept 2:1) to afford a pale yellow solid lOw (2.8 g, 84%).
Bis[4-(trzjluoromethoxy)phenyl]methanone (6q, Q1=OCF3, Q30CF3).To a solution of 1- bromo-4-(trifluoromethoxy)benzene (1.45 g, 6 mmol) in THF (30 ml) n-buthyllithium solution (2.5 M in hexane, 2.3 ml, 0.35 g, 5.7 mmol) was added dropwise at -60C. After 3 h at -60C Weinreb amide 12q (1.02 g, 4 mmol) in THF (12 ml) was added dropwise at -60C.The orange solution was allowed to warm up overnight (about 16 h) to it, quenched with aq. sat. NH4C1 (50 ml) and water (50 ml) and extracted with TBME (100 ml + 2 x 50 ml). The organic layers were washed with aq. sat. NaHCO3 and aq. sat. NaC1, combined, dried over Na2SO4 and concentrated at reduced pressure to afford an orange solid 6q (1.5 g, quant).
With silver trifluoromethanesulfonate; Selectfluor; trifluoroacetic acid; In dichloromethane; water; at 55℃; for 1h;Inert atmosphere; Glovebox;
General procedure: A microwave vial (5 mL) was sealed under an inert atmosphere (Argon glovebox) with a stir bar, Selectfluor (177.1 mg, 0.5 mmol, 2 equiv), silver trifluoromethanesulfonate (12.8 mg, 0.05 mmol, 20 mol%) and aryloxydifluoroacetic acids (0.25 mmol, 1.0 equiv). To this vial DCM (1.8 mL), trifluoroacetic acid (76.5 muL, 1.0 mmol, 4.0 equiv) and water (0.2 mL) were injected. This mixture was heated for an hour at 55 C. The resulting mixture was cooled down to room temperature, diluted with dichloromethane (4 mL), washed with water (3×5 mL), brine (5 mL), dried over anhydrous MgSO4 and filtered. The dried extract was concentrated on a rotary evaporator. The resulting crude product was dissolved in a small quantity of dichloromethane and loaded on to a silica cartridge (10 g, Biotage), airdried and eluted with pentane. The pure fractions were combined and the solvent was evaporated to obtain the pure products.
2-[4-(trifluoromethoxy)phenyl]-1,3-benzothiazole-5-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
352 mg
With copper(l) iodide; (bis(tricyclohexyl)phosphine)palladium(II) dichloride; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;
a) A dried vial was charged with copper(l) iodide (0.120 g, 0.630 mmol) and dichloromethane (7.93 g, 92.5 mmol, 5.99 mL). XANTPHOS (0.401 g, 0.693 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. The solvent was removed by bubbling through with argon. The remaining solid was directly used for the next step. b) A vial was set under argon and charged with Cu(Xantphos)l (0.0471 g, 0.0613 mmol) (procedure step a), dichloro-bis(tricyclohexylphosphine)palladium(ll) (0.119 g, 0.153 mmol), cesium carbonate (2.50 g, 7.66 mmol) and toluene (6.13 mL). To the resulting mixture was added 1 ,3-benzothiazole-5- carbaldehyde (0.500 g, 3.06 mmol) and 1 -bromo-4-(trifluoromethoxy)benzene (1 .11 g, 4.60 mmol, 0.683 mL). The reaction mixture was stirred at 100C overnight. After cooling to room temperature, it was diluted with ethyl acetate and quenched with a solution of ammonium chloride saturated/water (1/1 ). The resulting suspension was filtered over celite and washed several times with ethyl acetate. The organic layer was separated and washed with water, brine, dried over anhydrous magnesium sulfate, filtered of and evaporated. The crude product was purified over flash-chromatography to give 2-[4-(trifluoromethoxy)phenyl]-1 ,3-<strong>[394223-38-2]benzothiazole-5-carbaldehyde</strong> (352 mg) as a white solid. LC-MS: tR = 1 .82 min, m/z = 323 [M+1 ]. H NMR (400 MHz, DMSO-d6) delta ppm 7.62 (d, J=8.07 Hz, 2 H) 8.00 (dd, J=8.25, 1.28 Hz, 1 H) 8.30 (d, J=8.80 Hz, 2 H) 8.42 (d, J=8.44 Hz, 1 H) 8.63 (d,J=1.10 Hz, 1 H) 10.18 (s, 1 H).
With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium tert-butylate; In toluene; at 120℃; for 5h;Inert atmosphere;
Compound 1 (4-trifluoromethoxybromobenzene) (24.10 g, 0.1 mol) and compound 2 (4-trifluoromethoxyphenylamine) (17.71 g, 0.1 mol) were added to dry toluene solution (300 mL). 1,10-Bis(diphenylphosphino)ferrocene (DPPF) (6.65 g, 12 mmol), [1,10-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct [(DPPF)PdCl2.CH2Cl2] (0.33 g, 0.4 mmol) and potassium tert-butoxide (KOtBu) (9.61 g, 0.1 mol) were added to the reaction mixture under nitrogen atmosphere. The reaction was stirred for 5 h at 120 C. After completing the reaction, the mixture was poured into water (100 mL); the organic layer was extracted with ethyl acetate and distilled water. The obtained organic layer was isolated by silica gel column chromatography using the ethyl acetate:petroleum ether (1: 9) to get the oily product. Yield 67%. 1H NMR (300 MHz, Chloroform-d) delta = 7.15 (d, J = 8.4 Hz, 4H), 7.04 (d,J = 9.0 Hz, 4H), 5.72 (s, 1H). 13C NMR (126 MHz, Chloroform-d) delta = 143.65, 142.07, 122.79, 119.09.
With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; Schlenk technique;
Preparation of intermediate BT 5 In a Shlenck reactor, a solution of <strong>[885270-86-0]6-Boc-2,6-diazaspiro[3.4]octane</strong> (CAS [885270-86- 0], 0.5g, 2.36 mmol), l-Bromo-4-(trifluoromethoxy)benzene (CAS [407-14-7], 525 mu, 3.53 mmol) and sodium terbutoxide (0.453 g, 4.71 mmol) in 1,4-dioxane (25 mL) was purged with N2. Then Palladium (II) acetate (52.9 mg, 0.236 mmol) and Xantphos (0.136 g, 0.236 mmol) were added, the mixture was purged again with N2 and stirred at 10 100C for 2h. The mixture was combined filtered on a pad of Celite. The cake was washed with EtOAc and the fitlrate was evaporated in vacuo to give 1.2 g as a brown solid. The residue was purified by preparative LC (irregular SiOH, 15-40 muiotaeta, 50 g, Merck, dry loading (Celite), mobile phase gradient: from Heptane/EtOAc from 95/5 to 60/40) to give 0.756 g of intermediate BT as off-white solid (80%).
With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 100℃; for 2h;Sealed tube; Inert atmosphere;
Preparation of intermediate BZ Accordingly, intermediate BZ was prepared in the same way as intermediate BV starting from intermediate BY and l-bromo-4-(trifluoromethoxy)benzene CAS [407-14-7] affording 0.369 g, 73%.
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindole-2-carboxylic acid tert-butyl ester (690 mg, 2.0 mmol, Reference: J. Med. Chem. 2007, 50 (2) 199-210) was dissolved in tetrahydrofuran (20 mL). 1-bromo-4-trifluoromethoxybenzene (578 mg, 2.4 mmol) and water (5 mL) were added. Sodium carbonate (424 mg, 4.0 mmol) was added, purged with argon, tetrakis(triphenylphosphine)palladium (114 mg, 0.1 mmol) was added, reacted overnight at 80 C, diluted with water (50 mL), extracted with ethyl acetate (30 mL * 3). The ethyl acetate layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, dried solvent, column chromatographed (CH2Cl2 / CH3OH = 100/1) and the resulting intermediate product was directly charged to the next step. The intermediate was added to methylene chloride (20 mL). The ice salt was cooled and trifluoroacetic acid (20 mL) was added. The reaction was carried out at room temperature for 3h. The residue was dissolved in dichloromethane (100 mL) and saturated sodium bicarbonate solution (50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the intermediate TH-8 (312 mg, 56% in two steps).
A solution of tert-butyl 5-hydroxyisoindole-2-carboxylate (470 mg, 2.0 mmol, References Bioorg. Med. Chem. Lett., 2001, 11 (5), 685-688) and 1-bromo-4-trifluoromethoxybenzene (481 mg, 2.0 mmol) were dissolved in 1,4-dioxane (10 mL). Cuprous iodide (38 mg, 0.2 mmol), N,N-dimethylglycine (62 mg, 0.6 mmol) and cesium carbonate (977 mg, 3.0 mmol) were added and heated under reflux under argon for 24 h. The reaction was completed, filtered, concentrated and chromatographed (CH2Cl2 / CH3OH = 100/1). The resulting product was directly charged to the next step. The intermediate was obtained by dissolving the intermediate in methylene chloride (10 mL). The ice salt was cooled, and trifluoroacetic acid (10 mL) was added. The reaction was carried out at room temperature for 3 hours to stop the reaction and concentrate. The residue was dissolved in dichloromethane (100 mL), saturated sodium bicarbonate solution (50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was dried to give the intermediate TH-1 (312 mg, 53% in two steps).
2-methyl-N-(3-(4-(trifluoromethoxy)phenyl)oxetane 3-yl) propane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
520 mg
N-Butyllithium (1.6 M hexane solution, 1.5 mL) was added to a tetrahydrofuran (6 mL) solution of 620 mg of 1-bromo-4- (trifluoromethoxy) benzene over 10 minutes under a dry ice-acetone bath And the mixture was stirred at the same temperature for 1 hour.A solution of 300 mg of 2-methyl-N- (oxetan-3-ylidene) propane-2-sulfinamide (CAS No. 1158098-73-7) in tetrahydrofuran (2 mL) was added to the reaction solution under a dry ice- After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature for 45 minutes.Saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (mobile phase: n-heptane: ethyl acetate = 100: 0-50: 50) to give the title compound (520 mg) as a pale yellow oil.
1,2,3-trimethoxy-5-(1-(4-(trifluoromethoxy)phenyl)vinyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: To a solution of N-tosylhydrazone (0.6mmol, 1.1 eq) in distilled dioxane (8mL) was added bis(acetonitrile)palladium(II) chloride (0.05mmol, 5mol %), and dppp (0.1mmol, 10mol %). The resulting suspension was stirred RT for 2min, and cesium carbonate (1.5mmol, 3.0 eq) was added. Then, the reaction mixture was stirred for additional 2min, and aryl bromide (0.5mmol, 1.0 eq) was added in one portion. The mixture was then heated at 100C for 3h. The crude reaction mixture was allowed to cool to rt. EtOAc was added, and the mixture was filtrated through Celite. The solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography on silica gel.
N′-(1-(3,5-dimethoxyphenyl)ethylidene)-4-methylbenzenesulfonohydrazide[ No CAS ]
1,3-dimethoxy-5-(1-(4-(trifluoromethoxy)phenyl)vinyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: To a solution of N-tosylhydrazone (0.6mmol, 1.1 eq) in distilled dioxane (8mL) was added bis(acetonitrile)palladium(II) chloride (0.05mmol, 5mol %), and dppp (0.1mmol, 10mol %). The resulting suspension was stirred RT for 2min, and cesium carbonate (1.5mmol, 3.0 eq) was added. Then, the reaction mixture was stirred for additional 2min, and aryl bromide (0.5mmol, 1.0 eq) was added in one portion. The mixture was then heated at 100C for 3h. The crude reaction mixture was allowed to cool to rt. EtOAc was added, and the mixture was filtrated through Celite. The solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography on silica gel.
1,3,5-trimethoxy-2-(1-(4-(trifluoromethoxy)phenyl)vinyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: To a solution of N-tosylhydrazone (0.6mmol, 1.1 eq) in distilled dioxane (8mL) was added bis(acetonitrile)palladium(II) chloride (0.05mmol, 5mol %), and dppp (0.1mmol, 10mol %). The resulting suspension was stirred RT for 2min, and cesium carbonate (1.5mmol, 3.0 eq) was added. Then, the reaction mixture was stirred for additional 2min, and aryl bromide (0.5mmol, 1.0 eq) was added in one portion. The mixture was then heated at 100C for 3h. The crude reaction mixture was allowed to cool to rt. EtOAc was added, and the mixture was filtrated through Celite. The solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography on silica gel.
With potassium tert-butylate; copper(II) oxide; In dimethyl sulfoxide; at 80℃; for 18h;Sealed tube; Inert atmosphere;
Under an argon atmosphere, copper oxide (50 mumol), iminodibenzyl substrate (1 mmol), potassium tert-butoxide (2 mmol, 2.0 equiv), 4-trifluoromethoxy substituted aromatic hydrocarbon (2 mmol, 2.0 equiv) were successively The solvent (2 mL) was added to a 10 mL sealed tube and placed in an oil bath heated to 80 C. for 18 hours. After the reaction was completed, the reaction was exposed to air quenching, and the amine product was directly separated by column chromatography.According to the results of column chromatographic separation, when DMSO was used as the reaction solvent, the yields of 4-trifluoromethoxychlorobenzene, bromobenzene, and iodobenzene respectively reacted with the substrate were: 68%, 85%, and 79%; When DMF was used as the reaction solvent, the yields of reaction of 4-trifluoromethoxy chlorobenzene, bromobenzene, and iodobenzene with the substrate were 47%, 65%, and 62%, respectively
78%
With nickel(II) oxide; potassium tert-butylate; triphenylphosphine; In tetrahydrofuran; at 100℃; for 24h;Inert atmosphere; Sealed tube; Green chemistry;
General procedure: Under an argon atmosphere, nickel oxide (0.1 mmol, 10 mol%), triphenylphosphine (0.2 mmol, 20 mol%), iminodibenzyl substrate (1 mmol), potassium tert-butoxide (2 mmol, 2.0 equiv) were sequentially 4-trifluoromethoxyhalogenated aromatic hydrocarbon (2 mmol, 2.0 equiv) and tetrahydrofuran (2 mL) were added to a 10 mL sealed tube and placed in a 100 C. oil bath with heating and stirring for 24 hours. The reaction was completed and the reaction was exposed to air quenching. , and then directly separated by column chromatography to obtain amine products.According to the results of column chromatographic separation, the yields of 4-trifluoromethoxybromobenzene and 4-trifluoromethoxy iodobenzene respectively reacted with the substrate were 78% and 69%, respectively;
Weigh 1 g of urea, add 10% sodium hypochlorite solution (8 mL), 30% sodium hydroxide solution (2 mL), and stir at room temperature for 1.0 h.Further, 0.6 mol/L of <strong>[407-14-7]1-bromo-4-(trifluoromethoxy)benzene</strong> in ethanol (2 mL) was added, and the mixture was heated to reflux temperature for 20 hours.The reaction mixture was poured into ice water (about 150 mL), the white solid was filtered, washed with water, and dried to give 261 mg of white solid, a yield of about 92.5%,The HPLC purity was 94.8%.
Weigh 1g of urea into sodium hypochlorite solution (8mL) with 10% available chlorine and 30% sodium hydroxide solution (2mL),After stirring at room temperature for 1.0h, add 0.6mol / L 1-bromo-4- (trifluoromethoxy) benzene in ethanol (2mL),Heated to reflux temperature, after 20h of reaction, the reaction solution was poured into ice water (about 150mL), resulting in a white solid,Filtration, washing with water and drying yielded 261 mg of white solid with a yield of approximately 92.5% and a HPLC purity of 94.8%.The results of MS and NMR were consistent with the data of N- (4-trifluoromethoxyphenyl) carbazide.
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 palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere; Schlenk technique;
In a Schlenck, a mixture of intermediate B (1 g, 4.40 mmol), 4-bromotrifluoromethoxy- benzene (CAS [407-14-7], 0.981 mL, 6.60 mmol) and sodium t-butoxide (1.69 g, (0187) 17.6 mmol) in 1,4-dioxane (70 mL) was degassed by N2 bubbling for 10 min before the addition of palladium acetate (0.099 g, 0.44 mmol) and Xantphos (0.255 g, 0.44 mmol). The resulting mixture was stirred at 100 C overnight, then cooled to room temperature and filtered through a pad of Celite. The cake was washed with EtOAc and the filtrate was evaporated to dryness. The residue was solubilized in EtOAc and washed with brine (2x). The organic layer was dried over MgS04, filtered and concentrated to dryness. The crude product was purified by preparative LC (Regular SiOH 15-40 muiotaeta, 24 g Grace, dry loading (SiOH), mobile phase gradient: from Heptane/EtOAc 95:5 to 70:30). The fractions containing product were combined and the solvent was removed in vacuo to give to give 1.07 g of intermediate C as an off-white solid (63%).
General procedure: To a mixture of aryl halide (0.3 mmol), NiCl2(H2O)1.5 [1] (0.0075 mmol, 2.5 mol %), was charged dry THF (1 mL). The mixture was pumped and refilled with nitrogen for three times. The resulting mixture was stirred at -10 under nitrogen for 30 min. The reaction mixture was quenched through the addition of ice MeOH, then poured into a separatory funnel containing saturated aqueous NH4Cl (ca. 5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine and dried over Na2SO4. The crude product was purified by column chromatography. Extent of isomerization can be easily determined via 1H NMR spectroscopy by comparison of the intergral of the singlet from the t-butyl group (1.3-1.4 ppm, 9H) to the integral of the doublet from the benzylic S3 protons of the i-butyl group (2.4-2.5 ppm, 2H). The doublet from the methyls of the i-butyl group could additionally be used (ca. 0.8 ppm, 6H).
1-phenyl-5-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With Ir(dF(CF3)ppy)2(bpy)PF6; Ni(4,4'-dimethoxy-2,2'-bipyridine)(H2O)2Br2; dibutylphosphoric acid tetrabutylammonium salt; In toluene; tert-butyl alcohol; at 20℃; for 48h;Inert atmosphere; Sealed tube; Irradiation;
General procedure: An 8.0 mL screw-cap vial containing a stirring bar was charged with [Ni(dMeObpy)(H 2 O) 2 (Br) 2 ] (8.5 mg, 0.018 mmol, 6 mol %), [[Ir{dF(CF 3 ) 2 ppy} 2 (bpy)]PF 6 ] (9.0 mg, 0.009 mmol, 3 mol %), amide (0.36 mmol, 1.2 equiv), aryl bromide (if solid) (0.3 mmol, 1.0 equiv) and Bu 4 N[OP(O)(OBu) 2 ] (338.8 mg, 0.75 mmol, 2.5 equiv). Next, the vial was closed, and three vacuum/argon cycles were carried out. Under inert atmosphere, a 2:1 mixture of dry t-BuOH/PhCF 3 was added (6.0 mL, 0.05 M) followed by addition of the aryl bromide (if liquid). After further sealing with Parafilm, the reaction was placed in the blue LED bay and stirred at rt until completion (a fan was added to disperse any heat coming from the blue LEDs). When completed, the reactions were taken to dryness and purified by column chromatography using an automated system (hexanes/EtOAc gradient), delivering the corresponding pure product.
1,2-bis(4-(trifluoromethoxy)phenyl) diselenide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Adapted from a reported procedure. To a 500 mL, oven-dried,three-neck flask fitted with a glass stopper, rubber septum and nitrogen inlet, equipped with a magnetic stir-bar, Mg (2.5 equiv, 600 mg) and LiCl (2.5 equiv, 1.1 g) were added, and the vessel was evacuated and heated for 5 min with a heat gun. Next, the vessel was allowed to cool down to room temperature, re-pressurized with N2, and THF (20 mL) was added via syringe. TMSCl (5 mol %,30 mL) and 1,2-dibromoethane (5 mol %, 20 mL) were added under N2, and the mixture was stirred at room temperature for 10 min. The vessel was cooled to 0C in an ice bath (still under N2), and 4-bromo-1-trifluoromethoxybenzene (10 mmol, 2.41 g) was added slowly. The bath was removed, and the mixture was stirred at room temperature until all the bromoarene was consumed (monitored bytaking a GC-MS spectrum of a worked-up aliquot of the reaction mix) (60 min), and the vessel was once again cooled to 0C. Se (1.0equiv, 395 mg) was added in one portion, the bath was removed, and the mixture was stirred at room temperature for 2 h. The crudeproduct was extracted with CHCl3 (50 mL, three times) from water (150 mL). The combined organic layer was washed with brine (75 mL, one time) and dried over MgSO4. The crude product (caution: STENCH) was re-dissolved in EtOH (200 mL), 11 pellets of NaOH (excess) were added, and the suspension was stirred for 2 h at room temperature. The solution was concentrated under reduced pressure. 1h was obtained after column chromatography(gradient of 0%-20% EtOAc in hexanes) as a yellow oil in 59% yield (1.42 g). The NMR data matches previous reports [40].
1-methyl-5-(4-(trifluoromethoxy)phenyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 20 - 150℃; for 64h;Inert atmosphere;
1-methyl-1H-imidazole (0.681 g, 8.30 mmol, 2.0 eq) was dissolved in 78 N,N-dimethylacetamide (21 ml), and the inside of the reactor was replaced with argon. Subsequently, the mixture was stirred at room temperature. 79 1-Bromo-4-(trifluoromethoxy)benzene (1.0 g, 4.15 mmol, 1.0 eq), 80 palladium (II) acetate (4.7 mg, 0.021 mmol, 0.005 eq), 81 potassium acetate (0.814 g, 8.30 mmol, 2.0 eq) were added thereto, and then stirred for 64 hours at 150 C. The obtained liquid was naturally cooled to room temperature, and the solvent was removed by distillation under reduced pressure. 33 Water was added to the obtained residue, and extraction with chloroform was carried out. The obtained organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with silica gel. Thereby, the objective 34 product was obtained in an amount of 0.51 g (yield 51%).1H-NMR of the obtained objective product is shown below.1H-NMR (400 MHz, CDCl3): delta7.54 (s, 1H), 7.41 (m, 2H), 7.29 (m, 2H), 7.10 (s, 1H), 3.67 (s, 3H).
1-methyl-5-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.1%
With copper(II) acetate hydrate; potassium carbonate; 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole; In 1-methyl-pyrrolidin-2-one; at 0.2 - 150℃;Inert atmosphere;
A first reactor (Reactor A) was charged with 1 -methyl- 1 ,5-dihydro-4/7- imidazo[4,5-c]pyridin-4-one (1.0 mol equivalent), Cu(0Ac)2 H20 (0.1 mol equivalents), and K2C03 (1.1 mol equivalents). The reactor was closed and the atmosphere replaced with nitrogen. Next, l-bromo-4-(trifluoromethoxy)benzene (1.5 mol equivalents) and N- methylpyrrolidinone (5.4 volume equivalents) were added, whereupon a suspension was formed. The suspension was stirred until the temperature had fallen again to approximately 20-25 C and gas evolution had slowed. The reaction mixture was heated to approximately 130-150 C at which time a blue/green color was observed, changing to dark brown after some time. The reaction was stirred at 130-150 C for at least 40 hours. Stirring times of 40 hours up to 72 hours were required to reach an acceptable level of conversion. In general, higher reaction temperatures supported faster conversion. Next, the reaction mixture was cooled to approximately 20-30 C, and 25% aqueous NH3 (0.7 volume equivalents) was added, followed by water (3.5 volume equivalents). The resulting suspension was transferred into a second reactor (Reactor B). Additional water was added (18.1 volume equivalents) to the reaction mixture via Reactor A, followed by n-heptane (3.2 volume equivalents). The resulting suspension was cooled to approximately 0-5 C, and stirred for approximately 2 hours. The suspension was filtered, and the filter cake was washed with water (9.7 volume equivalents). The filter cake was then dissolved in dichloromethane (14.1 volume equivalents) and transferred back into reactor B. To this solution was added water (5.7 volume equivalents) via the filter, followed by 25% aq. NH3 (1.6 volume equivalents). The mixture was stirred for approximately 1 hour at approximately 15-25 C. Next, the layers were separated, and dichloromethane was added (3.6 volume equivalents) to the aqueous layer. The biphasic mixture was stirred at approximately 15-25 C for approximately 20-30 minutes. The layers were separated over a period of at least 1 hour, and to the combined organic layers was added a solution of NH4Cl (2.5 mol equivalents) in water (7.0 volume equivalents). The biphasic mixture was stirred at approximately 15-25 C for about 20-30 minutes, then the layers were separated over the course of 1 hour. The lower organic layer was filtered through a particle filter and diluted with toluene (7.1 volume equivalents) via the filter. The organic layer was concentrated under ambient pressure at approximately 80 C, until no further liquid was seen to evaporate and a precipitate began to form. Toluene was added (16.6 volume equivalents), then concentrated in vacuo, followed by addition of more toluene (7.1 volume equivalents) and again concentrated in vacuo. The suspension was cooled to approximately 0-5 C, stirred for approximately 2 hours, and filtered. The filter cake was washed with toluene (2.9 volume equivalents), and dried in vacuo at approximately 50 C until the loss on drying was 0.5% of the weight to give l-methyl-5-(4-(trifluoromethoxy)phenyl)-l,5-dihydro-47/-imidazo[4,5- c]pyridin-4-one as a beige-colored solid in 83.1% yield.
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
84
[ 407-14-7 ]
[ 5664-21-1 ]
2-cyclohexyl-1-(4-(trifluoromethoxy)phenyl)ethan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
To a solution of l-bromo-4-(trifluoromethoxy)benzene (486 mg, 0.3 mL, 2.0 mmol) in THF (3 mL) was added n-BuLi (2.5M in hexane, 435 pL, 6 mmol) at -78 C and the reaction mixture was stirred at -78 C for 1 h. A solution of 2-cyclohexylacetaldehyde (280 mg, 2.2 mmol) in THF (1 mL) was added and the mixture was stirred at 25 C for 5 h. The reaction mixture was poured into a saturated aqueous solution of NH4CI (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over MgS04, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (hexane: EtOAc; 10:1). The product was obtained as a colorless oil (450 mg, 80 %). (0216) NMR (500 MHz, CDCl3) £(ppm) 7.41 - 7.35 (m, 2H), 7.22 - 7.18 (m, 2H), 4.82 (dd, J = 8.8, 4.9 Hz, (0217) 1H), 1.87 - 1.79 (m, 1H), 1.79 - 1.61 (m, 4H), 1.56 - 1.47 (m, 2H), 1.47 - 1.38 (m, 1H), 1.32 - 1.14 (m, (0218) 3H), 1.07 - 0.89 (m, 2H); (0219) 13C NMR (126 MHz, CDCl3) £ (ppm) 148.7, 144.3, 127.4, 121.2, 120.7 (q, / = 256.9 Hz), 71.6, 47.4, 34.5, 26.8, 26.5, 26.3; (0220) 19F NMR (471 MHz, CDCl3) £(ppm) -57.89.
2-(4-(trifluoromethoxy)phenyl)propan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
A mixture of l-bromo-4-(trifluoromethoxy)benzene (20 g, 83 mmol, 12 mL, 1 eq) in THF (150 mL) was degassed and purged with N2 for 3 times, and then the mixture was cooled to -78 C under N2 atmosphere, then n-BuLi (2.5 M, 39.8 mL, 1.2 eq) in hexane was added dropwise at -78 C. The mixture was stirred at -78 C for 0.5 hr, then propan-2-one (5.3 g, 91.3 mmol, 6.7 mL, 1.1 eq) in THF (40 mL) was added dropwise at -78 C. The mixture was stirred at -78 C for 1.5 hr. The reaction mixture was pour into water (150 mL) at 0C, and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO; 120 g SepaFlash Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient 40 mL/min). The title compound (11 g, 50 mmol, 60% yield) was obtained as colorless liquid. 1 H NMR (400MHz, CDCL) d = 7.57 - 7.48 (m, 2H), 7.18 (br d , J = 8.4 Hz, 2H), 1.94 (br s, 1H), 1.58 (s, 6H). 19F NMR (376MHz, CDCl3) d = -57.96 (s, 3F).
3-hydroxy-7-methyl-3-(4-(trifluoromethoxy)phenyl)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
General procedure: A round bottom flask was charged with desired phenyl bromide (3.35 mmol) and dissolved in THF (2.8 mL). The reaction mixture was cooled to -78C and a solution of n-BuLi (2.79 mmol, 1.8 mL) added dropwise over 10 minutes. The reaction was stirred for 1 hour. In another flask, the desired isatin (1.86 mmol) was added and dissolved in THF (5.6 mL). This solution of isatin was added to the reaction vessel dropwise over 10 minutes. The resultant mixture was stirred at -78C for 1 hour, warmed to r.t., and then stirred for 1 hour. The reaction was quenched with water (10 mL). The solution was extracted with ethyl acetate (3x) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was run through a silica plug (elution solvent gradient: 10% EtO Ac/Hexanes ramped to 100% EtOAc). 3-hydroxy-7-methyl-3-(4-(trifluoromethoxy)phenyl)indolin-2-one (5): Utilizing General Procedure B, 5 was isolated in 68% yield over two steps. NMR (CD3OD, 500 MHz) d: 7.46 (d, J = 8.83 Hz 2H), 7.22 (dd, J = 1.02 Hz, 8.98 Hz, 2H), 7.13 (m, 1H), 6.98 (m, 2H), 2.31 (s, 3H). (0284) 13C NMR (CD3OD, 188 MHz) d: 181.41, 150.1 (q, J = l.6Hz), 141.55, 141.46, 134.03, 132.19, 128.67, 124.13, 123.4, 121.90 (q, J = 255.61 Hz), 121.32, 79.04, 16.61.
bis-(4-(trifluoromethoxy)phenyl)manganese[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
General procedure: A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a rubber septum, wascharged with LiCl (0.610 g, 14.4 mmol, 2.4 equiv), heated to 450 C under high vacuum and then cooledto room temperature. After being switched to argon, the same procedure was applied after MnCl2 wasadded (453 mg, 3.60 mmol, 0.6 equiv). After cooling to room temperature, magnesium turnings wereadded (0.350 g, 14.4 mmol, 2.4 equiv), followed by freshly distilled THF (12 mL). After the reactionmixture was cooled to -5 C, the aryl bromides 2a-g were then added drop by drop (6.0 mmol, 1.0 equiv)and the reaction mixture was stirred until a complete conversion of the starting material was observed.The reaction progress was monitored by GC-analysis of hydrolyzed and iodolyzed aliquots.When the metalation was completed, the concentration of the bis-(aryl)manganese species wasdetermined by titration against iodine in freshly distilled THF. The black solutions of the aryl reagents1a-g were then separated from the magnesium turnings using a syringe and subsequently transferredinto another pre-dried and argon-flushed Schlenk-tube, which was cooled to -5 C. After a titrationagainst iodine in freshly distilled THF was performed, the reagent was ready to be used for Cross-Couplings.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
