* 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.
EXAMPLE 5 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in acetic acid. 60 g of acetic acid are placed in a 100 cc flask, then slowly 30 g of 4- trifluoromethoxyaniline are added; the mixture is brought to 0-5°C and 27 g of elementary bromine are metered, slowly. A gas chromatograph analysis is performed at the end of the reaction:20percent of 4-trifluoromethoxyaniline, 37percent of mono-bromo-derivative as per the title, >41 percent of di-bromo-derivative.
34 %Chromat.
With bromine In water at 35℃; for 2 h;
EXAMPLE 6 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in water. 17.7 g of 4-trifluoromethoxyaniline and 53 g of water at room temperature are placed in a 100 cc flask, the mixture is brought to 35°C and 32 g of elementary bromine are metered slowly over a period of 2 hours. After 0.8 equivalents, a gas chromatograph analysis is performed:10percent of 4-trifluoromethoxyaniline, 34percent of mono-bromo-derivative as per the title, 54percent of di-bromo-derivative.
Stage #1: at 40℃; for 0.5 h; Stage #2: With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In sulfuric acid at 0 - 5℃; for 1.5 h;
EXAMPLE 3 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with DBI in concentrated sulphuric acid. 30.1 g of concentrated sulphuric acid (95-98percent) are placed in a 100 ml reactor and 10.1 g of 2-trifluoromethoxyaniline are added, dropwise. During said operation the temperature is maintained at approximately 400C for approximately 30 minutes.Once a uniform solution has been obtained, it is cooled to 0-50C using a cryostat and the portions of DBI are metered. During addition of the brominating agent, which takes approximately 1 hour, the mixture gradually turns brown. After completion of the reaction (30 minutes) a gas chromatograph analysis is performed: 13.6percent of 2-trifluoromethoxyaniline reagent, 34.0percent of mono-bromo-derivative as per the title, >40percent of di-bromo- and tri-bromo-derivatives.
66.6 %Chromat.
Stage #1: at 40 - 45℃; Stage #2: With N-Bromosuccinimide In sulfuric acid at 0 - 5℃; for 1.5 h;
EXAMPLE 4 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with NBS in concentrated sulphuric acid. 30.3 g of concentrated sulphuric acid (95-98percent) are placed in a 100 ml reactor and 10 g of 2-trifluoromethoxyaniline are added, dropwise, as in the previous example at approximately 40-450C. Once a uniform solution has been obtained, it is cooled to 0- 5°C with cryostat. 10.1 g of NBS are metered in portions over a period of 1 hour, then left to complete for a further 30 minutes. The mixture gradually turns yellow and then brown. A gas chromatograph analysis is performed at the end of the reaction:15.3percent of 2-trifluoromethoxyaniline, 66.6percent of mono-bromo-derivative as per the title, 11.1 percent of di-bromo and tri-bromo-derivatives.
The title compound was prepared in the manner analogous to Example 3A using 3-hydroxymethylphenylboronic acid and <strong>[2252-44-0]1-bromo-3-trifluoromethoxy-benzene</strong>. MS m/z 251 (M-1).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In ethyl acetate; at 50℃; for 18h;
Add copper (I) iodide (45. 0 mg, 0. 24 mmol), bis (triphenylphosphine) palladium (II) dichloride (147. 4 m g, 0. 21 mmol) and triethylamine (2. 37 mL, 16. 8 mmol), to a solution of l-bromo-3-trifluoromethoxybenzene (0. 62 mL, 4. 15 mmol) and trimethylsilylacetylene (0. 78 mL, 5. 4 mmol), in ethyl acetate (4 mL) and stir at 50 C for 18 h. Cool the reaction mixture to room temperature, concentrate and purify by silica gel chromatography, eluting with hexanes to give the title compound (1. 07g, 100%). 1H NMR (300 MHz, CDC13) 6 0. 26 (s, 9H), 7. 16 (br d, J = 7. 7 Hz, 1H), 7. 31 (m, 2H), 7. 37 (brd, J=7. 7Hz, 1H).
zinc chloride(4.0 ML, of a 1M solution in diethylether, 4.00 mmol)[ No CAS ]
bis(triphenylphosphine)-nickel(II)chloride[ No CAS ]
[ 75-09-2 ]
[ 2252-44-0 ]
[ 594-19-4 ]
[ 197847-90-8 ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; In tetrahydrofuran; pentane;
Step A 2-(3-Trifluoromethoxyphenyl)-5-methylpyridine To a solution of 3-bromotrifluoromethoxybenzene (0.590 mL, 4.00 mmol) in THF (12 mL) at -78 C. was added t-butyl lithium (4.71 mL, of a 1.7M solution in pentane, 8.00 mmol. After 10 minutes zinc chloride(4.0 mL, of a 1M solution in diethylether, 4.00 mmol) was added. The reaction was stirred for 10 minutes at -78 C. and then allowed to warm to 0 C. and stirred for 30 minutes. This solution was added via cannula to a solution of 2-bromo-5-methyl pyridine and bis(triphenylphosphine) Nickel II chloride. The reaction stirred for 1 hour at 0 C. and then at ambient temperature for a furthur 1 hour. Saturated ammonium hydroxide solution (3 mL) was added and the mixture stirred until homogenous, extracted with Et2 O and the organic extracts washed with saturated brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (Silica gel, 25-50% CH2 Cl2 in hexanes). 1 H NMR (CD3 OD, 400 MHz) delta 8.48(1H, s), 7.93(1H, brd, J=8.0 Hz), 7.87(1H, s), 7.79(2H, d, J=8.0 Hz), 7.74(2H, d, J=8.0 Hz), 7.56(1H, t, J=8.0 Hz), 7.32(1H, brd, J=8.0 Hz) and 2.40(3H, s) ppm.
bis(triphenylphosphine)palladium(II) dichloride[ No CAS ]
[ 2252-44-0 ]
[ 54060-30-9 ]
3-[[3-(Trifluoromethoxy)phenyl]ethynyl]aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(I) iodide; triphenylphosphine;
EXAMPLE 3 Preparation of 3-[[3-(Trifluoromethoxy)phenyl]ethynyl]aniline A multinecked flask as described in Example 1 was charged with 5.0 g (0.021 mol) of m-bromophenyl trifluoromethyl ether, 50 ml of dried, degassed triethylamine, 2.43 g (0.212 mol) of 3-aminophenylacetylene, 0.048 g (0.68 mmol) of bis(triphenylphosphine) palladium II chloride, 0.148 g (0.564 mmol) of triphenylphosphine, and 0.03 g (0.157 mmol) of cuprous iodide. The reaction mixture was heated at 65 C. for 20 hours at which point gas chromotography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product as a viscous orange-colored liquid. Short path distillation of the crude product under reduced pressure gave 5.1 g (0.018 mol, 86% yield) of the purified product as a colorless liquid.
First, meta-bromo(trifluoromethoxy)benzene is prepared by heating 4.4 g (0.02 mole) of meta-bromophenol fluoformate, 5 g of hydrogen fluoride, and 4 g of sulphur tetrafluoride in a 70-ml stainless steel autoclave at a temperature of 100 C for two hours. The autoclave is then cooled and gas is released out of it. The reaction products are distilled with steam. The distillate is extracted with ethyl ether. The ethereal solution is washed with water, a 10 percent of sodium hydroxide solution then once more with water, and dried over sodium sulphate. Diethyl ether is removed by distillation and the residue is distilled in vacuum. The yield of meta-bromo(trifluoromethoxy)benzene is 3.62 g (77.8 percent of theory). The boiling point is 78 - 81 C (at 55 mm Hg)
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 10h;Heating / reflux;
[0462] A mixture of l-bromo-3-(trifluoromethoxy)benzene (241 mg, 1.0 mmol), 4-amino- 2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-iV-(pyridin-3-yl)pyrimidin-4- amineas brown solid (260 mg, 85 %). A mixture of this intermediate (100 mg, 0.33 mmol) and 4-(2-(pyrrolidin-l-yl)ethoxy)benzenamine (67 mg, 0.33 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as white solid (11 mg, 7 %).[0463] 1B. NMR (500 MHz, DMSOd6): delta 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.51-2.55 (m, 2H, superimposed with solvent peak), 2.75 (t, J= 5.9 Hz, 2H), 3.25-3.34 (m, 2H, superimposed with water peak), 3.99 (t, J= 5.9 Hz, 2H), 6.79 (d, J= 8.9 Hz, 2H), 6.98 (d, J= <n="214"/>8.0 Hz, IH), 7.40 (dd, J= 7.6, 7.4 Hz, IH), 7.50 (d, J= 8.9 Hz, 2H), 7.76 (br s, IH), 7.87 (d, J= 8.4 IH), 7.90, 8.31, 8.41, 8.84 (4 s, IH each). MS (ES+): m/z 474 (M+H)+.
EXAMPLE 5 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in acetic acid. 60 g of acetic acid are placed in a 100 cc flask, then slowly 30 g of 4- trifluoromethoxyaniline are added; the mixture is brought to 0-5C and 27 g of elementary bromine are metered, slowly. A gas chromatograph analysis is performed at the end of the reaction:20% of 4-trifluoromethoxyaniline, 37% of mono-bromo-derivative as per the title, >41 % of di-bromo-derivative.
34%Chromat.
With bromine; In water; at 35℃; for 2h;Product distribution / selectivity;
EXAMPLE 6 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in water. 17.7 g of 4-trifluoromethoxyaniline and 53 g of water at room temperature are placed in a 100 cc flask, the mixture is brought to 35C and 32 g of elementary bromine are metered slowly over a period of 2 hours. After 0.8 equivalents, a gas chromatograph analysis is performed:10% of 4-trifluoromethoxyaniline, 34% of mono-bromo-derivative as per the title, 54% of di-bromo-derivative.
With potassium tert-butylate;palladium diacetate; In 1,4-dioxane;
Synthesis of 1-(3-trifluoromethoxy-phenyl)-piperazine: Following protocol A, 1-Bromo-3-(trifluoromethoxy)-benzene (1.0 g, 0.0042 mol), piperazine (5.4 g, 0.0632 mol), potassium tert-butoxide (0.72 g, 0.0076 mol), palladium acetate (0.94 g, 0.0002 mol) and Diisopropylimidazolium chloride (0.08 g, 0.0002 mol) in 5 mL of dry dioxane were heated at 100 C. for 24 hours under argon. The reaction mixture was cooled to ambient temperature, quenched with water, and extracted with ethyl acetate. The ethyl acetate phase was washed once each with water and brine, and was concentrated. The residue was purified by column chromatography to give the title compound.
With sulfuric acid; sodium nitrite; In water; isopropyl alcohol;Product distribution / selectivity;
1b. Preparation of 1 -bromo-3-trifluoromethoxybenzene. 2579.53 g of 2-propanol and 1100 g of the product from stage Ia are placed in a 10 litre lined glass reactor with 4 necks and outlet on bottom, and a previously prepared solution of 382.52 g of NaNO2 in 766.18 g of water is added. 459.6 g of concentrated sulphuric acid are then metered slowly. The acids are diluted and the upper organic phase is separated from the lower aqueous phase. The organic phase is washed and a first organic phase and an upper aqueous phase are separated. The latter is further diluted with water until a second organic phase is released. This organic phase is added to the first and everything is washed again, separating an aqueous phase and an organic phase which, after being anhydrified with CaCl2, undergoes distillation to provide the product indicated in the title (final yield 84%). B.p. 156-158C/760 mmHg.
EXAMPLE 3 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with DBI in concentrated sulphuric acid. 30.1 g of concentrated sulphuric acid (95-98%) are placed in a 100 ml reactor and 10.1 g of 2-trifluoromethoxyaniline are added, dropwise. During said operation the temperature is maintained at approximately 400C for approximately 30 minutes.Once a uniform solution has been obtained, it is cooled to 0-50C using a cryostat and the portions of DBI are metered. During addition of the brominating agent, which takes approximately 1 hour, the mixture gradually turns brown. After completion of the reaction (30 minutes) a gas chromatograph analysis is performed: 13.6% of 2-trifluoromethoxyaniline reagent, 34.0% of mono-bromo-derivative as per the title, >40% of di-bromo- and tri-bromo-derivatives.
66.6%Chromat.
EXAMPLE 4 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with NBS in concentrated sulphuric acid. 30.3 g of concentrated sulphuric acid (95-98%) are placed in a 100 ml reactor and 10 g of 2-trifluoromethoxyaniline are added, dropwise, as in the previous example at approximately 40-450C. Once a uniform solution has been obtained, it is cooled to 0- 5C with cryostat. 10.1 g of NBS are metered in portions over a period of 1 hour, then left to complete for a further 30 minutes. The mixture gradually turns yellow and then brown. A gas chromatograph analysis is performed at the end of the reaction:15.3% of 2-trifluoromethoxyaniline, 66.6% of mono-bromo-derivative as per the title, 11.1 % of di-bromo and tri-bromo-derivatives.
Synthesis 16; 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-yl]- 3-trifluoromethoxyphenyl-methanone (ABD454); 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid methoxy- methyl-amide (0.5 g) was dissolved in dry THF (20 mL) and reacted with a Grignard reagent prepared from 3-trifluoromethoxy-bromobenzene (5 g) and magnesium (3 g) in dry THF (30 mL) at 0C. The reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. The reaction was quenched with saturated NH4CI and the mixture extracted with petrol. Column chromatography gave the title compound as a thick oil which became an amorphous solid on standing.deltaC (CDCI3, 62.9 MHz): 9.9, 108.5, 112.5, 114.0, 120.1 , 123.2, 125.3, 126.7, 128.0, 129.1 , 130.4, 130.5, 130.9, 133.0, 135.4, 135.6, 136.4, 139.3, 143.2, 148.5, 157.1 and 188.7.
1-(4-fluorobenzoyl)-4-(3-trifluoromethoxybenzoyl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
A suspension of Rieke magnesium [(100MG)] in THF [(4ML)] was placed in a tube. To this suspension was added a solution of <strong>[2252-44-0]1-<strong>[2252-44-0]bromo-3-(trifluoromethoxy)benzene</strong></strong> (1g, 4. [LMMOLS)] in THF (2ml), The resultant reaction was stirred at room temperature for 20 minutes before the addition of a solution of [1- (4-FLUOROBENZOYL)-4- (N-METHYL-N-METHOXY] carbamoyl) piperidine (Method 2; 301mg, lmmol) in THF [(3ML).] The reaction was then left to stir for 2.5 hours before quenching with saturated [NH4CL] solution. The reaction was then treated with water (2ml), capped and shaken the allowed to settle. The organic layer was decanted off and evaporated to yield an oil. This oil was purified by column chromatography [(40G] Si, 20 to [100%] EA/isohexane) to yield the product as a white solid (86mg, 21 %). NMR (DMSO-d6): 1.50 (m, 2H), 1.80 (br m, 1H), 3.75 (m, 1H), 7.25 (t, 2H), 7.45 (m, 2H), 7.70 (m, 2H), 7.90 (s, 1H), 8.05 (d, 1H) ; m/z 396.
With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; at 100℃;
5-{3-[(Trifluoromethyl)oxy]phenyl}-2-pyridinamine To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (100 mg, 0.454 mmol) and 1-bromo-3-[(trifluoromethyl)oxy]benzene (131 mg, 0.545 mmol) in dry DMFEtOHH2O (2:1:1) tetrakis(triphenylphosphine)palladium(0) (42.0 mg, 0.036 mmol) and potassium acetate (89 mg, 0.909 mmol) were added and the mixture was shaken at 100 C. overnight. The mixture was diluted with DCM, filtered through filter tube and concentrated in vacuo to give a brown residue which was dissolved in methanol and loaded into SCX cartridge (2g), washed with MeOH and eluted with 2.0M ammonia in MeOH. The resulting ammoniamethanolic solution was concentrated in vacuo to give the title compound (87 mg, 0.329 mmol, 72%). UPLCMS: 0.55 min, 255 [M+H]+.
To a solution of <strong>[2252-44-0]1-<strong>[2252-44-0]bromo-3-(trifluoromethoxy)benzene</strong></strong> (1.52 g, 6.3 mmol) in diethyl ether (50 mL) at -78 C. was added dropwise a solution of 1.6 M n-BuLi in hexane (4.2 mL, 6.6 mmol) and the reaction mixture was stirred at -78 C. for 30 min. A solution of 3-(trifluoromethoxy)benzonitrile (1.23 g, 6.6 mmol) in diethyl ether (5 mL) was added dropwise and the reaction mixture was stirred at -78 C. for 1.5 h. 3N HCl (40 mL) was added and the reaction was allowed to warm to rt followed by stirring at rt for 1.5 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by a silica gel ISCO cartridge with elution at gradient 10% EtOAc/hexane to give bis(3-(trifluoromethoxy)phenyl)methanone (1.99 g, 90% yield) as a white solid. LCMS: RT=2.10 min [M+H] 351.3 (2 min Phenomenex Luna C18 column, 4.6 X 30 mm eluting with 10-90% MeOH/H20 over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz IH (CDC13) ppm 7.46 (d, J=8.35 Hz 1H), 7.54 (t, J=7.91 Hz, 1H), 7.64 (s, 1H), 7.70 (d, J=7.91 Hz,
Synthesis of tert-butyl 2-hydroxy-2-[3-(trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carboxylate; 3-(Trifluoromethoxy)bromobenzene (32.2 g, 134 mmol; CAS No.2252-44-0) was added to a solution of isopropylmagnesium chloride lithium chloride complex in THF (1.3 M solution, 101 mL, 132 mmol; Aldrich) at -5 C. under nitrogen. The solution was allowed to slowly warm to rt overnight, and the Grignard solution was added to a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (16.0 g, 66.9 mmol) in THF (300 mL) at 0 C. via cannula. After 1.5 h, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude alcohol as an off-white solid (27.75 g, quant.). m/z 346 (MH+ minus t-Bu), 424 (MNa+).
(3RS)-3-[3-(trifluoromethoxy)phenyll-1-oxa-8-azaspiro[4.5ldecane hydrochloride 3-(trifluoromethoxy)bromobenzene (16.0 g, 9.91 mmol; CAS No. 2252-44-0) was added to a -5 0C soln of isopropylmagnesium chloride lithium chloride complex in THF (50.4 mL, 65.6 mmol; 1.3M soln from Aldrich). The solution was stirred on an ice-salt bath which was allowed to warm to room temperature overnight. The resulting solution was added to <strong>[954236-44-3]tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate</strong> (8.5 g, 33 mmol) in 2-MeTHF (150 mL) at 0 0C via an addition funnel and the reaction was stirred at RT overnight. More Grignard reagent (prepared from 11.2 mL isopropyl magnesium chloride and 2.3 mL 3-(trifluoromethoxy) bromobenzene) was added to the reaction at 0 0C and the reaction was stirred for 30 min. The reaction was quenched with ammonium chloride (200 mL) and the layers were separated. The aqueous was extracted with ethyl acetate (2x100 mL). The organic layers were dried over magnesium sulfate, filtered, and concentrated to give a crude oil. A solution of the oil and triethylsilane (26.4 mL, 165 mmol) in methylene chloride (150 mL) was treated with borontrifluoride diethyl etherate (8.14 mL, 66.0 mmol) and trifluoroacetic acid (12.3mL, 165 mmol) at 0 0C. After standing overnight in the freezer, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and water. The aqueous was made basic with 2.5 N NaOH and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give an oil. The oil was dissolved in MeOH (60 mL) and treated with 10% Pd/C (0.67 g), acetic acid (5 mL), and stirred under hydrogen (20 psi) over several days to remove alkene byproduct. Added another portion of 10% Pd/C (0.50 g) and stirred under hydrogen (20 psi) overnight. Another portion of 10% Pd/C (0.20 g) was added to the mixture and stirred under hydrogen (20 psi) overnight. The mixture was filtered through a pad of celite and the filtrate evaporated to give an oil. The oil was treated with water (100 mL) and 2.5 N NaOH (80 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an orange oil. The oil was treated with anhydrous diethyl ether (50 ml_) and the resulting solution was treated with HCI (15 ml_, 2N in diethyl ether) to give a ppt. The precipitate was collected by vacuum filtration and washed with diethyl ether (2x20 ml_) to give the title compound as an off white solid (4.62 g, 41 %). m/z 302 (MH+).
A dry 250 mL pear-shaped flask was equipped with a stir bar and fitted to an adapter connected to the vacuum line. The flask was dried with a heat gun under vacuum, cooled and then purged several times with nitrogen. Under a stream of nitrogen, <strong>[2252-44-0]3-(trifluoromethoxy)bromobenzene</strong> (5.2 g, 21.5 mmoles) was added to the flask and dissolved in anhydrous ether (120 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge 1½ PrecisionGlide needle. The stirring solution was cooled to -78 C. for 10 minutes, n-BuLi (1.6M in hexanes, 13.5 mL. 21.5 mmoles) was added drop wise. After 15 minutes, a solution of 2-cyanopyridine (2.99 g, 21.5 mmoles) in anhydrous THF (20 mL) was added from a syringe. The reaction was stirred for 2 hours at -78 C. and trimethylchlorosilane (2.73 mL, 21.5 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to -78 C., Benzylmagnesium chloride (2.0M in THF, 10.75 mL, 21.5 mmoles) was added and the reaction was allowed to slowly warm to room temperature. The reaction was quenched with H2O (50 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The light brown solution was washed with saturated aqueous NH4Cl (3×100 mL), then with water (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on a silica gel ISCO with 100-90% hexanes in ethylacetate to yield 1-(5-chloropyridin-2-yl)-2-phenyl-1-(3-(trifluoromethoxy)phenyl)ethanamine 3.63 g (43% yield). LC-MS (methanol) [M+1]=393 1H NMR (CDCl3) delta 1.85 (broad s, 2H), delta 3.49 (d, J=13.20, 1H), delta 3.87 (d, J=13.20, 1H), delta 6.78-6.80 (d, 2H), delta 7.08 (d, 1H) delta 7.12-7.42 (m, 7H), delta 7.58-7.56 (dd, 1H), delta 8.55 (d, 1H).
With tetrabutylammomium bromide; palladium diacetate; sodium carbonate; In water; at 150℃; for 0.0833333h;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.
A mixture of zinc (807 mg, 12.3 mmol) and lithium chloride (523 mg, 12.3 mmol) under argon was warmed for 10 minutes using a hot air gun, allowed to cool and then anhydrous THF (50 mL) added. The zinc was activated by treatment with 1,2-dibromoethane (39 mg, 0.21 mmol) and TMSCl (4.3 mg, 0.04 mmol). To the resulting mixture at 25 C. was added ethyl 4-(bromomethyl)benzoate (1.0 g, 4.15 mmol) and the mixture stirred for 15 minutes. 3-(Trifluoromethoxy)bromobenzene (694 mg, 2.88 mmol) was added, followed by (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride [PEPPSI-SIPr] (28 mg, 0.04 mmol) and the mixture stirred at 25 C. for 1 hour. Saturated ammonium chloride solution was added and the crude product extracted with ether. The ether extract was washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with 7:3 hexane:ethyl acetate to afford the title compound (950 mg, 71%).LCMS Rt=3.98 minutes, MS m/z 325 [MH]+1HNMR (400 MHz, CDCl3): delta 1.37 (t, 3H), 4.03 (s, 2H), 4.33-4.38 (m, 2H), 7.01 (s, 1H), 7.07 (m, 2H), 7.24-7.30 (m, 3H), 7.97 (d, 2H).
General procedure: Aryl or heteroaryl bromide (4 mmol) was charged in oven dried Radley's synthesis tube that was equipped with a stir bar under a stream of nitrogen. Anhydrous diethyl ether was added and the reaction mixture was cooled to -78 C. n-BuLi (1.6 M in hexanes, 2.5 mL, 4.00 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 10 min. A solution of aryl or heteroaryl nitrile in THF (4 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 2 h. TMSCl (0.550 mL, 4.00 mmol) was added to the reaction mixture at -78 C and the reaction mixture was allowed to warm up to 0 C. The reaction mixture was cooled to -78 C, benzylmagnesium chloride in either THF or ether (2 mmol) or benzyl zinc(II) bromide in ether (2 mmol), was added dropwise, stirred at -78 C for 2 h, and then stirred at rt for 12 h. The reaction mixture was worked up and purified as in general procedure 1.
Under N2 atmosphere, a flame-dried 250 mL three-necked, round-bottomed flask was charged with magnesium turnings (0.528 g, 22.0 mmol), THF (20 mL), and catalytic amount of iodine. Tothe solution was added dropwise <strong>[2252-44-0]1-<strong>[2252-44-0]bromo-3-(trifluoromethoxy)benzene</strong></strong> 1 (3.0 mL, 20.0 mmol) in THF (20 mL) and stirred at room temperature until the color of iodine faded. Then, the remaining solution of <strong>[2252-44-0]1-<strong>[2252-44-0]bromo-3-(trifluoromethoxy)benzene</strong></strong> 1 in THF was added dropwise keeping thesystem at the boiling state and the mixture was further refluxed for 2 h. After cooled to 0 C, a solution of chlorodiphenylphosphine (4.1 mL, 22.0 mmol) in THF (15 mL) was added dropwise over 10 min. The reaction mixture was gradually warmed to room temperature and further stirred for 3 h. Then cooled to 0 C, to the solution was added anhydrous methanol (10 mL) and stirred for another 30 min at room temperature. Then cooled to 0 C again, 30% H2O2 (2.3 mL) was added dropwise over 10 min and stirred at room temperature for 40 min. To the system was added saturated aqueous NaHSO3 (6.0 mL) at 0 C. After stirred at room temperature for 1 h, the reaction mixture was added 1 mol/L HCl (4.0 mL) and stirred for another 1 h. Finally, THF was evaporated under reduced pressure and the remaining mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude product was purified by recrystallization (CH2Cl2/n-hexane) to give 2 as a white solid (6.594 g, 91% yield).
3-[4-(4-methoxyphenyl)-3,3-dimethyl-1-piperazinyl]-1-methyl-N-[3-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-5-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
l-Bromo-3-trifluoromethoxy-benzene (0.093 mL, 0.95 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 flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was suspended in DIPE, filtered off. The residue was suspended in 2-propanol and treated with a 6 N HC1 sol. in 2-propanol. The resulting precipitate was collected by filtration and dried. Yield: 130 mg of compound 4 (41 %) as HC1 salt.
With sodium acetate;palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 135℃; for 10h;Inert atmosphere;
According to route (B), 1-nitro-3-vinylbenzene (661 mg, 4.4 mmoles, 1.1 eq.) was placed in dimethylformamide (4 mL) with 1-bromo-3 (trifluoromethoxy)benzene (600 muL, 4 mmoles, 1 eq.), NaOAc (661 mg, 8 mmoles, 2 eq.), Pd(OAc)2 (45 mg, 0.2 mmole, 5 mol%), PPh3 (105 mg, 0.4 mmole, 10 mol%). The reaction mixture was heated at 135C and stirred for 10 hours under an inert atmosphere of argon. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Upon decantation, the aqueous phase was further extracted with dichloromethane. The organic phases were gathered, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford (E)-1-nitro-3-(4-(methoxy)styryl)benzene (355 mg, 28%). 1H NMR (300 MHz, CDCl3) delta 8.37 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.49 - 7.34 (m, 3H), 7.20 - 7.00 (m, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tert-butyl XPhos; In toluene; at 110℃; under 760.051 Torr; for 3h;Inert atmosphere;
In a 25 niL sealed tube, sodium 2-methylpropan-2-olate (62.7 mg, 653 muetaiotaomicron, Eq: 1.20), bis(dibenzylideneacetone)palladium (31.3 mg, 54.4 muetaiotaomicron, Eq: 0.1) and 2-di-tert-butyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (23.1 mg, 54.4 muetaiotaomicron, Eq: 0.1) were combined with toluene (5.00 ml) to give a dark brown suspension. N5,N5,l-tris(4-methoxybenzyl)-lH-l ,2,4-triazole- 3,5-diamine (250 mg, 544 muetaiotaomicron, Eq: 1.00) and l-<strong>[2252-44-0]bromo-3-(trifluoromethoxy)benzene</strong> (131 mg, 544 muetaiotaomicron, Eq: 1.00) were added. The reaction mixture was degassed with argon for 15 min, and then heated to 110C for 3 hours. The reaction mixture was cooled and diluted with EtOAc (50 mL), washed with H20 (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSC>4, filtered and volatiles were removed under reduced pressure to yield an oil from which the compound was isolated by column chromatography (Hexanes/EtOAc = 70/30) to give an off- white solid 85 mg (25%). MH+ 620.4
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 0.666667h;Inert atmosphere; Microwave irradiation;
Example 34: Preparation of (/f)-2-phenyl-2-[5-(3-trifluoromethoxy-phenyl)-pyridin-3- ylamino] -ethanol Under an Ar atmosphere, a mixture of (/?)-2-(5-boronic acid-pyridin-3-ylamino)-2-phenyl- ethanol (50 mg, 0.2 mmol), l-bromo-3-trifluoromethoxy-benzene (48 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (12 mg) and potassium carbonate (56 mg, 0.4 mmol) in DME/H2O (1 :5, 5 mL) was heated at 90 C under microwave for 40 mins. Then the residue was partitioned between EtOAc and brine. The aqueous layer was separated and then extracted with EtOAc. The combined organic layers were concentrated, and then the residue was purified by Prep-HPLC to give (/?)-2-phenyl-2-[5-(3-trifluoromethoxy-phenyl)-pyridin-3-ylamino]-ethanol (11 mg).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; for 3h;Inert atmosphere; Reflux;
4-Ethoxy-4-oxobutylzinc bromide solution (25 mL, 0.5 Min THF, 12.5 mmol) was added to a solution of <strong>[2252-44-0]1-<strong>[2252-44-0]bromo-3-(trifluoromethoxy)benzene</strong></strong> (2.6 g, 10.8 mmol) in THF (10 mL) under N2 . Pd(dppf)Clz (1.18 g, 1.62 mmol) was added, and the reaction was heated at reflux for 3 h. The solution was concentrated and purified by silica gel chromatography (0-20% EtOAc/hexanes) to give 1.22 g (41%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): 8 1.26 (3H, t, J = 7.2 Hz), 1.91-2.00 (2H, m),2.32 (2H, t, J = 7.4 Hz), 2.67 (2H, t, J = 7.4 Hz), 4.13 (2H, q, J = 7.2 Hz), 7.03-7.07 (2H,m), 7.11 (1H, d, J = 7.7 Hz), 7.30 (1H, t, J = 7.7 Hz).
2-(3-bromo-5-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 1-(4,4'-di-tert-butyl-[2,2'-bipyridin]-6-yl)-2-(dimethyl(phenyl)silyl)-2,3-dihydro-1H-benzo[d][1,3,2]diazaborole;Inert atmosphere; Schlenk technique; Sealed tube;
General procedure: B2pin2, [IrCl(COD)]2 (1.0 mol%), preligand 1 (2.0 mol%), and (hetero)arene (0.2 mmol, ifsolid) were placed in a dried Schlenk flask (15 mL in volume) equipped with a stirring bar. Afterevacuating and refilling the flask with dry nitrogen three times, (hetero)arene (0.2 mmol, if liquid)and methoxycyclopentane (CAPE, 0.5 mL) were added with syringes under a stream of nitrogen.The resulting mixture was stirred at the corresponding temperature for the assigned time. After cooling to room temperature, the reaction mixture was concentrated and then purified by columnchromatography on silica gel to give the target product (The spectra data for the borylated compoundscan be seen in the Supplementary Material).
3-(3-(trifluoromethoxy)phenyl)pyridazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); lithium carbonate; In N,N-dimethyl acetamide; at 160℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added <strong>[2164-61-6]pyridazine-3-carboxylic acid</strong> (0.6 mmol, 1.0 eq), aryl- and heteroaryl-bromides (1.2 mmol, 2.0 eq), Pd(PPh3)4 (35 mg, 0.03 mmol, 5.0 mol %), Cu2O (84 mg, 0.6 mmol, 1.0 eq), Li2CO3 (107 mg, 1.8 mmol, 3.0 eq), 3A MS (200 mg) and DMA (4.0 mL). The mixture was stirred at 160 C for 24 h under N2. After the reaction was complete, the mixture was washed with brine and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/1), the eluent need bubbled NH3 five seconds. The eluent of TLC (ethyl acetate / petroleum ether 1:1) need bubbled NH3 two seconds.
1-(3-(trifluoromethoxy)phenyl)propan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 1-bromo-3-(trifluoromethyl)benzene (2.00 g, 8.30 mmol) in THF (20 mL) was dropped a solution of n-BuLi in n-hexane (2.5 M, 3.3 mL, 8.30 mmol) at - 78oC under nitrogen and the mixture was stirred at -78oC for 15 minutes. To the solution at - 78oC was dropped a solution of Compound 4A (1.17 g, 9.93 mmol) in THF (4 mL) and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was quenched with saturated NH4Cl solution (50 mL) at -20oC, and extracted with ethyl acetate (160 mL). The organic layer was separated, washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 8% v/v) to give Compound 4B. LC-MS (ESI) m/z: 219 [M+H]+.
2-(3,5-bis(trifluoromethyl)phenyl)-4-nitro-1-(trifluoromethoxy)-6-(trifluoromethyl)-1H-benzo[d]imidazole[ No CAS ]
[ 2252-44-0 ]
[ 64115-88-4 ]
[ 407-14-7 ]
Yield
Reaction Conditions
Operation in experiment
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 16h;Glovebox; Irradiation; Sealed tube; Inert atmosphere;
In a glovebox, to an oven-dried 20 mL screw cap vial was added 2- (3, 5-bis (trifluoromethyl) phenyl) -4-nitro-l- (trifluoromethoxy) -6- (trifluoromethyl) -lii-benzo [d] imidazole (1) (105 mg, 0.200 mmol, 1.00 equiv) , arene (2.00 mmol, 10.0 equiv) and Ru (bpy) 3 ( REe) 2, (0.0516 mg, 0.0600 pmol, 0.0300 moll) . Then MeCN (1.00 mL, 0.200 M) and a magnetic stir bar were added. The vial was capped and taken out of the glovebox. The reaction mixture was then stirred and irradiated with a 10 W LED (402 nm) at room temperature. After 16 h, an internal standard PhCF3 (5.84 mg, 4.95 pL, 0.04 mmol, 0.200 equiv) was added to the reaction vial, 0.200 mL of the resulting mixture was transferred to a 2 mL vial containing 0.500 mL of CDCI3. After the yield was determined using 19F NMR, the NMR sample was combined with the rest of the reaction mixture and the solvent was removed in vacuo. The crude material was purified by HPLC under noted conditions. The fractions containing the desired product were combined and extracted with CDCI3 (3 1 mL) , dried with magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to furnish the desired product of trifluoromethoxylation . For volatile compounds, after purification by HPLC, the desired product was extracted with 1 mL CDC13 and then directly characterized. The NMR peaks are referring to CH3CN residue signal ^H-NMR: d 1.94, 13C~NMR: 5 118.26, 1.32).2
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; In acetonitrile; at 20℃; for 16h;Glovebox; Irradiation; Sealed tube; Inert atmosphere;
General procedure: In a glovebox, to an oven-dried 20 mL screw cap vial was added 3- methyl-4-nitro-l- ( trifluoromethoxy) -6- (trifluoromethyl ) -1H- benzo[d] [1, 2, 3] triazol-3-ium trifluoromethanesulfonate (lb) (98.0 mg, 0.200 mmol, 1.00 equiv), arene (2.00 mmol, 10.0 equiv) and Ru (bpy) 3 (PFe) 2, (1.72 mg, 2.00 pmol, 1.00 mol%). Then MeCN (1.00 mL, 0.200 M) and a magnetic stir bar were added. The vial was capped and taken out of the glovebox. The reaction mixture was then stirred and irradiated with 2 of 10 W LED (Xmax = 447 nm) at room temperature. After 16 h, an internal standard PhCF3 (24.6 pL, 0.200 mmol, 1.00 equiv) was added to the reaction vial, 0.200 mL of the resulting mixture was transferred to a 2 mL vial containing 0.500 mL of CDC13. After the yield was determined using 19F NMR, the NMR sample was combined with the rest of the reaction mixture and the solvent was removed in vacuo. The crude material was purified by HPLC under noted conditions. The fractions containing the desired product were combined and extracted with CDC13 (3 x 10.0 mL) , dried with magnesium sulfate, and filtered unless otherwise noted. The filtrate was concentrated in vacuo to furnish the desired product of trifluoromethoxylation . For volatile compounds, after purification by HPLC, the desired product was extracted with 1 mL CDCI3 and then directly characterized. The NMR peaks are referring to CCN residue signal (1H-NMR : d 1.94, 13C-NMR: d 118.26, 1.32).2
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