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Structure of 392-83-6 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 3932
[2] Patent: CN106905104, 2017, A,
2
[ 392-83-6 ]
[ 444-30-4 ]
Reference：
[1] Angewandte Chemie, International Edition, 2009, vol. 48, # 41, p. 7595 - 7599
3
[ 392-83-6 ]
[ 123-62-6 ]
[ 711-33-1 ]
Yield
Reaction Conditions
Operation in experiment
34.5 %Chromat.
Stage #1: With ethylmagnesium bromide; magnesium; lithium chloride In tetrahydrofuran; ethyl bromide at 45 - 50℃; for 5 h; Inert atmosphere Stage #2: at 20 - 30℃; for 2 h; Inert atmosphere
General procedure: To a 200 ml-four-necked flask with a thermometer,75.0 g of tetrahydroffiran (1.04 mol; manufactured by Nacalai Tesque, Inc.), 5.1 g of magnesium powder (0.208 mol; manufactured by Chuo-kosan), 1.7 g of LiC1 (0.04 mol; manufactured by Nacalai Tesque, Inc.) were placed and the mixture was stirred while the inside of the system was substituted with a nitrogen gas. To this, 0.5 g of 1 mol/L ethylmagnesium bromide THF solution (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and water in the system was removed. Subsequently, 0.44 g of ethyl bromide (0.004 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred for a while; and the generation of heat was confirmed. Subsequently, 36.1 g of o-chlorobenzotrifluoride (0.2 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was gradually added dropwise, while the temperature of the reaction solution was kept at 45 to 50° C. After the completion of the dropwise addition, the mixture was allowed to mature while stirred at 45° C. for five hours, thereby obtaining a Grignard reagent solution.10043] Next, to a 200 ml-four-necked flask with a thermometer, 30.6 g of acetic anhydride (0.3 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 10.8 g of toluene (0.3 fold by weight/o-chlorobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) were placed and the mixture was stirred in a water bath while the inside of the system was substituted with a nitrogen gas. To this, the above Grignard reagent solution was added dropwise while the temperature of the reaction solution was controlled so as to be 20 to 30° C. The entire volume of the Grignard reagent solution was added dropwise and then the mixture was stirred at 25° C. for two hours. After the completion of the stirring, the temperature of the reaction solution was decreased to room temperature; and 39.2 g of 3percent hydrogen chloride aqueous solution was gradually added dropwise thereto in a water bath. Afier the dropwise addition, the hydrolysis was completed by stirring for one hour. After the hydrolysis, the stirring was stopped; and the resultant was lefi to stand for separation, thereby obtaining an oil phase containing o-trifluoromethyl acetophenone. The obtained oil phase was analyzed by a gas chromatography method (GC) and as a result, the yield of 2’-trifluoromethyl acetophenone reaction was 82.7percent (based on the raw material, o-chlorobenzotrifluoride). A reaction was carried out in the same manner as described in Example 1 except that 36.1 g (0.2 mol) of o-chlorobenzotrifluoride was altered to 45.0 g (0.2 mol) of o-bromobenzotrifluoride in Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 2’-tri- fluoromethyl acetophenone reaction was 85.5percent (based on the raw material, o-bromobenzotrifluoride). [0054] A reaction was carried out in the same manner as described in Comparative Example 1 except that 45.0 g (0.2 mol) of m-bromobenzotrifluoride was altered to 45.0 g (0.2 mol) of p-bromobenzotrifluoride in Comparative Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 4’-trifluoromethyl acetophenone reaction was 40.0percent (based on the raw material, p-bromobenzotrifluoride). [0055] A reaction was carried out in the same manner as described in Comparative Example 2 except that 30.6 g (0.3 mol) of acetic anhydride was altered to 39.0 g (0.3 mol) of propionic anhydride in Comparative Example 2. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 4’-trifluoromethyl propiophenone was 34.5percent (based on the raw material,p-bromobenzotrifluoride).
Reference：
[1] Chemical Communications, 2009, # 40, p. 6011 - 6013
5
[ 392-83-6 ]
[ 71-43-2 ]
[ 23450-18-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 4, p. 1417 - 1421[2] Angew. Chem., 2016, vol. 55, # 4, p. 1439 - 1443,5
6
[ 392-83-6 ]
[ 108-24-7 ]
[ 17408-14-9 ]
Yield
Reaction Conditions
Operation in experiment
85.5 %Chromat.
Stage #1: With ethylmagnesium bromide; magnesium; lithium chloride In tetrahydrofuran; ethyl bromide at 45 - 50℃; for 5 h; Inert atmosphere Stage #2: at 20 - 30℃; for 2 h; Inert atmosphere
General procedure: To a 200 ml-four-necked flask with a thermometer,75.0 g of tetrahydroffiran (1.04 mol; manufactured by Nacalai Tesque, Inc.), 5.1 g of magnesium powder (0.208 mol; manufactured by Chuo-kosan), 1.7 g of LiC1 (0.04 mol; manufactured by Nacalai Tesque, Inc.) were placed and the mixture was stirred while the inside of the system was substituted with a nitrogen gas. To this, 0.5 g of 1 mol/L ethylmagnesium bromide THF solution (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and water in the system was removed. Subsequently, 0.44 g of ethyl bromide (0.004 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred for a while; and the generation of heat was confirmed. Subsequently, 36.1 g of o-chlorobenzotrifluoride (0.2 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was gradually added dropwise, while the temperature of the reaction solution was kept at 45 to 50° C. After the completion of the dropwise addition, the mixture was allowed to mature while stirred at 45° C. for five hours, thereby obtaining a Grignard reagent solution.10043] Next, to a 200 ml-four-necked flask with a thermometer, 30.6 g of acetic anhydride (0.3 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 10.8 g of toluene (0.3 fold by weight/o-chlorobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) were placed and the mixture was stirred in a water bath while the inside of the system was substituted with a nitrogen gas. To this, the above Grignard reagent solution was added dropwise while the temperature of the reaction solution was controlled so as to be 20 to 30° C. The entire volume of the Grignard reagent solution was added dropwise and then the mixture was stirred at 25° C. for two hours. After the completion of the stirring, the temperature of the reaction solution was decreased to room temperature; and 39.2 g of 3percent hydrogen chloride aqueous solution was gradually added dropwise thereto in a water bath. Afier the dropwise addition, the hydrolysis was completed by stirring for one hour. After the hydrolysis, the stirring was stopped; and the resultant was lefi to stand for separation, thereby obtaining an oil phase containing o-trifluoromethyl acetophenone. The obtained oil phase was analyzed by a gas chromatography method (GC) and as a result, the yield of 2’-trifluoromethyl acetophenone reaction was 82.7percent (based on the raw material, o-chlorobenzotrifluoride). A reaction was carried out in the same manner as described in Example 1 except that 36.1 g (0.2 mol) of o-chlorobenzotrifluoride was altered to 45.0 g (0.2 mol) of o-bromobenzotrifluoride in Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 2’-tri- fluoromethyl acetophenone reaction was 85.5percent (based on the raw material, o-bromobenzotrifluoride).
Reference：
[1] Organic Process Research and Development, 2016, vol. 20, # 9, p. 1633 - 1636
9
[ 392-83-6 ]
[ 98-88-4 ]
[ 727-99-1 ]
Reference：
[1] Synlett, 2009, # 8, p. 1321 - 1325
10
[ 392-83-6 ]
[ 367-67-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 50 - 60℃;
At room temperature and stirring to 260 g concentrated sulfuric acid (98percent) slowly add 120 g fuming nitric acid, dubbed nitric acid. 50-60°C to the mixed acid slowly add the product of the next step o-bromotrifluorotoluene 390 g, after adding insulation stir, GC detection has no raw materials that For the end of the reaction. Liquid, the upper organic phase washed by alkali to neutral, washed immediately after the bright yellow liquid liquid 2-bromo-5-nitro-trifluorotoluene 450.4 g, GC content: 95percent, yield: 92percent.
Reference：
[1] Patent: CN106905104, 2017, A, . Location in patent: Paragraph 0020-0021
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 3932
11
[ 392-83-6 ]
[ 40161-55-5 ]
Reference：
[1] Patent: CN106905104, 2017, A,
12
[ 121-43-7 ]
[ 392-83-6 ]
[ 1423-27-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922
13
[ 392-83-6 ]
[ 1423-27-4 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
[2] Patent: US6103737, 2000, A,
14
[ 5419-55-6 ]
[ 392-83-6 ]
[ 1423-27-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane
Part A. Preparation of 2-(trifluoromethyl)phenylboronic acid To a solution of 58.8 g (0.261 mol) of 1-bromo-2-(trifluoromethyl)benzene in 250 mL of THF under Ar was added 110 mL (0.275 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5°C. The reaction mixture was allowed to warm to 10°C. Triisopropylborate (95 mL, 0.313 mol) was added, keeping the temperature below 35°C. After 1 hour, the reaction mixture was cooled, 1N HCl (425 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 100 mL of ether three times, and the combined organic extracts were extracted with 100 mL of 1N NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 100 mL ether three times. The combined ether extracts were dried over MgSO4, and the solvents evaporated in vacuo to give 46.1 g (93percent) of the desired compound as a light yellow oil. 1H NMR (CDCl3) δ: 7.77 (d, 1H); 7.72 (d, 1H); 7.56 (m, 2H); 4.87 (br s, 2H).
93%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane
Part A. Preparation of 2-(trifluoromethyl)phenylboronic acid To a solution of 58.8 g (0.261 mol) of 1-bromo-2-(trifluoromethyl)benzene in 250 mL of THF under Ar was added 110 mL (0.275 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5° C. The reaction mixture was allowed to warm to 10° C. Triisopropylborate (95 mL, 0.313 mol) was added, keeping the temperature below 35° C. After 1 hour, the reaction mixture was cooled, 1N HCl (425 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 100 mL of ether three times, and the combined organic extracts were extracted with 100 mL of 1N NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 100 mL ether three times. The combined ether extracts were dried over MgSO4, and the solvents evaporated in vacuo to give 46.1 g (93percent) of the desired compound as a light yellow oil. 1H NMR (CDCl3) δ: 7.77 (d, 1H); 7.72 (d, 1H); 7.56 (m, 2H); 4.87 (br s, 2H).
With sodium carbonate In 1,4-dioxane; water at 80 - 100℃;
To a stirred solution of 2-trifluromethyl-bromobenzene (0.7 g, 2.75 mmol) and 4-carbaldehyde boronic acid (0.5 g, 3.3 mmol) in dioxane (20 ml_) under nitrogen at 80 5C was added Pd(PPh3)4 (0.05 g) followed by the addition of a solution of Na2CO3 (0.7 g) in H2O (5 m). The mixture was stirred at 100 5C for 6 h. The solvent was evaporated and the residue was diluted to 50 ml with EtOAc and washed with H2O. The solvent was devaporated to dryness and the residue was purified by FCC (SiO2) to give the title compound (0.61 g; 88percent), as creamy solid. 1H-NMR (CDCI3) 7.49 (d, 1 H, J = 7.41 Hz); 7.48 (d, 2H, J = 8.13 Hz); 7.61 - 7.53 (m, 2H); 7.76 (d, 1 H, J = 7.8 Hz); 7.91 (d, 2H, J = 8.34 Hz); 10.07 (s, 1 H).
At room temperature and stirring to 260 g concentrated sulfuric acid (98%) slowly add 120 g fuming nitric acid, dubbed nitric acid. 50-60C to the mixed acid slowly add the product of the next step o-bromotrifluorotoluene 390 g, after adding insulation stir, GC detection has no raw materials that For the end of the reaction. Liquid, the upper organic phase washed by alkali to neutral, washed immediately after the bright yellow liquid liquid 2-bromo-5-nitro-trifluorotoluene 450.4 g, GC content: 95%, yield: 92%.
While stirring slowly, 308 g (1.9 mol) of o-trifluoromethylaniline was added to 970 mL of hydrobromic acid (40%) with stirring After cooling with ice bath to 0 C. 140 g (2.03 mol) of sodium nitrite was dissolved in 325 mL of water and slowly added dropwise with stirring Reaction system, and the reaction temperature does not exceed 5 C. After dripping, continue stirring for 20 min, keep warm. To 2 L four mouth The flask was charged with 23.5 g (0.34 mol) of cuprous bromide, 65 mL of hydrobromic acid (40%), stirred vigorously at room temperature, and the above diazonium Poured into the four reaction bottles, the reaction has a large amount of gas generated, the diazonium solution added after the continuous stirring 20 min, liquid, the lower The substrate was washed with alkali and washed with water. The product was simply distilled to obtain a yellow liquid product o-bromotrifluorotoluene 386 g, GC content: 99% yield: 89%. The upper aqueous phase is recyclable with hydrobromic acid and cuprous bromide.
87%
1000ml four reaction bottle was added o-aminobenzotrifluoride 120g and 48% hydrobromic acid 500ml, cooled to below -5 C,Dropping sodium nitrite 54g and water 100ml solution, dropping temperature was -5 ~ 0 C, after dropping continued stirring for 15 minutes. Diazonium salt solution was obtained. equipped with a mechanical stirrer, thermometer, distillation apparatus 1L four reaction flask was added cuprous bromide 64g, 48% hydrobromic acid 200ml, heated to reflux, the above prepared diazonium salt solution was added dropwise, While dropping the edge of atmospheric distillation, maintaining the drop rate and distillation rate quite, collecting the distilled liquid until the liquid is no longer turbid turbidity. The steamed liquid was added dichloromethane 400ml extraction, the organic layer was washed with 300ml water three times, with lmol / L sodium hydroxide solution 300ml wash 1 times,The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to a solvent-free 30 ~ 35 C.Concentrated residual liquid distillation with atmospheric distillation, collecting 167 ~ 168 C liquid to give a colorless transparent liquid 146g.Yield 87%.
With copper(ll) sulfate pentahydrate; ethane-1,2-dithiol; potassium hydroxide; In water; dimethyl sulfoxide; at 90℃; for 20h;Inert atmosphere;
General procedure: A test tube equipped with a magnetic stir bar was charged with an aryl halide(aryl halide, 1 mmol),CuSO4.5H2O(12.5 mg, 0.05 mmol),KOH (280 mg, 5 mmol) orCs2CO3 (1.62 g, 5 mmol), DMSO (2 mL), and water (0.2 mL; water was not used in case of using Cs2CO3 as base).After flushing with argon, 1,2-ethanedithiol (0.18 mL, 2 mmol) was added.The mixture was heated in a preheated oil bath for 20 hours90 C or 110 C bath which is pre-heated with agitation.After cooling to ambient temperature, the reaction mixture was distributed in aqueous HCl (5%) and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc / n-Hexane) to give the aryl thiol (see Table 2 below).
With bis(bipyridine)nickel(II) bromide; ethylene dibromide; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 3.5h;Electrochemical reaction; Inert atmosphere;
General procedure: DMF (40 mL), NaI (375 mg, 2.5 mmol), and 1,2-dibromoethane (100muL, 1.16 mmol) were added to an undivided electrochemical cell, fitted with an iron/nickel (64/36) anode, and surrounded by a nickel foam as the cathode (surface: 40 cm2, porosity: 500 mum, Goodfellow).The mixture was electrolyzed under argon at a constant current intensity of 0.2 A at r.t. for 15 min. The current was then stopped, then NiBr2bpy (187 mg, 0.5 mmol) and aryl or heteroaryl halide (5 mmol),were sequentially added. The solution was electrolyzed at 0.2 A untilthe starting aryl or heteroaryl halide had been totally consumed (2-5h). Sat. aq EDTA-Na2 solution (50 mL) was added, and the resultingsolution was extracted either with EtOAc (for aryl halides) or withCH2Cl2 (for heteroaryl halides) (3 × 50 mL). The combined organic layerswere washed with brine (50 mL), dried (MgSO4), filtered, and concentratedunder vacuum. The crude product was purified by flashchromatography (silica gel, 70-200 mum).
With potassium carbonate; In ethanol; at 78℃; for 1h;Catalytic behavior;
General procedure: An Agilent 6890 N-GC-5973 N-MSD chromatograph,using a 30 m x 0.25 mm Restek, Rtx-5SILMS columnwith a film layer of 0.25 mum was used for GC-MSmeasurements. The temperature of the injector was250 C. The initial temperature of column was 45 C for1 min, followed by programming at 10 C/min up to310 C and a final period at 310 C (isothermal) for17 min. The carrier gas was He and the operation modewas splitless. 1H NMR spectra were made on BRUKER Avance-300instrument using TMS as internal standard in CDCl3. Before the reaction, the catalyst was treated at 120 Cfor 1 h. Iodobenzene (1 mmol), phenylboronic acid(1.5 mmol), the pretreated catalyst (0.1 g) and potassiumcarbonate (3 mmol) were stirred for 1 h in refluxing ethanol(5 ml). Then the solid was separated by filtration, andthen washed by ethanol. The solvent was evaporated. Theresidue was subjected three times to extraction withdichloromethane-water. Anhydrous sodium sulphate wasused to eliminate the residual water from the organic phase,then it was filtered and the solvent was evaporated. Theproduct?s structure was verified by 1H NMR and/or GC-MS analysis. The catalyst was recovered by washing withethanol and drying at 120 C for 1 h before reuse. 1,1'-Biphenyl was isolated as white powder. 1H NMR(300 MHz, CDCl3) delta (ppm): 7.61-7.58 (d, 4H); 7.46-7.41(dd, 4H); 7.37-7.34 (d, 2H);. GC: Rt: 12.101 min. MS (m/z): 154 (M+), 128, 115, 102, 76. 4-Methyl-1,1'-biphenylwas isolated as white solid. 1H NMR (300 MHz, CDCl3) delta(ppm): 2.39 (s, 3H), 7.23-7.26 (m, 2H), 7.32-7.34 (t, 1H),7.40-7.44 (t, 2H), 7.48-7.51 (d, 2H), 7.56-7.59 (d, 2H).3-Methyl-1,1'-biphenyl was isolated as yellow liquid. 1HNMR (300 MHz, CDCl3) delta (ppm): 2.39 (s, 3H), 7.13-7.14(d, 1H), 7.29-7.32 (t, 2H), 7.37-7.41 (m, 4H), 7.55-7.57(d, 2H). 2-Trifluoromethyl-1,1'-biphenyl was isolated aslight yellow liquid. 1H NMR (300 MHz, CDCl3) delta (ppm):7.30-7.44 (m, 7H), 7.49-7.54 (t, 1H), 7.71-7.74 (d, 1H).
72%
With potassium carbonate; In ethanol; at 78℃; for 1.5h;
General procedure: The catalyst Cu-Pd-4A-TSI was prepared according to the method described in [22]. The catalyst was treated at 120 C for 1 h before the reaction. Boronic acid (1.5 mmol or 1.2 mmol), aryl halide (1 mmol), potassium carbonate (3 mmol) and the pretreated catalyst Cu-Pd-4A-TSI (0.1 g; 2.26 mol% Pd and 9.86 mol% Cu) were stirred in 5 ml refluxing ethanol for 1 or 1.5 h. Then the solid was filtered out, and washed with ethanol. The filtrate was evaporated. The residue was extracted three times with dichloromethane and with water. The organic phase was dried over anhydrous sodium sulphate, filtered and the solvent was evaporated. The product was subjected to either GC-MS analysis and/or 1H NMR. If required, the product was recrystallized.
With diisopropylamine;9-(ethylfluoren-9-yl)diisopropylphosphine; copper(l) iodide; sodium tetrachloropalladate(II); at 80℃; for 20h;Product distribution / selectivity;
I. Sonogoshira coupling reactions (i) Sonogashira coupling of aryl bromides (in diisopropylamine) Dry diisopropylamine (10 ml), arylbromide (10 mmol) and acetylene (11 mmol) were placed in a Schlenk tube. Then the catalyst was added in the given concentration as a ready-made mixture of Na2PdCl4 / ligand (phosphonium salt) / CuI (4:8:3) under argon. Unless otherwise noted the reaction mixture was stirred at 50C in an aluminum block. After cooling to room temperature the reaction mixture was diluted with ether (15 ml), washed with water (10 ml), the organic phase dried over MgSO4, filtered and concentrated in vacuo. The product was isolated by column chromatography (silica, cyclohexane / ethylacetate (100:2). Alternatively the yield was either determined via gas chromatography with hexadecane or diethylene glycol di-n-butylether as an internal standard or by determination of the mass of the isolated iPr2NH2+Br-.;
51%
With diisopropylamine;9-(ethylfluoren-9-yl)diisopropylphosphine; copper(l) iodide; sodium tetrachloropalladate(II); at 80℃; for 16h;Product distribution / selectivity;
I. Sonogoshira coupling reactions (i) Sonogashira coupling of aryl bromides (in diisopropylamine) Dry diisopropylamine (10 ml), arylbromide (10 mmol) and acetylene (11 mmol) were placed in a Schlenk tube. Then the catalyst was added in the given concentration as a ready-made mixture of Na2PdCl4 / ligand (phosphonium salt) / CuI (4:8:3) under argon. Unless otherwise noted the reaction mixture was stirred at 50C in an aluminum block. After cooling to room temperature the reaction mixture was diluted with ether (15 ml), washed with water (10 ml), the organic phase dried over MgSO4, filtered and concentrated in vacuo. The product was isolated by column chromatography (silica, cyclohexane / ethylacetate (100:2). Alternatively the yield was either determined via gas chromatography with hexadecane or diethylene glycol di-n-butylether as an internal standard or by determination of the mass of the isolated iPr2NH2+Br-.;
3-benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole[ No CAS ]
Ar[ No CAS ]
[ 392-83-6 ]
3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With phosphorous acid trimethyl ester;SiO2; In 1,4-dioxane; toluene;
Preparation 118 Preparation of 3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 3-Benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.50 g, 6.00 mmol), triturated potassium phosphate (3.01 g, 14.2 mmol) and tris(dibenzylideneacetone) dipalladium(0) (0.562 g, 0.613 mmol) were combined in dioxane (63 mL) at rt under N2. 2-Bromobenzotrifluoride (0.98 mL, 1.62 g, 7.21 mmol) and trimethylphosphite (0.22 mL, 0.231 g, 1.86 mmol) were added to the reaction mixture by syringe. Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was heated to reflux for 22 h. The reaction mixture was concentrated and the residue was taken up in toluene (150 mL) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with toluene (1*100 mL, 1*50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product (3.90 g) was chromatographed (SiO2 250 g, eluted with 2:1 toluene:EtOAc) to yield 3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.48 g) in 95% yield. IR (diffuse reflectance) 3294, 1617, 1575, 1461, 1439, 1423, 1346, 1334, 1316, 1276, 1266, 1259, 1178, 1170, 1126, 1113, 1105, 1058, 1034, 792, 775, 755, 719, 701, 626 cm-1; MS (ESI+) for C26H21F3N2O m/z 435.0 (M+H)+; Anal. Calcd for C26H21F3N2O: C, 71.88; H, 4.87; N, 6.45; found: C, 71.94; H, 4.93; N, 6.48.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃;Microwave irradiation;
EXAMPLE 16; Example 16A. 1.1.1 -trifluoro-2-f4-( ((2R)-2-methyl-4-r2-f trifluoromethvDphenyl'lpiperazin- 1 - yl 1 sulfonvOphenyl'lpropan-sigma-ol; Step 16A; A mixture of (R)-2-methyl-piperazine (300 mg, 2.99 mmol), 2-bromo benzotrifluoride (612 mg, 2.72 mmol), tris(dibenzylidineacetone)dipalldium (0) (24.72 mg, 0.027 mmol), rac-2,2'-bis(diphenylphosphino)-l,l'-binaphtyl (51.06 mg, 0.082 mmol) and sodium tert- butoxide (326.77 mg, 3.4 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 1 1O0C for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated at (R)-2- methyl-piperazine (1.0 g, 9.98 mmol). Reaction mixtures were combined, diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-3-methyI-l -(2- trifluoromethyl-phenyO-piperazine as yellow oil (1.23 g, 39.6percent yield). IH NMR (400 MHz, CHLOROFORM-D) delta ppm 1.07 (d, J=6.32 Hz, 3 H) 2.41 - 2.51 (m, 1 H) 2.74 - 2.84 (m, 1 H) <n="157"/>2.90 - 2.98 (m, 2 H) 3.00 - 3.13 (m, 3 H) 7.18 - 7.25 (m, 1 H) 7.35 (d, J=8.08 Hz, 1 H) 7.47 - 7.55 (m, 1 H) 7.62 (d, J=7.83 Hz, 1 H).
4-(2-naphthylsulfonyl)-1-[2-(trifluoromethyl)phenyl]piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 16h;Microwave irradiation;
Example 7Q; 4-(2-naphthylsulfonvD- 1 -f 2-(trifluoromethyl)phenyllpiperidine; Step 7E; A 5 mL microwave reaction vial was charged with 4-(2- naphthylsulfonyl)piperidine (82 mg, 0.30 mmol), 2-bromobenzotrifiuoride (67 mg, 0.30 mmol), NaOt-Bu (40 mg, 0.42 mmol), Pd2(dba)3 (26 mg, 0.025 mmol), racemic BINAP (31 mg, 0.05 mmol), and dioxane (1.5 mL). The mixture was degassed with N2, capped, and heated in a 90 0C oil bath for 16 h. The mixture was diluted with CH2Cl2 (10 mL) and filtered through a plug of SiO2. The organic phase was concentrated and purified by SiO2 chromatography (15 to 30% EtOAc-hex) to afford the title compound (63 mg), a yellow oil, in 50% yield.1H NMR (400 MHz, CDCl3) delta 1.94 - 2.19 (m, 4 H), 2.60 - 2.77 (m, 2 H), 2.92 - 3.31 (m, 3 H), 7.09 - 7.32 (m, 2 H), 7.44 - 7.52 (m, 1 H), 7.56 - 7.77 (m, 3 H), 7.89 (dd, J=8.6, 1.8 Hz, 1 H), 7.96 (d, J=8.3 Hz5 1 H), 7.99 - 8.11 (m, 2 H), 8.50 (d, J=I .5 Hz, 1 H). HRMS: calcd for C22H20F3NO2S + H+, 420.12396; found (ESI-FTMS, [M+H]I+), 420.1245. HPLC Method 1: room temperature, 6.82 min, 98.5%. HPLC Method 2: room temperature, 7.36 min, 98.4%.
Example 10 Production of 6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide Under an argon atmosphere, 2-bromobenzotrifluoride (33.05 g) was dissolved in dry THF (600 ml), and the mixture was cooled to -65 C. in a dry ice-acetone bath. An n-butyl lithium hexane solution (1.6M: 93.7 ml) was added with stirring and the mixture was stirred at the same temperature for 30 min. After stirring the mixture, a dry THF (2.88L) solution of <strong>[426219-35-4]6-bromo-N-methyl-2-naphthamide</strong> (38.03 g) cooled to 10 C. was added at not more than -55 C. The mixture was stirred for 20 min. An n-butyl lithium hexane solution (1.6M: 94.5 ml) was added at not more than -65 C. The mixture was stirred for 30 min and 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (14.66 g) in a dry THF solution (240 ml) was added dropwise. The mixture was stirred at the same temperature for 1.5 h and saturated aqueous ammonium chloride solution (520 ml) was added to stop the reaction. The solvent was evaporated under reduced pressure and an ethanol-soluble material was extracted from the resulting residue and the solvent was evaporated again. The resulting residue was purified by flash silica gel column chromatography (eluent; chloroform/methanol containing ammonia (7%); 19/1?9/1). The elude was recrystallized from methanol to give the title compound (16.44 g) as colorless crystals. The physical and chemical data were identical with those of the compound obtained in Example 5.
To a suspension of magnesium turnings in tetrahydrofuran (2mL) at room temperature under nitrogen atmosphere was added a solution of [L-BROMO-2-] trifluoromethyl-benzene (7.6g, 5equiv. , available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled to-78 C and copper iodide (646 mg) was added followed by dropwise addition of a solution of 4- Benzyl-2- (2-phenyl-oxiranyl)-morpholine (2g, 1 equiv. ) in tetrahydrofuran (10 [ML).] The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with [MGS04,] and evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12 %). LCMS (6 minutes method) [M+H] [+=442] [&COMMAT; ] Rt 3.05 min. major peak.
12%
To a suspension of magnesium turnings in tetrahydrofuran (2mL) at room temperature under nitrogen atmosphere was added a solution of 1-BROMO-2- trifluoromethyl-benzene (7.6g, 5EQUIV., available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled TO-78 C and copper iodide (646 mg) was added followed by dropwise addition of a solution OF 4-BENZYL-2- (2- PHENYL-OXIRANYL)-MORPHOLINE (2g, 1 equiv.) in tetrahydrofuran (10 mL). The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with MGSO4, and evaporated IN VACUO. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12 %). LCMS (6 minutes method) [M+H] +=442 Rt 3.05 min. major peak
12%
To a suspension of magnesium turnings in tetrahydrofuran (2mL) at room temperature under nitrogen atmosphere was added a solution of L-BROMO-2- trifluoromethyl-benzene (7.6g, 5EQUIV., available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled to-78 C and copper iodide (646 mg) was added followed by dropwise addition of a solution of 4-Benzyl-2- (2- PHENYL-OXIRANYL)-MORPHOLINE (2g, 1 equiv.) in tetrahydrofuran (10 mL). The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with MGS04, and evaporated IFA VACUO. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12 %). LCMS (6 minutes method) [M+H] +=442 Rt 3.05 min. major peak.
12%
To a suspension of magnesium turnings in tetrahydrofuran (2mL) at room temperature under nitrogen atmosphere was added a solution of 1-bromo-2-trifluoromethyl- benzene (7.6g, 5equiv., available from Acros) in tetrahydrofuran (32 mL) and the mixture was stirred for an hour. The solution was cooled to-78 C and copper iodide (646 mg) was added followed by dropwise addition of a solution of 4-Benzyl-2- (2-phenyl-oxiranyl)- morpholine (2g, 1 equiv. ) in tetrahydrofuran (10 mL). The resulting mixture was warmed to room temperature over 2 hours and then treated with water (10 mL). The solution was extracted with diethyl ether, the organic phase dried with MgS04, and evaporated in vacuo. The crude material was purified using a column chromatography on silica gel eluting with a mixture of ethyl acetate/heptane (10/90) to give 352 mg of the title compound as a colourless oil (12 %). LCMS (6 minutes method) [M+H] +-442 Rt 3.05 min. major peak.
With N,N,N,N,-tetramethylethylenediamine; magnesium;iron(III) chloride; In tetrahydrofuran; at 20 - 30℃;Inert atmosphere;Product distribution / selectivity;
Method 1Preparation of l-Cyclopentyl-2-(trifluoromethyl)benzene (Compound of Formula(lib)), 500 g scale reaction.To a 10 L jacketed reactor was added dry THF (2.4 L) and magnesium turnings (81.0 g, 3.33 mol, 1.5 eq.) under N2. In a separate flask FeCl3 (36 g, 0.22 mol, 0.1 eq.) was dissolved in THF (150 mL) (caution, exothermic) under N2. This dark brown solution was allowed to cool to ambient temperature and then added over 10 min to the reactor content under N2 at an internal temperature of about 10 C. TMEDA (402 mL) was added to this yellow/green mixture keeping the internal temperature below about 20 C (slightly exothermic). The resulting rust brown mixture was stirred at ambient temperature for 1 h under N2 then 1 h at 45 C. The reactor contents were allowed to cool below about 20 C and a mixture of l-bromo-2-(trifluoromethyl)benzene (500 g, 2.22 mol) and bromocyclopentane (397 g, 2.66 mol, 1.2 eq.) added dropwise under N2 at a rate as to maintain the internal temperature between about 25-30 C. After the addition, the reaction mixture was stirred at about 25 C under N2 overnight, allowed to cool to an internal temperature of about 0 C and quenched with 6 N HC1 (2 L) at a rate as to maintain the internal temperature below about 15 C (caution, exothermic). [Note:IPC's after completing the addition and stirring overnight were similar indicating that the reaction may have been completed much sooner.] After the quench, hexane (3 L) was added and the reactor contents were stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with hexane (1 L). The combined organic layers were dried (Na2S04), slurried with silica (750 g) and filtered washing the solids with hexane (1 L). The filtrate was concentrated under reduced pressure (100 torr at 37 C) to give an amber oil (317 g, 97.3 Area % by HPLC, 87.7 wt% by HPLC (contained residual hexane by NMR), corrected yield 58%) which was used in the next step without further purification.
Step A: Preparation of l-Cyclopentyl-2-(trifluoromethyl)benzene.In a 5 L 3-necked, round-bottomed flask fitted with a mechanical stirrer, a temperature probe, a dry nitrogen inlet, a condenser and an addition funnel was placed anhydrous THF (750 mL) and magnesium (40.5 g, 1667 mmol) under N2. The slurry was cooled to 10 C in an ice bath. A solution OfFeCl3 (18.02 g, 111 mmol) in anhydrous THF (80 mL) (Note: dissolution of FeCl3 in THF was exothermic) was added dropwise to the magnesium slurry via a syringe.Nl,Nl,N2,N2-tetramethylethane-l,2-diamine (201 mL, 1333 mmol) was added to the reaction mixture via a 500 mL addition funnel at 15 0C causing the temperature to go up to 22.5 0C. The reaction mixture was cooled to 18 0C and stirred at that temperature for 1 h and 45 min. It was then heated to 44-45 0C, stirred for 1 h, cooled to 5-10 0C, and added a mixture of l-bromo-2- (trifluoromethyl)benzene (150 mL, 1111 mmol) and bromocyclopentane (143 mL, 1333 mmol) dropwise while keeping internal temperature under 300C (temperature was maintained between 22 to 300C ). After addition was complete, the reaction mixture was cooled to 17-18 0C and stirred overnight at room temperature. This main reaction mixture was cooled to 10 0C and added magnesium (15 g). Meanwhile, in a separate 1 L round-bottomed flask under N2, Mg (20 g, 0.5 eq) in THF (300 mL) was added a solution OfFeCl3 (9 g, 0.5 eq) in anhydrous THF (30 mL) like described above. The obtained mixture was stirred at room temperature for 30 min, heated to 45 0C for 1 h, cooled to room temperature, and added dropwise into the main reaction mixture via an addition funnel (remaining magnesium was transferred by a spatula) while keeping the internal temperature under 30 0C. The reaction was continued at room temperature for 1 h, cooled to 5 0C (ice bath) and quenched slowly with saturated NH4Cl solution (150 mL) (quench was exothermic satd. NH4C1 was added slowly with efficient stirring). Celite was added after quenching the reaction and stirred well. The mixture was filtered through a 3 L sintered funnel. The filter cake was washed with THF. The filtrate was concentrated under reduced pressure at 37 0C (bath temperature)/ 155 Torr to obtain a brown oil. The oil was cooled by ice bath and 6N HCl (500 mL) was poured into it slowly with efficient stirring) (addition of HCl was exothermic initially, then the exotherm subsided). The mixture was extracted with hexane (2 x 400 mL). The hexane layer was separated out and filtered through a pad of celite. The filtrate (hexane layer) was washed with water (3 X 300 mL), dried (Na2SO4) and silica (55Og) added; slurried well. The slurry was filtered and the filtrate (light yellow in color) was concentrated under reduced pressure (rotavapor; bath temp. 37C at 185-188 Torr), to give the title compound as a light orange oil, (19O g, 91.4% purity by LC at 214 nm). 1H NMR (400 MHz, DMSO-^6) delta 1.56-1.71 (m, 4H), 1.80-1.88 (m, 2H), 1.96-2.05 (m, 2H), 3.22-3.29 (m, IH), 7.35-7.40 (m, IH), 7.16-7.65 (m, 2H).
With iron(III) chloride; N,N,N,N,-tetramethylethylenediamine; magnesium; In tetrahydrofuran; at 0 - 45℃;Inert atmosphere;
To a 50 L three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet, was added dry THF (35 L) and cooled to 0-5 C. To the flask was added Iron (III) chloride (2.7 kg, 0.15 eq) portion wise over 30-60 min. and stirred for 15-30 min. resulting in a clear greenish solution. Under a nitrogen atmosphere in a dry lOO-gallon glass lined reactor was added THF (87.5 L) and magnesium turnings (4.05 kg, 1.5 eq), and cooled to 0-5 C. To the THF and magnesium mixture was added the solution of FeCF in THF at a rate to maintain the internal temperature below 10 C. To the resulting yellow/green mixture was added TMEDA (15.5 kg, 1.2 eq) at a rate to maintain the internal temperature below 20 C. The resulting reaction mixture was heated to 40-45 C for 1 hour and a mixture of 1 bromo-2-(trifluoromethyl) benzene (25 kg, 1.0 eq) and bromocyclopentane (19.9 kg, 1.2 eq) was added to the reaction mixture at a rate to maintain an internal temperature below 25 C. The resulting reaction mixture was allowed to stir at room temperature overnight and subsequently cooled to an internal temperature of 0-5 C. To the resulting mixture was added 6 N HC1 (100 L, 1.5 h) at such a rate as to maintain the internal temperature below 15 C (caution, very exothermic). After the quench, MTBE (200 L) was added and the reactor contents was stirred for 30 min. The phases were separated, and the aqueous layer back extracted with MTBE (75 L). The combined organic layers were washed with 0 (50 L), brine (50 L) and dried (MgSCb). The mixture was filtered through an in-line (1 micron) filter cartridge followed by an additional in-line (0.45 micron) filter cartridge into a clean dry reactor. The solvent was evaporated under vacuum (jacket < 30 C) and co-evaporated with heptanes (2 x 25 L) to provide a viscous liquid. The viscous liquid was dissolved in heptanes (100 L) and passed through a silica plug (25 kg). The silica plug was eluted with heptanes (TLC, Rf~ 0.8, silica gel, heptanes) and the fractions containing the product were evaporated to provide the title compound as a yellow liquid, 11.7 kg (49.2%), purity as determined by HPLC was 94.1%. 'H NMR conforms to reference standard.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80 - 100℃;
To a stirred solution of 2-trifluromethyl-bromobenzene (0.7 g, 2.75 mmol) and 4-carbaldehyde boronic acid (0.5 g, 3.3 mmol) in dioxane (20 ml_) under nitrogen at 80 5C was added Pd(PPh3)4 (0.05 g) followed by the addition of a solution of Na2CO3 (0.7 g) in H2O (5 m). The mixture was stirred at 100 5C for 6 h. The solvent was evaporated and the residue was diluted to 50 ml with EtOAc and washed with H2O. The solvent was devaporated to dryness and the residue was purified by FCC (SiO2) to give the title compound (0.61 g; 88%), as creamy solid. 1H-NMR (CDCI3) 7.49 (d, 1 H, J = 7.41 Hz); 7.48 (d, 2H, J = 8.13 Hz); 7.61 - 7.53 (m, 2H); 7.76 (d, 1 H, J = 7.8 Hz); 7.91 (d, 2H, J = 8.34 Hz); 10.07 (s, 1 H).
bis<2-(trifluoromethyl)phenyl>monochlorophosphine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
~ 62%
Synthesis of Bis-(o-trifluoromethylphenyl)dithiophosphinic Acid; The following synthesis example is made by reference to Schemes 3 and 4 set forth below. Magnesium metal shavings (Mg0, 6.1 g; 0.25 mol) were placed into a 250 mL round-bottom flask. The flask was equipped with a gas inlet adapter and magnetic stir bar. This system was placed under vacuum and the system was then purged with nitrogen. First, 225 mL of anhydrous diethyl ether was transferred to the flask by syringe, and then 50 g (0.222 mol) of o-(CF3)C6H4Br (8) was introduced by syringe. The solution was stirred during the reaction. An ice bath was needed to cool down the reaction as the magnesium was consumed. After most of the magnesium metal was consumed, the reaction mixture was allowed to set overnight under nitrogen. An 1.0 M solution of o-(CF3)C6H4MgBr (9) was produced.Following a similar procedure as before and by reference to Scheme 4, a 500-mL three-neck, round-bottom flask, equipped with a gas inlet, a 125-mL addition funnel, magnetic stir bar, and a rubber septum was charged with nitrogen, PCl3 (5 mL, 7.6 g, 0.055 mol), and anhydrous tetrahydrofuran (THF, 300 mL). The Grignard reagent, o-(CF3)C6H4MgBr (9) (1.0 M in diethyl ether, 110 mL, 0.110 mol), was added to the addition funnel via syringe and then slowly added to the solution at room temperature. After finishing, the addition funnel was removed and replaced with a stopper. The mixture remained at room temperature while stirring overnight. Next day, approximately 50% of the ether/THF solution was removed under reduced pressure, leaving behind a slurry. The slurry was carefully washed three times with 200 mL of hexanes to precipitate the salts. The supernatant, (o-(CF3)C6H4)2P-Cl (10), was decanted into a nitrogen-purged, 1000-mL round-bottom flask equipped with a magnetic stir bar. The hexanes were removed at reduced pressure, leaving an oil. The concentrated solution was then purified by vacuum distillation at 0.125 mmHg/110-120 C. to give (o-(CF3)C6H4)2P-Cl (10) as a colorless liquid. Isolated yields for compound (10) were roughly 62% with good purity as determined by P NMR.
With 1,2,3,4-tetrakis(carbazol-9-yl)-5,6-dicyanobenzene; triethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 1h;Inert atmosphere; Irradiation;
General procedure: To a 10 mL photocatalytic reactor containing a solution of an aryl halide (0.5 mmol, 1equiv) and 5CzBN (0.01 mmol, 0.02 equiv) in dry NMP (3 mL) was added Et3N (0.8 mmol, 1.6 equiv) under nitrogen atmosphere. The solution was stirred under their radiation of 5 W blue LED for the indicated time until complete consumption of starting material as monitored by GC-MS analysis at rt. The yields were calculated from GC measurements using internal standards.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 19h;Inert atmosphere; Reflux;
Example6.1 tert-butyl [4-(2-[2-(trifluoromethyl)phenyl]amino}[1 ,2,4]triazolo[1 ,5- a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int4.1 (2.0 g) in toluene (28 ml) was added 1 -bromo-2- (trifluoromethyl)benzene (5.53 g), Pd2dba3 (562 mg) and rac-BINAP (765 mg). The flask was twice degased and backfilled with argon. The mixture was stirred at r.t. for 5 minutes. Caesium carbonate (10 g) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 15h. Further Pd2dba3 (562 mg) and rac-BINAP (765 mg) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 4h. Water was added and the reaction mixture was extracted with a mixture of dichloromethane and methanol (10: 1 ). The combined organic phases were washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.48 g of the title compound.1 H-NMR (400MHz, DMSO-d6): delta [ppm]= 1 .45 (s, 9H), 7.25 (t, 1 H), 7.47 - 7.60 (m, 3H), 7.60 - 7.71 (m, 4H), 7.85 (dd, 1 H), 8.03 (d, 1 H), 8.34 (s, 1 H), 9.00 (s, 1 H), 9.46 (s, 1 H).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 19h;Reflux; Inert atmosphere;
Intermediate Example Int6.1tert-butyl [4-(2-[2-(trifluoromethyl)phenyl]amino}[1 ,2,4]triazolo[1 ,5- a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int4.1 (2.0 g) in toluene (28 ml) was added 1 -bromo-2- (trifluoromethyl)benzene (5.53 g), Pd2dba3 (562 mg) and rac-BINAP (765 mg). The flask was twice degased and backfilled with argon. The mixture was stirred at r.t. for 5 minutes. Caesium carbonate (10 g) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 15h. Further Pd2dba3 (562 mg) and rac-BINAP (765 mg) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 4h. Water was added and the reaction mixture was extracted with a mixture of dichloromethane and methanol (10:1 ). The combined organic phases were washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.48 g of the title compound. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.45 (s, 9H), 7.25 (t, 1H), 7.47 - 7.60 3H), 7.60 - 7.71 (m, 4H), 7.85 (dd, 1H), 8.03 (d, 1H), 8.34 (s, 1H), 9.00 (s, 1 9.46 (s, 1H).
To a stirred solution of Int4.1 (2.0 g) in toluene (28 ml) was added 1-bromo-2-(trifluoromethyl)benzene (5.53 g), Pd2dba3 (562 mg) and rac-BINAP (765 mg). The flask was twice degased and backfilled with argon. The mixture was stirred at r.t. for 5 minutes. Caesium carbonate (10 g) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 15h. Further Pd2dba3 (562 mg) and rac-BINAP (765 mg) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 4h. Water was added and the reaction mixture was extracted with a mixture of dichloromethane and methanol (10:1). The combined organic phases were washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.48 g of the title compound. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.45 (s, 9H), 7.25 (t, 1H), 7.47 - 7.60 (m, 3H), 7.60 - 7.71 (m, 4H), 7.85 (dd, 1 H), 8.03 (d, 1 H), 8.34 (s, 1 H), 9.00 (s, 1 H), 9.46 (s, 1 H).
With caesium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 19h;Inert atmosphere; Reflux;
To a stirred solution of lnt4.1 (2.0 g) in toluene (28 ml) was added 1-bromo-2-(trifluoromethyl)benzene (5.53 g), Pd2dba3 (562 mg) and rac-BINAP (765 mg). The flask was twice degased and backfilled with argon. The mixture was stirred at r.t. for 5 minutes. Caesium carbonate (10 g) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 15h. Further Pd2dba3 (562 mg) and rac-BINAP (765 mg) was added, the flask was twice degased and backfilled with argon and the mixture was heated to reflux for 4h. Water was added and the reaction mixture was extracted with a mixture of dichloromethane and methanol (10:1). The combined organic phases were washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.48 g of the title compound. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.45 (s, 9H), 7.25 (t, 1H), 7.47 - 7.60 (m, 3H), 7.60 - 7.71 (m, 4H), 7.85 (dd, 1 H), 8.03 (d, 1 H), 8.34 (s, 1 H), 9.00 (s, 1 H), 9.46 (s, 1 H).
The compound 1 (3.0 g, 13.3 mmol, 1.0 eq) at room temperature is soluble in tetrahydrofuran (30 ml) in, lowering the temperature to -78 C, compound is added to the system in the 2 (2.5 g, 13.3 mmol, 1.0 eq) tetrahydrofuran (15 ml), the reaction 1 hours. LCMS display raw material reaction end, a product is generated. The reaction is cooled down to the room temperature, [...] and ammonium chloride solution (20 ml) quenching. System of ethyl acetate (50 ml) extraction twice, combined with the organic phase, the organic phase for saturated sodium chloride aqueous solution (50 ml) washing three times, dried with anhydrous sodium sulfate, filtered, concentrated to obtain the crude product. Eluent (PE/EA=100:1 - 20:1), to obtain light yellow liquid compound 3 (2.6 g, yield: 59%)
With n-butyllithium; In tetrahydrofuran; at -78℃; for 2h;Inert atmosphere;
Step A: To a solution of l-bromo-2- (trifluoromethyl) benzene ( 1 , 35.0 g, 156 mmol) in THF (350 mL) cooled to -78 C under an atmosphere of K2 gas was slowly added a solution of n-BuLi (70.4 mL, 2.5 M in THF, 176 mmol) over a period of 15 minutes . The mixture stirred at -78 C for 40 minutes, was allowed to warm to 0 C and then cooled back down to -78 C. To this was added a solution of l-benzylpiperidin-4-one (22.1 g, 117 mmol) in THF (80 mL) over a period of 10 minutes. The resulting mixture continued to stir at -78 C for 2 hours. The reaction was carefully quenched with aqueous, saturated NH4C1 solution (500 mL) and the mixture was extracted with EtOAc (300 mL) . The organic extract was washed with H2O , brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 330 g Redisep column, 0-30% EtOAc in hexanes) to give l-benzyl-4- (2- {trifluoromethyl) henyl) piperidin-4-ol (2) as a light-yellow oil (29.2 g, 74%) : NMR (500 MHz, CDClj) 8 7.78 id, J - 1.6Hz, 1H) , 7.59 (m, 1H), 7.47 (m, 1H) , 7.36 (m, 5H) , 7.31 (m, 2H) , 3.58 (s, 2H) , 2.80 (m, 2H , 2.55 im, 2H) , 2.27 ( , 2H) , 1.88 (m, 2H) ; MS (ESI+) m/z 336 [M + H] * .
General procedure: All glassware used in the following procedure was flame dried and then cooled under nitrogen prior to use. A portion (1 mmol) of the required aryl bromide (10.00 mmol) was added to a suspension of magnesium turnings (250 mg, 10.5 mmol) in tetrahydrofuran (12 mL) containing a few iodine crystals and the mixture gently heated whilst stirring vigorously. Once the reaction forming the Grignard reagent had initiated (reflux became self-sustaining) the remaining bromobenzene was added dropwise at such a rate that gentle reflux was maintained. The mixture was then heated at reflux until the magnesium was consumed (usually 30-60 min) and then was cooled for 30 min using an ice bath. A solution of 1-benzyl 4-piperidone (5.00 - 6.25 mmol) in tetrahydrofuran (8 mL) was added dropwise over 1-2 h and the mixture was stirred for 1 h and then the ice bath was removed and the reaction mixture allowed to warm to room temperature whilst stirring for at least a further 2 h. The reaction was quenched by the addition of saturated ammonium chloride solution (60 mL) and extracted into diethyl ether (2 × 30 mL) followed by ethyl acetate (3 × 30 mL). The organic phases were combined and subjected to standard work up conditions to give the required crude product. Purification of the title compound was achieved by flash chromatography on silica or, where indicated, by elution through a short length silica column using the eluant specified. In some cases, the crude piperidinol was dehydrated directly without purification as indicated.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 120℃; for 20h;Inert atmosphere;
General procedure: As a typical experiment, the reaction of 4-(trifluoromethyl)bromobenzene (0.225 g, 1 mmol), methyl 3-amino-4-methylthiophene-2-carboxylate (0.342 g, 2 mmol) and KOAc (0.196 g, 2 mmol) at 120 C during 20 h in DMAc (3 mL) in the presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02 mmol) under argon affords methyl 3-amino-4-methyl-5-(4-trifluoromethylphenyl)-thiophene-2-carboxylate 1a after extraction with dichloromethane, evaporation and filtration on silica gel (pentane/ether) in 82% (0.258 g) yield.
With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 100℃; for 16h;Inert atmosphere;
2-Bromobenzotrifluoride (0.086 mL, 0.63 mmol), Cs2C03 (618 mg, 1.9 mmol), X-Phos (73 mg, 0.13 mmol) and Pd2(dba)3 (58 mg, 0.063 mmol), were added to a sol. of intermediate 21 (200 mg, 0.63 mmol) in 2-methyl-2-propanol (14 mL) under a N2 atmosphere. The r.m. was heated at 100 C for 16 h. Then, the r.m. was cooled to r.t., water was added and the r.m. was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by RP preparative HPLC [RP Vydac Denali CI 8 - IotaOmicronmu?iota, 250 g, 5cm); mobile phase: a gradient of (0.25% H4HC03 sol. in water)/MeOH)] . The product fractions were collected and concentrated in vacuo. Then the residue was repurified by RP preparative HPLC [RP Vydac Denali C18 - IotaOmicronmuiotaeta, 250 g, 5cm); mobile phase: a gradient of (0.15 % formic acid solution in water, MeOH/CH3CN]. The product fractions were collected and concentrated in vacuo. Yield: 44 mg of compound 2 (15 %).
General procedure: To a flask containing dried LiCl (0.35 g, 8.24 mmol) was added iPrMgCl (2 M in THF, 4.1 mL) and THF (5 mL) at 15 C. After beingstirred for 15 min, 3-bromo-1-benzonitrile (1.46 g, 8.03 mmol) inTHF (1 mL) was added to the reaction mixture and the obtainedmixture was stirred for 15 min. Then, DMF (1.3 mL, 12 mmol) wasadded at 0 C and the mixture was stirred for 2 h. Then, aq NH3 (7 mL, 28-30%) and I2 (4.06 g, 16 mmol) were added to the reaction mixture. After being stirred for 2 h at room temperature, the reactionmixture was poured into satd aq Na2SO3 solution and was extracted with CHCl3 (3?30 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue waspurified by short column chromatography on silica gel (eluent:hexane/ethyl acetate=9:1, v/v) to provide pure 1,3-dicyanobenzene (0.73 g) in 71% yield. Most nitriles mentioned in this work are commercially availableand were identified by comparison with the authentic samples.
With potassium acetate; palladium diacetate; at 120℃; for 16h;Inert atmosphere;
General procedure: The reaction of the aryl bromide (1mmol), cyclopropyl 2-thienyl ketone (0.228g, 1.5mmol) and KOAc (0.196g, 2mmol) at 120C or 150C (see tables) during 16h in DMA (4mL) in the presence of Pd(OAc)2 (1.12mg, 0.005mmol) or PdCl(C3H5)(dppb) (12.2mg, 0.02mmol) [35] (see tables) under argon affords the coupling product after evaporation of the solvent and purification on silica gel.
1-(2-ethyl-3-benzofuranyl)-2-(2-trifluoromethylphenyl)perfluorocyclopentene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
General procedure: To a stirred THF solution (50 mL) of 2-bromoanisole (0.4 g, 2 mmol) was slowly added n-BuLi/hexane solution (0.7 mL of 2.93 mol L-1) at 195 K under an argon atmosphere. After 40 min, compound 8 (0.7 g, 2 mmol) was added and the mixture was stirred for 2 h at this temperature. The reaction mixture was extracted with diethyl ether, dried with anhydrous MgSO4, filtered, and evaporated in vacuo, then purified by column chromatography (petroleum ether) to give 1o as a pale yellow solid (0.3 g) in 29% yield.
(3aR,6aS)-tert-butyl 5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; for 18h;Reflux;
Step A: To a stirring mixture of (3aR,6aS)-tert-butylhexahydropyrrolo[3, 4-c]pyrrole-2 (lH) -carboxylate (62, 200 mg, 0.94 mmol), rac-BINAP (25 mg, 0.04 amol), and NaOt-Bu (120 mg, 1.25 mmol( in degassed toluene (2 mL) was added a l-bromo-2-trifluoromethylbenzene (0.20 mL, 1.47 mmol( and Pd(OAc), (4 mg 0.018 mmol( and the mixture was heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and was diluted with H,O (10 mL) and extracted with EtOAc (3 x 10 mL) . The combined organic extracts were dried over Na,S04, filtered, and concentrated under reducedpressure. The resulting residue was chromatographed over silica gel(Isco CombiFlash Companion unit, 12 g Redisep column, 0% to 100%EtOAc in hexanes( to provide (3aR,6aS(-tert-butyl 5-(2-(trifluoromethyl(phenyl(hexehydropyrrolo[3, 4-c]pyrrole-2 (lH)carboxylate (63) as a light brown oil (247 mg, 74%) : ?H NMR (300MHz, CDC1,( 7.6l-7.58 (m, iN>, 7.46-7.41 (m, iN), 7.17-7.14 (m, 1H). 7.07-7,02 (m, 1H), 3.70-3.66 (m, 2H), 3.64-3.28 (m, 45), 3.14-3.10 (m, 2H), 2.96-2.90 (m, 2H), 1.47 (5, 9H); MS (251÷) rn/s 357 [M÷H]?.
6,6-dimethyl-4-trifluoromethyl-6H-dibenzo[b,d]pyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With norborn-2-ene; trifuran-2-yl-phosphane; palladium diacetate; cesium pivalate; In N,N-dimethyl-formamide; at 105℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: A DMF solution (8mL) of the o-substituted aryl iodide (0.36mmol), the o-bromobenzyl alcohol (0.36mmol) and norbornene (34mg, 0.36mmol) was added under nitrogen to a Schlenck-type flask, containing Pd(OAc)2 (4mg, 0.018mmol), the phosphine (0.036mmol), when required, and K2CO3 (124mg, 0.90mmol) or CsOPiv (211mg, 0.90). The reaction mixture was stirred at 105C for 24h. After cooling to room temperature the organic layer was diluted with EtOAc (20mL), washed twice with water (20mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography on silica gel using mixtures of hexane-EtOAc as eluent.
6,6-diethyl-4-trifluoromethyl-6H-dibenzo[b,d]pyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With norborn-2-ene; trifuran-2-yl-phosphane; palladium diacetate; cesium pivalate; In N,N-dimethyl-formamide; at 105℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: A DMF solution (8mL) of the o-substituted aryl iodide (0.36mmol), the o-bromobenzyl alcohol (0.36mmol) and norbornene (34mg, 0.36mmol) was added under nitrogen to a Schlenck-type flask, containing Pd(OAc)2 (4mg, 0.018mmol), the phosphine (0.036mmol), when required, and K2CO3 (124mg, 0.90mmol) or CsOPiv (211mg, 0.90). The reaction mixture was stirred at 105C for 24h. After cooling to room temperature the organic layer was diluted with EtOAc (20mL), washed twice with water (20mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography on silica gel using mixtures of hexane-EtOAc as eluent.
tert-butyl 4-(2-(trifluoromethyl)-phenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.73%
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃; for 6h;Inert atmosphere;
To a stirred solution of 1-bromo-2-(trifluoromethyl)benzene (1 g) and tert-butyl piperazine-1-carboxylate(993.3 mg, 5.33 mol, 1.20 equiv.) in Toluene (15 mL) were added BINAP(276.7 mg, 0.44 mmol, 0.1 equiv.) and t-BuONa (854.2 mg, 8.89 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. To the solution was added Pd(AcO)2(49.9 mg, 0.22 mmol, 0.05 equiv.) at room temperature. The solution was stirred at 110 degrees Celsius for 6 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1 to 1:1) to afford tert-butyl 4-[2- (trifluoromethyl)phenyl]piperazine-1-carboxylate(1.2 g ,81.73%) as a colorless oil.
General procedure: A mixture of aryl halide (1.0 mmol), DAAD (1.1 mmol), and CuI (9 mg, 0.05 mmol) in DMF (2 mL) was stirred for 30 min at 0 C. A suspension of NaH (0.050 g, 1.1 mmol) in DMF (1 mL) was slowly added to the reaction mixture over 20 min. The mixture was then evacuated and back-filled with N2 (3 times) and stirred for 12-20 h at the appropriate temperature. The crude reaction mixture was diluted with CH2Cl2 (5 mL) and a saturated NH4Cl solution (3 mL). The mixture was stirred for an additional 30 min and two layers were separated. The aqueous layer was extracted with CH2Cl2 (3 2 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/EtOAc 3:1) to give the desired product.
6-bromo-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 1-bromo-2-(trifluoromethyl)benzene (495 mg, 2.2 mmol) in dry THF (10 mL) was added n-BuLi (2.5 M in hexane, 0.88 mL, 2.2 mmol) dropwise at -78 C under a nitrogenatmosphere. After completion of the addition, the mixture was stirred at -78 C for an hour. Then a solution of <strong>[125114-77-4]7-bromo-1-indanone</strong> 3-1 (422 mg, 2.0 mmol) in dry THF (5 mL) was added dropwise and the reaction mixture was stirred at -78 C for 3 hr. Then saturated aqueous NH4C1 was added to the reaction and the mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2504 and concentrated to afford a residue, which was purifiedby column chromatography over silica gel (eluting with PE:EA1O: 1 to 5:1) to give compound 3-2.
6-bromo-4-(2-(trifluoromethyl)phenyl)chroman-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 1-bromo-2- (trifluoromethyl)benzene (4.5 g, 0.02 mol) in dry THF (50 mL) at -78 C under N2 was added nBuLi (2.5 M in hexanes, 8 mL, 0.02 mol) dropwise. After completion of the addition, the mixture was stirred at -78 C for an hour. Then a solution of <strong>[49660-57-3]6-bromochroman-4-one</strong> A21-1 (2.27 g, 0.01 mol) in dry THF (20 mL) was added dropwise. The reaction mixture was stirred 3 h at -78 C, thenquenched with saturated aqueous NH4 Cl, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2504 and concentrated in vacuo to afford a residue, which was purified by chromatography over silica gel to give compound A21-2. MS (ESI)m/e(M+H-18): 372.0 (-17).
2-fluoro-3-methyl-N-(2-(trifluoromethyl)phenyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 16h;
A mixture of 2-(dicyclohexylphosphino)-2?,4?,6?-triisopropylbiphenyl (133 mg, 0.28 mmol), Cs2CO3 (19.53 g,59.91 mmol). Pd2(dba)3 (183 mg, 0.21 mmol). 1-bromo-2-(trifluoromethyl) benzene (13.48 g, 59.91mmol) and <strong>[1978-33-2]2-fluoro-3-methyl-aniline</strong> A24-1 (6.00 g, 22.29 mmol) in 1,4-dioxane (100 mL) was heated to 100 C for 16 h. Then the reaction was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (eluting with PE;EA=100:0 to 95:5) to afford compound A24-2. MS (ESI) m / e (M+H): 270.1.
General procedure: The aryl bromide (2.00 mmol) was weighed in a 2-5 ml Smith process vial and 2.5 ml dry THF was added after flushing with nitrogen. The mixture was cooled to -78 C in a dry ice/acetone bath and n-BuLi (0.80 ml, 2.5 M, 2.0 mmol) was added by syringe. In a second vial DABSO (121 mg, 0.500 mmol) was weighed and cooled in a dry ice/acetone bath followed by slow addition of the aryl lithium reagent by syringe and the mixture was then stirred for 3 hours at -78 C and then allowed to reach room temperature. In cases where the lithium reagent was insoluble at -78 C, the vial was allowed to warm until the reagent became sufficiently soluble before addition. The reaction mixture was worked up and purified as described above.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
l-(2-trifluoromethylphenyl)-lH-pyrrole-3-carbaldehyde was not commercially available but instead synthesized through arylation of lH-pyrrole-3- carbaldehyde (commercially available from Sigma, Enamine (Kiev, Ukraine) etc.) with 2-Bromobenzotrifluoride (commercially available from Sigma, Enamine (Kiev, Ukraine) etc.) as follows:A mixture of lH-pyrrole-3-carbaldehyde (50 mmol), 2-Bromobenzotrifluoride (50 mmol) and potassium carbonate (50 mmol) in DMF (25 ml_) was stirred at 80 °C until reaction complete by TLC analysis. The mixture was treated with water and extracted with DCM. The organics were washed with brine, dried, and concentrated. The resultant solids were recrystallized from 2-propanol to yield 1- (2-trifluoromethylphenyl)-lH-pyrrole-3-carbaldehyde in 80-85percent purity which was used in the next steps without further purification.
With 1,3-bis(4-chlorobenzyl)imidazolium chloride; potassium tert-butylate; nickel dichloride; In N,N-dimethyl-formamide; at 135℃; for 72h;Schlenk technique; Inert atmosphere;
General procedure: In a typical procedure, NiCl2 (6.5 mg, 0.05 mmol), NHC ligand precursor L4 (35 mg, 0.1 mmol), KOtBu (168 mg, 1.5 mmol) were added to a Schlenk tube under an atmosphere of nitrogen, DMF (3 mL) was then injected and stirred. After 30 min, aryl halide (1.0 mmol) andthiol (1.1mmol) were injected, and the mixturewas immediately heated to 135 C under vigorous stirring. After the reaction, the mixture was cooled to room temperature and quenched by addition of distilled water. The aqueous phase was extracted with ethyl acetate for three times. The combined organic layers were dried with MgSO4, and the samplewas used for GC analysis. The sample solution was further evaporated under vacuum to remove the solvent. The obtained crude produc twas purified by column chromatography (eluent, petroleum) on silica gel to afford the desired thioethers.
General procedure: To a 200 ml-four-necked flask with a thermometer,75.0 g of tetrahydroffiran (1.04 mol; manufactured by Nacalai Tesque, Inc.), 5.1 g of magnesium powder (0.208 mol; manufactured by Chuo-kosan), 1.7 g of LiC1 (0.04 mol; manufactured by Nacalai Tesque, Inc.) were placed and the mixture was stirred while the inside of the system was substituted with a nitrogen gas. To this, 0.5 g of 1 mol/L ethylmagnesium bromide THF solution (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and water in the system was removed. Subsequently, 0.44 g of ethyl bromide (0.004 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred for a while; and the generation of heat was confirmed. Subsequently, 36.1 g of o-chlorobenzotrifluoride (0.2 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was gradually added dropwise, while the temperature of the reaction solution was kept at 45 to 50 C. After the completion of the dropwise addition, the mixture was allowed to mature while stirred at 45 C. for five hours, thereby obtaining a Grignard reagent solution.10043] Next, to a 200 ml-four-necked flask with a thermometer, 30.6 g of acetic anhydride (0.3 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 10.8 g of toluene (0.3 fold by weight/o-chlorobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) were placed and the mixture was stirred in a water bath while the inside of the system was substituted with a nitrogen gas. To this, the above Grignard reagent solution was added dropwise while the temperature of the reaction solution was controlled so as to be 20 to 30 C. The entire volume of the Grignard reagent solution was added dropwise and then the mixture was stirred at 25 C. for two hours. After the completion of the stirring, the temperature of the reaction solution was decreased to room temperature; and 39.2 g of 3% hydrogen chloride aqueous solution was gradually added dropwise thereto in a water bath. Afier the dropwise addition, the hydrolysis was completed by stirring for one hour. After the hydrolysis, the stirring was stopped; and the resultant was lefi to stand for separation, thereby obtaining an oil phase containing o-trifluoromethyl acetophenone. The obtained oil phase was analyzed by a gas chromatography method (GC) and as a result, the yield of 2?-trifluoromethyl acetophenone reaction was 82.7% (based on the raw material, o-chlorobenzotrifluoride). A reaction was carried out in the same manner as described in Example 1 except that 36.1 g (0.2 mol) of o-chlorobenzotrifluoride was altered to 45.0 g (0.2 mol) of o-bromobenzotrifluoride in Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 2?-tri- fluoromethyl acetophenone reaction was 85.5% (based on the raw material, o-bromobenzotrifluoride).
General procedure: To a 200 ml-four-necked flask with a thermometer,75.0 g of tetrahydroffiran (1.04 mol; manufactured by Nacalai Tesque, Inc.), 5.1 g of magnesium powder (0.208 mol; manufactured by Chuo-kosan), 1.7 g of LiC1 (0.04 mol; manufactured by Nacalai Tesque, Inc.) were placed and the mixture was stirred while the inside of the system was substituted with a nitrogen gas. To this, 0.5 g of 1 mol/L ethylmagnesium bromide THF solution (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and water in the system was removed. Subsequently, 0.44 g of ethyl bromide (0.004 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred for a while; and the generation of heat was confirmed. Subsequently, 36.1 g of o-chlorobenzotrifluoride (0.2 mol; manufactured by Wako Pure Chemical Industries, Ltd.) was gradually added dropwise, while the temperature of the reaction solution was kept at 45 to 50° C. After the completion of the dropwise addition, the mixture was allowed to mature while stirred at 45° C. for five hours, thereby obtaining a Grignard reagent solution.10043] Next, to a 200 ml-four-necked flask with a thermometer, 30.6 g of acetic anhydride (0.3 mol; manufactured by Wako Pure Chemical Industries, Ltd.), 10.8 g of toluene (0.3 fold by weight/o-chlorobenzotrifluoride: manufactured by Wako Pure Chemical Industries, Ltd.) were placed and the mixture was stirred in a water bath while the inside of the system was substituted with a nitrogen gas. To this, the above Grignard reagent solution was added dropwise while the temperature of the reaction solution was controlled so as to be 20 to 30° C. The entire volume of the Grignard reagent solution was added dropwise and then the mixture was stirred at 25° C. for two hours. After the completion of the stirring, the temperature of the reaction solution was decreased to room temperature; and 39.2 g of 3percent hydrogen chloride aqueous solution was gradually added dropwise thereto in a water bath. Afier the dropwise addition, the hydrolysis was completed by stirring for one hour. After the hydrolysis, the stirring was stopped; and the resultant was lefi to stand for separation, thereby obtaining an oil phase containing o-trifluoromethyl acetophenone. The obtained oil phase was analyzed by a gas chromatography method (GC) and as a result, the yield of 2?-trifluoromethyl acetophenone reaction was 82.7percent (based on the raw material, o-chlorobenzotrifluoride). A reaction was carried out in the same manner as described in Example 1 except that 36.1 g (0.2 mol) of o-chlorobenzotrifluoride was altered to 45.0 g (0.2 mol) of o-bromobenzotrifluoride in Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 2?-tri- fluoromethyl acetophenone reaction was 85.5percent (based on the raw material, o-bromobenzotrifluoride). [0054] A reaction was carried out in the same manner as described in Comparative Example 1 except that 45.0 g (0.2 mol) of m-bromobenzotrifluoride was altered to 45.0 g (0.2 mol) of p-bromobenzotrifluoride in Comparative Example 1. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 4?-trifluoromethyl acetophenone reaction was 40.0percent (based on the raw material, p-bromobenzotrifluoride). [0055] A reaction was carried out in the same manner as described in Comparative Example 2 except that 30.6 g (0.3 mol) of acetic anhydride was altered to 39.0 g (0.3 mol) of propionic anhydride in Comparative Example 2. The obtained oil phase was analyzed by a gas chromatography method; and as a result, the yield of 4?-trifluoromethyl propiophenone was 34.5percent (based on the raw material,p-bromobenzotrifluoride).
dicyclohexyl(2-trifluoromethylphenyl)phosphine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With bis(eta3-allyl-mu-chloropalladium(II)); potassium hydroxide; In water; at 100℃;Inert atmosphere;
General procedure: A mixture of L1 (0.05 or 0.10 mmol of P), [PdCl(eta3-C3H5)]2 (0.025mmol), arylhalides (0.55 mmol) and dicyclohexylphosphine (0.50 mmol) in 20 M KOH aqueous solution (0.5-1.0 mL) under nitrogen atmosphere was shaken for several hours at 100 C. The mixture was cooled and filtered. After being cooled, the reaction mixture was filtered and the aqueous filtrate was extracted with degassed toluene (2 mL x 2 times). Recovered catalyst resin beads were extracted with degassed toluene (2 mL x 4 times). The combined extract was dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude residue. The residue was purified by silica-gel flash chromatography to give an aryl dicyclohexylphosphine 3. Chromatographic purification was carried out with the YAMAZEN medium pressure liquid chromatograph system using degassed eluent (n-hexane/Et2O = 10/0-9/1).
tert-butyl 4-(((2-(trifluoromethyl)phenyl)amino)methyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos; In toluene; at 80℃;
To a mixture of 2-bromobenzotrifluoride (0.41?ml, 3?mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (62; 0.77?g, 3.6?mmol), sodium tert-butoxide (0.41?g, 4.2?mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.14?g, 0.3?mmol) in toluene (10?ml) was added tris(dibenzylideneacetone)dipalladium(0) (0.14?g, 0.15?mmol). The mixture was stirred at 80?C for 16?h under argon atmosphere. After cooling to room temperature, the mixture was passed through a celite pad. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (hexane/EtOAc?=?100/0-4/1) to give tert-butyl 4-(((2-(trifluoromethyl)phenyl)amino)methyl)piperidine-1-carboxylate (63; 0.64?g, 59%) as a pale yellow oil. 1H NMR (CDCl3, 400?MHz) delta: 1.31-1.11 (m, 3H), 1.46 (s, 9H), 1.85-1.71 (m, 3H), 2.70 (t, J?=?12.4?Hz, 2H), 3.08 (t, J?=?6.0?Hz, 2H), 4.14 (s, 2H), 4.39 (s, 1H), 6.74-6.67 (m, 2H), 7.36 (t, J?=?7.8?Hz, 1H), 7.43 (d, J?=?7.9?Hz, 1H).
2-(4-chlorophenyl)-1-[2-(trifluoromethyl)phenyl]ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
A solution of 1 -bromo-2-(trifluoromethyl)benzene (2.9 g, 12.9 mmol) in anhydrous THF (5 mL) was added to activated magnesium metal (0.31 g, 12.9 mmol) in a sealed tube under a nitrogen atmosphere. The resulting mixture was stirred vigorously for 3 hours at room temperature. The resulting solution was added to a stirred solution of 2-<strong>[4251-65-4](4-chlorophenyl)acetaldehyde</strong> (1 .0 g, 6.4 mmol) in anhydrous THF (25 mL) at 0C under a nitrogen atmosphere. The resulting mixture was allowed to warm slowly to room temperature and then heated to reflux for 2 hours. The mixture was allowed to cool to room temperature and then poured in to saturated NH4CI solution (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (2 x 25 mL), dried (Na2S04) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on silica gel (60-120 mesh) using 4% EtOAc/hexanes as the eluent to give the title compound (0.6 g, 31 %) as a colourless oil.
tert-butyl (4-oxo-4-(2-(trifluoromethyl)phenyl)butyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.91%
To a solution of 1-bromo-2- (trifluoromethyl) benzene (2 g, 8.89 mmol, 1.21 mL) in THF (15 mL) at -78C was added n-BuLi (2.5 M, 3.56 mL). The reaction was stirred at -78C for 15 minutes, then added to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.65 g, 8.89 mmol, 1.51 mL) in THF (15 mL) at -78C. After addition, the reaction mixture was warmed to 15C and stirred at 15C for 1 hr. TLC showed the reaction was ok. The mixture was quenched with sat. NH 4Cl (20 mL), extracted with EA (20 mL*2). The organic layer was separated, washed with brine, dried over with Na 2SO 4, filtered and concentrated. The residue was purified by silica gel (PE: EA = 50: 1 to 10: 1) to afford tert-butyl (4-oxo-4- (2- (trifluoromethyl) phenyl) butyl) carbamate (2 g, 6.04 mmol, 67.91% yield) as yellow oil. 1H NMR (400MHz, CDCl 3) delta ppm: 7.72 (d, J = 7.4 Hz, 1H), 7.64-7.53 (m, 2H), 7.44 (d, J = 7.4 Hz, 1H), 4.63 (br s, 1H), 3.23 (q, J = 6.4 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 1.93 (quin, J = 7.0 Hz, 2H), 1.44 (s, 9H).
(R)-1-(tert-butylsulfonyl)-2-(tricyclohexylstannyl)azetidine[ No CAS ]
(S)-1-(tert-butylsulfonyl)-2-(2-(trifluoromethyl)phenyl)azetidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium fluoride; bis(3,5-bis(trifluoromethyl)phenyl)(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; copper(l) chloride; bis(dibenzylideneacetone)-palladium(0); In toluene; at 110℃; for 12h;Sealed tube; Inert atmosphere;
General procedure: On the benchtop, the electrophile (aryl bromide/triflate, thioester, or acyl chloride, 1.0equiv), organotin (1.1 to 1.3 equiv), Pd(dba)2 (5 mol %), JackiePhos (10 mol % or 15mol %), CuCl (0.5 or 2.0 equiv), and anhydrous KF (for aryl bromide/triflate, 2.0equiv) were added to an oven-dried 8 mL screw-top test tube equipped with a stirbar.The test tube was sealed with a screw-top septum and electrical tape. The reaction vessel was evacuated (ca. 100 mtorr) and backfilled with argon 3 times. If the electrophile were liquid, it was added to the reaction vessel via syringe at this point. Solvent(CH3OH, 1,4-dioxane, or toluene, 1.0 or 0.5 mL) was then added via syringe. The septum was covered with electrical tape, and the reaction vessel was heated for 12 h(unoptimized reaction time) using a heating block. The cooled reaction mixture was transferred to a separatory funnel, diluted with water, and extracted with diethyl ether(3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The organic layer was filtered, concentrated under reduced pressure,and purified by column chromatography.
1-(tert-butylsulfonyl)-2-(tricyclohexylstannyl)azetidine[ No CAS ]
1-(tert-butylsulfonyl)-2-(2-(trifluoromethyl)phenyl)azetidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium fluoride; bis(3,5-bis(trifluoromethyl)phenyl)(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; copper(l) chloride; bis(dibenzylideneacetone)-palladium(0); In toluene; at 110℃; for 12h;Sealed tube; Inert atmosphere;
General procedure: On the benchtop, the electrophile (aryl bromide/triflate, thioester, or acyl chloride, 1.0equiv), organotin (1.1 to 1.3 equiv), Pd(dba)2 (5 mol %), JackiePhos (10 mol % or 15mol %), CuCl (0.5 or 2.0 equiv), and anhydrous KF (for aryl bromide/triflate, 2.0equiv) were added to an oven-dried 8 mL screw-top test tube equipped with a stirbar.The test tube was sealed with a screw-top septum and electrical tape. The reaction vessel was evacuated (ca. 100 mtorr) and backfilled with argon 3 times. If the electrophile were liquid, it was added to the reaction vessel via syringe at this point. Solvent(CH3OH, 1,4-dioxane, or toluene, 1.0 or 0.5 mL) was then added via syringe. The septum was covered with electrical tape, and the reaction vessel was heated for 12 h(unoptimized reaction time) using a heating block. The cooled reaction mixture was transferred to a separatory funnel, diluted with water, and extracted with diethyl ether(3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The organic layer was filtered, concentrated under reduced pressure,and purified by column chromatography.
1,5-dimethyl-2-phenyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium acetate; palladium diacetate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere; Schlenk technique;
General procedure: As a typical experiment, the reaction of the aryl bromide (1 mmol), anitipyrine (0.282 g, 1.5 mmol) and KOAc (0.196 g, 2 mmol) at 150 C for 16 h in DCE or DMA (4 mL) in presence of Pd(OAc)2 (1.12 mg, 0.005 mmol) under argon afforded the arylation product after evaporation of the solvent and purification on silica gel.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
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