* 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 Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361
2
[ 372-39-4 ]
[ 2713-34-0 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
3
[ 372-39-4 ]
[ 2106-40-3 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 153[2] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 153[4] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
4
[ 372-39-4 ]
[ 315-14-0 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 153[2] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 153[4] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
5
[ 372-39-4 ]
[ 372-38-3 ]
[ 1435-43-4 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 153[2] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
6
[ 372-39-4 ]
[ 363-69-9 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 153[2] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 153[4] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
7
[ 372-39-4 ]
[ 1542-34-3 ]
Reference：
[1] Journal of Fluorine Chemistry, 2003, vol. 124, # 1, p. 39 - 43
[2] Synthetic Communications, 2009, vol. 39, # 6, p. 1100 - 1108
[3] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
8
[ 372-39-4 ]
[ 361-72-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 29, p. 6451 - 6466
9
[ 946839-66-3 ]
[ 372-39-4 ]
Yield
Reaction Conditions
Operation in experiment
69%
With sulfuric acid; palladium 10% on activated carbon; hydrogen In methanol at 120℃; for 15 h; Autoclave
Add N-benzyl-3,5-difluoroaniline (4.42 g, 0.02 mol) in a 250 mL autoclave.Methanol (50 mL), sulfuric acid (5 g), 10percent palladium on carbon (0.35 g), sealed container, H2 was replaced 2-3 times, then the pressure was charged to 3.0 MPa, and reacted at 120 ° C for 15 h.After distilling off the solvent, the reaction mixture was evaporated to dryness m.Column chromatography (PE) gave white solid 3,5-difluoroaniline (1.8 g, 69percent).
Reference：
[1] Patent: CN108314624, 2018, A, . Location in patent: Paragraph 0054; 0055; 0056; 0057
10
[ 461-96-1 ]
[ 372-39-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 120℃; for 6 h; Autoclave; Green chemistry
(3) 190.5g of 3,5-difluorobromobenzene was added to a 1000.0mL autoclave, 291.7 g of 30.0percent aqueous ammonia solution and 1.44 g of cuprous oxide catalyst were further added, Heated to 120 , the reaction was stirred 6.0h, The gas phase was detected until the reaction of the raw material was complete. The crude product was extracted with 200.0 g of dichloroethane and the organic phase was distilled to obtain 109.7 g of the final product of 3,5-difluoroaniline with purity of about 99.0percent. The total yield was 85.0percent in two steps.
Reference：
[1] Patent: CN105949067, 2016, A, . Location in patent: Paragraph 0029
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 2272,2277
20
[ 372-39-4 ]
[ 5509-65-9 ]
Reference：
[1] Patent: US5294742, 1994, A,
21
[ 372-39-4 ]
[ 99389-26-1 ]
Reference：
[1] Canadian Journal of Chemistry, 1985, vol. 63, p. 2471 - 2475
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 9, p. 2225 - 2230
[3] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2363 - 2373
[4] Patent: WO2013/127267, 2013, A1,
22
[ 372-39-4 ]
[ 210532-25-5 ]
Reference：
[1] Magnetic Resonance in Chemistry, 1998, vol. 36, # SPEC. ISS., p. S169-S178
[2] Patent: US6509499, 2003, B1,
23
[ 372-39-4 ]
[ 126674-93-9 ]
Reference：
[1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1078 - 1087
[2] Patent: US2008/293749, 2008, A1,
24
[ 372-39-4 ]
[ 379228-58-7 ]
Reference：
[1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1078 - 1087
25
[ 372-39-4 ]
[ 379228-57-6 ]
Reference：
[1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1078 - 1087
26
[ 372-39-4 ]
[ 126674-77-9 ]
Reference：
[1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1078 - 1087
[2] Patent: WO2012/69380, 2012, A1,
[3] Patent: US2008/293749, 2008, A1,
27
[ 372-39-4 ]
[ 203302-95-8 ]
Yield
Reaction Conditions
Operation in experiment
80.2%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃;
Intermediate H5,7-difluoro-quinoline-6-carbaldehyde 2 1 DnM"BFuLi i ii intermediate H 5,7-difluoro-phenylamine (10.0 g, 77.5 mmol) was dissolved in DMF (100 ml_). NBS (13.9 g, 78.0 mmol) was then added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with Et2O and washed with brine. The separated organic phase was dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography to give 4-bromo-3,5-difluoro-phenylamine (i) (12.9 g, 80.2percent)A mixture of 4-bromo-3,5-difluoro-phenylamine (i) (6.0 g, 28.8 mmole), 1.82 g ferrous sulfate, 8.6 ml. glycerol, 1.79 ml. nitrobenzene , and 5.0 ml. concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate= 12/1 ) to give 6-bromo-5,7-difluoroquinoline (ii) as a white solid (3.5 g, 49.8percent).To a solution of 6-bromo-5,7-difluoroquinoline (ii) (250 g, 1.02 mol) in anhydrous THF (2200 ml.) at -780C, was added a solution of n-BuLi in hexane ( 2.5 M, 408 ml ,1.02 mol) dropwis. The resulting mixture was stirred for additional 30 min at -780C. Then, a solution of DMF (79 ml_, 1.02 mol) in anhydrous THF (200 ml.) was added while the temperature was kept lower than -700C, and the mixture was stirred at the same temperature for 30 mins. The reaction mixture was warmed slowly to room temperature and diluted with aqueous saturated solution of NH4CI (1000 ml.) and water (800 ml_). The mixture was extracted with ethyl acetate twice, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give brown oil, which was purified by column chromatography on silica gel eluted with petroleum and ethyl acetate (10:1 ) to give 5,7-difluoro-quinoline-6- carbaldehyde (intemediate H) as a yellow soild (100 g, 50percent). 1H NMR (DMSO, 300MH) δ(ppm): 10.38(s, 1 H), 9.10~9.12(m, 1 H), 8.62~8.66(m,1 H),7.68~7.78(m,2H)
148 g
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 2.16667 h;
To a solution of commercial 3,5-difluoronaniline (100 g, 770 mmoles) in DMF (310 mL) there is added a solution of N-bromosuccinimide (140 g, 786 mmoles) in DMF (310 mL) in the course of 40 minutes. The resulting solution is stirred at ambient temperature for 1½ hours. The whole is transferred to 8 L of water, which causes the desired intermediate to precipitate. The solid is filtered over a frit and then rinsed with copious amounts of water. The solid obtained is dried in the air for 48 hours: 148 g of the expected intermediate in the form of a white solid are obtained and used without additional treatment in the following step. 1H NMR (400 MHz, DMSO-d6): δ 6.3 (2d, 2H), 3.90 (m, 2H) IR (cm-1): 3479-3392;
With n-butyllithium In tetrahydrofuran; hexane 1.) -70 deg C, 20 min, 2.) -70 deg C, 45 min;
Stage #1: 3,5-difluoroaniline With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h;
Stage #2: 1,2-bis-(chlorodimethylsilyl)ethane In tetrahydrofuran; hexane at -78 - 20℃;
3; 7
n-Butyllithium (55 mL, 1.6 M in hexane, 7.18 mmol) was added drop wise to a solution of 3,5-difluoroaniline (5 grams, 38. 76 mmol) in THF (78 mL) at-78°C under nitrogen atmosphere and stirred for 20 minutes. A solution of 1,2- bis (chlorodimethylsilyl) ethane (8. 33 grams, 38.76 mmol) in THF (78 mL) was added to the reaction mixture and stirred for 45 minutes and then it was brought to room temperature. The reaction mixture was quenched with water (115 mL) and extracted with diethyl ether. The combined organic layers were washed with water and brine and dried over NA2SO4. The solvent was removed under vacuum to obtain 1- (3, 5-difluorophenyl) -2, 2,5, 5-tetramethyl- [1, 2,5] azadisilolidine (10.12 grams) and this crude product was used in the next step without purification. To a solution OF 1-(3, 5-difluorophenyl) -2, 2,5, 5-TETRAMETHYL- [1, 2,5] azadisilolidine (10.12 grams, 37.3 mmol) in THF (60 mL) was slowly added 27 mL (42.96 mmol) OF 71-BULI (1.6 M in hexane) at-78 °C under nitrogen and stirred for 4 h. A solution OF TETRAHYDRO-4- pyranone (7.11 grams, 71.1 MMOL) IN dry THF (10 mL) was added to the above mixture and warmed to room temperature. The reaction mixture was stirred for 18 h, then quenched with 100 mL of water and concentrated under vacuum. The resulting residue was acidified with cone. HCl and the acidic solution was extracted with diethyl ether (150 mL). The aqueous layer was basified with 40% aqueous NAOH solution at 0 °C and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and evaporated on rotavapor. The resulting residue was refluxed with cone. HCl (40 mL) for 3 h and then allowed to cool to room. temperature. The reaction mixture was basified with aqueous NH3 (30%) and was extracted with dichloromethane. The solvent was evaporated on rotavapor and the residue was purified through silica gel column (ethyl acetate/hexane ; 3: 17) to furnish the required product (2.2 grams, 27%) as a pale brown solid. 'H NMR (CDC13) : 8 6.21-6. 10 (D, J= 11. 6 Hz, 2H), 5.83-5. 78 (m, 1H), 4.18-4. 12 (m, 2H), 3.93-3. 87 (m, 4H), 2.42-2. 26 (m, 2H); MS (M/E) : 212 (M+L) ; IR (KBr) : 3464,3346, 3229,1761, 1649,1571, 1364,1015 CM .; Preparation-7 4- (3, 6-DIHYDRO-2H-THIOPYRAN-4-YL)-3, 5-DIFLUORO-PHENYLAMINE : n-Butyllithium (55 mL, 1.6 M in hexane, 87.18 mmol) was added drop wise to a solution of 3,5-difluoroaniline (5 grams, 38. 75 mmol) in THF (78 mL) at-78 °C under nitrogen atmosphere and stirred for 20 minutes. , a solution of 1,2- bis (chlorodimethylsilyl) ethane (8.5 grams, 39.53 RNMOL) in THF (78 mL) was added drop wise. The reaction mixture was stirred at the same temperature for 0.5 h and then allowed to warm to room temperature. The reaction mixture was quenched with water (100 mL), extracted with diethyl ether and then the organic layer was washed with brine. The solvent was removed under vacuum to obtain 1- (3, 5-difluorophenyl) -2, 2,5, 5-TETRAMETHYL- [1, 2,5] azadisilolidine (10.7 grams) and this crude product was used in the next step without purification. To a solution of 1- (3, 5-difluorophenyl)-2, 2,5, 5-TETRAMETHYL- [1, 2,5] azadisilolidine (10.7 grams, 39.4 MMOL)) in THF (80 mL) was slowly added 28.4 mL of n- BuLi (45.3 mmol, 1. 6 M in hexane) AT-78 °C. under nitrogen and stirred the same for 4 h. Then a solution of tetrahydro-4-thiopyranone (5.26 grams, 45.3 mmol) in THF (30 mL) was added to the reaction mixture and slowly brought to room temperature and stirred for further 18 h. The reaction mixture was quenched with water (50 ML), concentrated under vacuum and the resulting residue was acidified with conc. HC1. The acidic solution was extracted with diethyl ether. The aqueous layer was basified with 40% aqueous NAOH solution and extracted with diethyl ether (3 x 150 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated under vacuum. The resulting residue was refluxed with conc. HC1 (60 mL) for 3.5 h and then allowed to cool to room temperature. The reaction mixture was basified with aqueous NH3 (30%) and was extracted with dichloromethane. The solvent was evaporated on a rotavapor and the crude product was column chromatographed over silica gel (ethyl acetate/petroleum ether; 3: 17) to get the desired compound (3. 8 grams, 43%) as a pale brown solid. 'H NMR (CDC13) : 8 6.20-6. 16 (m, 2H), 5.96-5. 82 (m, 1H), 3.95-3. 81 (m, 2H), 3.36-3. 27 (m, 2H), 2.85 (t, J= 5.9 Hz, 2H), 2.56-2. 43 (m, 2H); MS (m/e): 228 (M++1), 142; IR (KBr): 3496,3386, 2925,1648, 1578,1459, 1159,1007, 822 CRRI 1.
With hydrogenchloride; acetic acid; sodium nitrite;copper(I) chloride; In water;
The starting material, 3,5-difluorobenzenesulphonyl chloride, is obtained according to the procedure described in Example 28, using, on the one hand, 22 ml of concentrated hydrochloric acid, 7.7 ml of acetic acid, 10.0 g (77.5 mmol) of 3,5-difluoroaniline and 5.8 g (84.1 mmol) of sodium nitrite in 15 ml of water, and, on the other hand, 77 ml of acetic acid saturated with sulphur dioxide and 1.9 g (19.2 mmol) of cuprous chloride.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
Intermediate H5,7-difluoro-quinoline-6-carbaldehyde 2 1 DnM"BFuLi i ii intermediate H 5,7-difluoro-phenylamine (10.0 g, 77.5 mmol) was dissolved in DMF (100 ml_). NBS (13.9 g, 78.0 mmol) was then added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with Et2O and washed with brine. The separated organic phase was dried (Na2SO4) and concentrated to give an oil which is purified by column chromatography to give 4-bromo-3,5-difluoro-phenylamine (i) (12.9 g, 80.2%)A mixture of 4-bromo-3,5-difluoro-phenylamine (i) (6.0 g, 28.8 mmole), 1.82 g ferrous sulfate, 8.6 ml. glycerol, 1.79 ml. nitrobenzene , and 5.0 ml. concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for five hours. Nitrobenzene was removed by distillation in vacuo. The aqueous solution was acidified with glacial acetic acid, and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate= 12/1 ) to give 6-bromo-5,7-difluoroquinoline (ii) as a white solid (3.5 g, 49.8%).To a solution of 6-bromo-5,7-difluoroquinoline (ii) (250 g, 1.02 mol) in anhydrous THF (2200 ml.) at -780C, was added a solution of n-BuLi in hexane ( 2.5 M, 408 ml ,1.02 mol) dropwis. The resulting mixture was stirred for additional 30 min at -780C. Then, a solution of DMF (79 ml_, 1.02 mol) in anhydrous THF (200 ml.) was added while the temperature was kept lower than -700C, and the mixture was stirred at the same temperature for 30 mins. The reaction mixture was warmed slowly to room temperature and diluted with aqueous saturated solution of NH4CI (1000 ml.) and water (800 ml_). The mixture was extracted with ethyl acetate twice, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give brown oil, which was purified by column chromatography on silica gel eluted with petroleum and ethyl acetate (10:1 ) to give 5,7-difluoro-quinoline-6- carbaldehyde (intemediate H) as a yellow soild (100 g, 50%). 1H NMR (DMSO, 300MH) delta(ppm): 10.38(s, 1 H), 9.10~9.12(m, 1 H), 8.62~8.66(m,1 H),7.68~7.78(m,2H)
With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide); at 20℃;
L 4-Cyclopropyl-3, 5-difluoro-2-chloroaniline 3, 5-Difluoroaniline (10.0 g, 77.5 MMOL) is dissolved in DMF (100 mL). NBS (13.9 g, 78.0 MMOL) is added portionwise at room temperature. After stirring overnight at room temperature, the reaction mixture is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give an oil which is purified by column chromatography (METHYLENE CHLORIDE/HEXANES) to give 4-bromo-3, 5-difluoroaniline. 4-Bromo-3, 5-difluoroaniline (10.5 g, 50.5 MMOL) is dissolved in DMF (100 mL). NCS (28.6 g, 50.5 MMOL) is added portionwise at room temperature. After 48 hours, the reaction is diluted with ET20 and washed with brine. The separated organic phase is dried (NA2SO4) and concentrated to give an oil. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-bromo-2-chloro-3, 5-difluoroaniline. A mixture of 4-bromo-2-chloro-3, 5-difluoroaniline (5.35 g, 22.0 MMOL), cyclopropylboronic acid (2.20 g, 24.0 MMOL), K3P04 (16 g, 78 MMOL) and tricyclohexyl phosphine (0.623 g, 2.24 MMOL) in toluene (30 mL) and water (8 mL) is degassed with N2 and heated to 100C. Pd (OAC) 2 (0.25 g, 1.16 MMOL) is added. The reaction mixture is heated to 100C overnight, cooled and loaded directly on a column of silica gel. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-cyclopropyl-3, 5-difluoro-2- chloroaniline.
148 g
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2.16667h;
To a solution of commercial 3,5-difluoronaniline (100 g, 770 mmoles) in DMF (310 mL) there is added a solution of N-bromosuccinimide (140 g, 786 mmoles) in DMF (310 mL) in the course of 40 minutes. The resulting solution is stirred at ambient temperature for 1½ hours. The whole is transferred to 8 L of water, which causes the desired intermediate to precipitate. The solid is filtered over a frit and then rinsed with copious amounts of water. The solid obtained is dried in the air for 48 hours: 148 g of the expected intermediate in the form of a white solid are obtained and used without additional treatment in the following step. 1H NMR (400 MHz, DMSO-d6): delta 6.3 (2d, 2H), 3.90 (m, 2H) IR (cm-1): 3479-3392;
N-(3,4-Difluoro-phenyl)-acetamide.l Acetyl chloride (82.61 mL, 774.50 mmol) was added slowly to a solution of 3,4-Difluoro-phenylamine (100 g, 774.50 mmol) in pyridine (250 mL) in ice bath. The mixture was stirred at 0 C for 45 min then was kept at room temperature for 3 hrs. Solvent was removed under reduced pressure. The residue was crystallized in acetone/ water to give a solid. ¹H NMR (300 MHz, CDC13): No. 7.86 (br, 1H), 7.62 - 7.55 (m, 1H), 7.07 (m, 2H), 2.16 (s, 3H).
N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In 1,4-dioxane; water;
Step B: N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea To a stirred solution of 2.7 grams (0.021 mole) of 3,5-difluoroaniline in 100 ml of dioxane was added via syringe 1.5 ml (0.013 mole) of trichloromethyl chloroformate. The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature, and 2.0 grams (0.021 mole) of <strong>[20744-39-2]4-aminopyridazine</strong> and 7.01 ml (0.05 mole) of triethylamine were added. The reaction mixture was heated at 50 C. for one day, cooled to ambient temperature and filtered. The filter cake was washed with dioxane and dried. The solid was slurried in hot water for one hour. The mixture was filtered and the filter cake dried to give 4.1 grams of N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea; m.p. 272-273 C. The nmr spectrum was consistent with the proposed structure.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 1.5h;
Example 11; Preparation of 3-(3,5-Difluorophenyl)-2-[l-(9H-purin-6-ylamino)propyl]thieno[3,2- d] pyrimidin-4(3H)-one; 11a. Synthesis of tert-Butyl {2-[(3,5-difluorophenyl)carbamoyl]-3- thienyl}carbamate.; [00190] Following the procedure from Example Ia and using 3-[(tert- butoxycarbonyl)amino]thiophene-2-carboxylic acid (2.000 g, 8.221 mmol) and [B] 3,5-difluoroaniline (2.65g, 20.5 mmol ) for 6 days the product was obtained as a yellow solid (1.447g 49%).
With triethylamine; In toluene; at 20℃; for 0.166667h;
Example 53; N-(3,5-difluorophenyl)-5-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)nicotinamide; Example 53A; 5-bromo-N-(3,5-difluorophenyl)nicotinamide; Oxalyl chloride (1.2 mL) and DMF (25 muL) were added to 5-bromonicotinic acid (1.0 g, 4.95 mmol) suspended in CH2Cl2 (30 mL). The resulting mixture was stirred at room temperature for 12 min. It was then concentrated to dryness and azeotroped with toluene. The residual was then dissolved in toluene (30 mL). 3,5-Difluoroaniline (1.0 g, 7.8 mmol) was added followed by triethylamine (1.1 mL, 7.5 mmol). The resulting suspension was stirred at room temperature for 10 min. The reaction mixture was taken in 5% acetic acid(aq) (300 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extract was washed with 1.0 M Na2CO3(aq) (2×100 mL) and brine. The organic layers were combined, dried (Na2SO4) and concentrated to dryness to provide the title compound (1.4 g, 93%). MS (APCI) m/z 313, 315 (M+H)+.
Intermediate 10: N-(3,5-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine-2-carboxamide To a solution of 980 mg of aniline in 100 mL of toluene cooled to 0 C. are added dropwise 5 mL of a 2M solution of trimethylaluminium in toluene and then, at 20 C., 1.5 g of <strong>[214958-32-4]ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate</strong>. The reaction mixture is stirred for 2 hours at 20 C. The resulting mixture is cooled to 4 C. and 100 mL of saturated ammonium chloride solution are then added. After concentrating under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure. The residue is triturated in ethyl ether, filtered off and dried to give 258 mg of N-(3,5-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid. 1H NMR spectrum (DMSO-d1, delta in ppm): 6.92 (tt, J=2.0 and 9.0 Hz, 1H), 7.51 (d, J=9.5 Hz, 1H), 7.59 (dd, J=1.5 and 9.5 Hz, 1H), 7.72 (m, 2H), 8.47 (s, 1H), 9.02 (broad s, 1H), 10.75 (s, 1H).
With dichlorotriphenylphosphorane; In tetrahydrofuran; for 2.0h;Inert atmosphere;
General procedure: To a stirred solution of <strong>[88598-08-7]furazancarboxylic acid</strong> 2 (2.6 mmol) and the appropriate aniline 3-14 (2.6 mmol) in dry THF (25 mL) Ph3PCl2 (5.46 mmol, 2.1 eq) was added portionwise under an inert atmosphere. The resulting suspension was stirred for 2 h, then poured into chilled 2 M HCl (50 mL). The mixture was extracted exhaustively with Et2O, then the collected organic layers were dried and concentrated under reduced pressure. The residue was purified by flash chromatography obtaining the title compound.
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 4h;
To a solution of <strong>[315-14-0]2,4,6-trifluoronitrobenzene</strong> (1.37 g, 7.74 mmol) and 3,5 difluoroaniline (1 g, 7.74 mmol) in THF (23 mL) was added potassium tert-butoxide (1.3 g, 11.6 mmol) and reaction mixture was stirred at rt for 4 h. After completion of the reaction, water (50 mL) was added and the organic phase extracted with EtOAc (200 mL), dried over sodium sulfate and purified by column chromatography using 100-200 mesh silica gel and 0-10% EtOAc in hexane to provide N-(3,5-difluorophenyl)-3,5-difluoro-2-nitroaniline: LC-MS (ESI) m/z 284.9 [M+H]+.
Stage #1: 3-chloro-2-nitropyridine; 3,5-difluoroaniline With caesium carbonate In ISOPROPYLAMIDE for 0.25h; Inert atmosphere;
Stage #2: With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In ISOPROPYLAMIDE at 100℃; for 12h;
57
To a degassed solution of 3-chloro-2-nitro-pyridine (1.35 g, 8.51 mmol) and 3,5 difluoroaniline (1.0 g, 7.74 mmol) in dimethyl acetamide (23.2 mL) was added cesium carbonate (6.34 g, 19.35 mmol) and the reaction mixture was further degassed with nitrogen for 15 min. xanthophos (267 mg, 0.46 mmol) and Pd2 (dba)3 (212 mg, 0.23 mmol) were added to the reaction mixture and stirred at 100° C. for 12 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl actate (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to get the crude material, which was purified by column chromatography using silica gel (100-200 mesh) and 0-30% EtOAc in hexane to provide (3,5-difluorophenyl)-(2-nitro-pyridin-3-yl)-amine: 1H NMR (DMSO-d6, 400 MHz) δ 6.856-6.980 (m, 3H), 7.659-7.691 (m, 1H), 8.017 (dd, J=1.6 Hz, J=1.6 Hz, 1H), 8.126-8.140 (m, 1H), 9.094 (s, 1H); LC-MS (ESI) m/z 252.0 [M+H]+.
6-(3,5-difluorophenylamino)-3-nitropicolinonitrileA mixture of 6.5 g of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (0.065 mol) and 6.2 g of 3,5- difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.
33%
In toluene; at 70℃; for 5h;
Example 8a 6-(3,5-difluorophenylamino)-3-nitropicolinonitrile A mixture of 6.5 g of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (0.065 mol) and 6.2 g of 3,5-difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70 C. for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.
33%
In toluene; at 70℃; for 5h;
A mixture of 6.5 g of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (0.065 mol) and 6.2 g of 3,5-difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid
33%
In toluene; at 70℃; for 5h;
Example 8a: 6-(3,5-difluorophenylamino)-3-nitropicolinonitrile A mixture of 6.5 g of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (0.065 mol) and 6.2 g of 3,5- difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.
33%
In toluene; at 70℃; for 5h;
Example 8a: 6-(3,5-difluorophenylamino)-3-nitropicolinonitrile A mixture of 6.5 g of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (0.065 mol) and 6.2 g of 3,5- difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.
33%
In toluene; at 70℃; for 5h;
A mixture of 6.5 g of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (0.065 mol) and 6.2 g of 3,5-difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
) A/-(3,5-Difluorophenyl)-1 H-imidazole-2-carboxamideTo a solution of 1 /-/-<strong>[16042-25-4]imidazole-2-carboxylic acid</strong> (2.50 g, 22.3 mmol) in DMF (30 mL) were added 3,5-difluoroaniline (2.23 mL, 22.3 mmol), EDC-HCI (6.41 g, 33.46 mmol) and HOBt (4.52 g, 33.46 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuum and the crude was dissolved in dichloromethane. The solution was washed with a diluted aqueous solution of potassium carbonate, dried over sodium sulphate, filtered and concentrated. 2.75 g (55% yield) of the title compound were obtained as a solid.LRMS (m/z): 224 (M+1 )
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
N,N'-bis(3,5-difluorophenyl)pyridine-2,6-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
In toluene for 12h; Inert atmosphere; Schlenk technique; Reflux;
70%
With dmap; tributyl-amine In dichloromethane at 20℃; for 24h;
5 2.1.5 Preparation of N,N'-bis(3,5-difluorophenyl)pyridine-2,6dicarboxamide, 5
2.1.5 Preparation of N,N'-bis(3,5-difluorophenyl)pyridine-2,6dicarboxamide, 5 N,N'-Bis(3,5-difluorophenyl)pyridine-2,6dicarboxamide, 5 was synthesized by the coupling reactions in dichloromethane (DCM) (30 mL) between 2,6-pyridine dicarbonyl chloride (0.25 g, 1.22 mmol, 1 equiv.) and 3,5-difluoroaniline (0.40 g, 3.10 mmol, 2.5 equiv.). Tri-n-buthylamine (1.2 mL, 4 equiv.) and 4-dimethylaminopyridine (DMAP) (10 mg) were used as base and catalyst. The reactions mixture was stirred at room temperature for 24 h. After removal of the solvent, the residue was washed with water, DCM and methanol to give product 5 as a white solid (0.33 g, 70% yield). 1H NMR (DMSO-d6, 400 MHz) δ 7.05 (2H, t, J = 9.0 Hz, ArHC para to NHCO), 7.71 (4H, d, J = 8.0 Hz, ArHC ortho to NHCO), 8.32 (1H, t, J = 7.6 Hz, ArHC meta to CONH), 8.41 (2H, d, J = 7.2 Hz, ArHC ortho to CONH), 11.15 (2H, s, CONH). 13C NMR (DMSO-d6, 100 MHz) δ 100.0 (2*CHAr), 104.0 (2*CHAr), 104.3 (2*CHAr), 126.4 (2*CHPyridine), 140.8 (CHPyridine), 141.0 (CAr-NH), 141.2 (CAr-NH), 148.6 (2*CPyridine-CONH), 161.8 (2*CONH), 162.5 (2*CAr-F), 164.0 (CAr-F), 164.2 (CAr-F). ESMS (-ve): m/z (% rel. Intensity) 388.2 [M-H]- (100), m.p. > 270 °C. Elemental analysis, Calc. for C19H11F4N3O2: C 58.62, H 2.85, N 10.79; found: C 58.72, H 2.79, N 10.74.
Multi-step reaction with 3 steps
1.1: 1 h / 100 °C / Inert atmosphere
1.2: 4 h / Heating
2.1: diphenylether / 0.33 h / 200 °C
3.1: trichlorophosphate / 12 h / Reflux
Multi-step reaction with 3 steps
1.1: 1 h / 100 °C / Heating / reflux
1.2: 4 h / Heating / reflux
2.1: diphenylether / 0.33 h / 200 °C / Heating / reflux
3.1: trichlorophosphate / 12 h / Heating / reflux
With aluminum oxide; In 5,5-dimethyl-1,3-cyclohexadiene; for 8h;Reflux;
General procedure: Ferrocene-1,1-dicarbaldehyde (0.22 g, 0.90 mmol), aromatic amine (2.14 mmol), and 75 mL xylene were sequentially added to a 150 mL three-neck round bottom flask. When the ferrocene-1,1-dicarbaldehyde was completely dissolved with stirring vigorously, 0.2 g basic Al2O3 (1.96 mmol) was added. The reaction mixture was heated to reflux for 8 h and then filtered. Solvent was evaporated and the product was washed with solvent, affording a corresponding product in a certain yield.
(S)-3-(3,5-difluorophenylamino)-4-(1-(naphthalen-1-yl)ethylamino)cyclobut-3-ene-1,2-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: 3,5-difluoroaniline; 3,4-dimethoxy-3-cyclobutene-1,2-dione In methanol at 20℃; for 30h;
Stage #2: (S)-1-(1-Naphthyl)ethylamine In methanol for 3h;
2; 18
General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.
N-((1R,2R)-2-(2-(3,5-difluorophenylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.
4-chloro-N-(3,5-difluorophenyl)-2,3-dihydro-1H-inden-1-imine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,2-dichloro-ethane; at 90℃; for 24h;Molecular sieve;
General procedure: To a solution of 1-indanone (264 mg, 2.0 mmol) and 5-fluoropyridin-3-amine (235mg, 2.1 mmol) in 20 mL dichloroethane was added 20 g 4A molecular sieves, and the mixture was stirred at 90 C for 24 hours. The reaction was monitored by TLC. After consumption of indanone, the sieves were removes by filtration through celite, and the filtrate was evaporated to afford the imine product 4 which was used for next step without further purification.
7-chloro-N-(3,5-difluorophenyl)-2,3-dihydro-1H-inden-1-imine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,2-dichloro-ethane; at 90℃; for 24h;Molecular sieve;
General procedure: To a solution of 1-indanone (264 mg, 2.0 mmol) and 5-fluoropyridin-3-amine (235mg, 2.1 mmol) in 20 mL dichloroethane was added 20 g 4A molecular sieves, and the mixture was stirred at 90 C for 24 hours. The reaction was monitored by TLC. After consumption of indanone, the sieves were removes by filtration through celite, and the filtrate was evaporated to afford the imine product 4 which was used for next step without further purification.
Stage #1: 2-(2,4-dithia-1,5-disodapentan-3-ylidene)propanedinitrile; 2,3,6,7-tetrabromonaphthalene-1,4,5,8-tetracarboxylic dianhydride In N,N-dimethyl-formamide at 55℃; for 1h;
Stage #2: 2-decyl-1-tetradecylamine; 3,5-difluoroaniline In N,N-dimethyl-formamide at 55℃; for 12h;
2,2-[2-(3,5-difluoro-4-iodo)phenyl-8-(2-decyltetradecyl)-1,2,3,7,8,9-hexahydro-1,3,7,9-tetraoxo[1,3]benzodithiolo[4,5,6,7-lmn][1,3]dithiolo[4,5-f][3,8]phenanthroline-5,11-diylidine]bis(malononitrile) (1).
General procedure: Under ambient conditions, a solution of 3 (500 mg, 0.86 mmol) and sodium 1,1-dicyanoethene-2,2-dithiolate (480 mg, 2.57 mmol) in DMF (25 mL) was stirred at 55 °C for 1 hour. Then 2-decyltetradecylamine (394 mg, 1.11 mmol) and 3,5-difluoroiodoaniline[2] (371 mg, 1.46 mmol) were added to the reaction mixture. The resulting purple black solution was stirred at 55 °C for 12 hours, and water (200 mL) was added to quench the reaction. The product was extracted with CH2Cl2 (3 × 50 mL), and the combined organic solution was washed with water, brine, and dried over anhydrous MgSO4. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography with CH2Cl2 as eluent. Compound 1 was obtained as a purple red solid (yield: 10 %).
7-bromo-N-(3,5-difluorophenyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: 7-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid With 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 0.5h;
Stage #2: 3,5-difluoroaniline In dichloromethane at 20℃;
5.1.3. General synthetic method for compounds (3a-d)
General procedure: The carboxylic acid (0.8 mmol), HATU (hexafluorophosphateazabenzotriazole tetramethyl uranium) (455 mg, 1.2 mmol) and triethylamine (324 mg, 3.2 mmol) were stirred for 30 min in 20 mL dichloromethane. The corresponding amine (1.19 mmol) was added to the reaction mixture and stirred overnight. The resulting solid was filtered, washed with dichloromethane and crystallized from methanol unless otherwise noted. Purification was carried out over silica gel chromatography till purity reached >95%.
N-(3,5-difluorophenyl)-5-nitropyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In acetonitrile;Inert atmosphere;
first step:A dry 50 mL reaction jar was vacuumed three times with nitrogen and added to the reaction jar.3,5-difluoroaniline(129mg, 1.0mmol, 1.0equiv),Add 10.0 mL of dried acetonitrile and stir until3,5-difluoroaniline is completely soluble,Then <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (0.1593 g, 1.0 mmol, 1.0 equiv) was added to the reaction flask. Mix allThe reaction was carried out under nitrogen pressure for 4-5 hours. The reaction was detected by TLC, and if the reaction of aniline was completely detected,The reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction flask with ethyl acetate, andTransfer to a 100 mL round bottom flask and add 2 mL (200-300 mesh) of silica gel to the round bottom flask for spin-drying (Petroleum Ether and B)Ethyl acetate) passed through the silica gel at the column. Wait until the intermediate product is pale yellow crystalN-(3,5-difluorophenyl)-5-nitropyrimidin-2-amine(224 mg, 89% yield)
2-(2-cyanophenyl)-N-(3,5-difluorophenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: 3,5-difluoroaniline With trimethylaluminum In toluene at 0 - 20℃; for 0.5h;
Stage #2: methyl 2-(2-cyanophenyl)acetate In toluene at 0 - 80℃; for 9h;
General procedure for synthesis of substituted 2-(2-cyanophenyl)-N-phenylacetamide 3(a-u) derivatives
General procedure: Trimethyl aluminium (1.5 mmol, 2.0 M in toluene) was added to a solution ofamine (2 mmol) in toluene (10 mL) at 0 °C and stirred at room temperature for 30 min. Compound 4 (1 mmol) was added at 0 °C and stirred at 80 °C for 9 h. Afterthe completion of the reaction (by TLC), the reaction mixture was quenched withwater (15 mL), stirred for 10 min, ltered through a pad of Celite, and the Celitebed washed with AcOEt (10 mL). The organic layer was separated from the ltrate,and the aqueous layer was extracted with AcOEt (2 9 15 mL). The combinedorganic layers were washed with 1 N HCl and brine solution, dried over anhydroussodium sulphate and concentrated in vaccuo. Crude product was puried by ashchromatography (Hexane/AcOEt 7:3 v/v) to afford 2-(2-cyanophenyl)-N-phenylac-etamide 3(a-u) derivatives.
2-(3,5-difluorophenyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With tert.-butylnitrite; sodium acetate; tetra-(n-butyl)ammonium iodide; dibenzoyl peroxide; In acetonitrile; at 80℃;Schlenk technique; Inert atmosphere;
General procedure: In air, Bpin-B(dan) (0.1 mmol, 1.0 eq.), aryl amide (0.2 mmol, 2.0 eq.), TBAI (0.01 eq.),NaOAc (0.15 eq.), and BPO (0.01 eq.) were sequentially weighed and added to a screw-cappedSchenk tube containing a magnetic stir bar. The vessel was evacuated and refilled with nitrogen forthree times. t-BuONO (0.2 eq.) and MeCN (0.6 mL) were added in turn under N2 atmosphere usingsyringes through a septum which was temporarily used to replace the screw cap. The reaction mixturewas then vigorously stirred at 80 C for the indicated time. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with ethyl acetate (3 mL x 2). The combined filtratewas evaporated under vacuum to dryness and the residue was purified by column chromatography toyield the desired product.
5-(4-chlorophenyl)-N-(3,5-difluorophenyl)furan-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: 5-(4-chlorophenyl)-2-furoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: 3,5-difluoroaniline In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
4.2.3 General procedure 'A' for synthesis of compounds SH01 to SH10
General procedure: The ice-cold suspension of intermediate compound 3 (100mg, 0.45mmol, 1 equivalent) with dimethyl formamide (1.5mL) was prepared and carbonyldiimidazole (1.5 to 2.0 equivalent) was added under nitrogen atmosphere, the resulting reaction mixture was warmed to room temperature and allowed to stir for 1h. Later, the reaction mixture was cooled to 0°C, different substituted amines (1 to 2 equivalent) were added, the resulting reaction mixture was warmed to room temperature and stirred for 3 to 6h. The reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to 0°C and diluted with water, the resultant separated product was filtered off, washed with water and dried. The resulting residues were purified by silica gel column chromatography to get final compounds SH01-SH10 (except SH02).
N-(3,5-difluorophenyl)-3-hydroxynaphthalene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With phosphorus trichloride In chlorobenzene at 100 - 130℃; for 0.75h; Microwave irradiation;
General Procedure for the Synthesis of N-(Disubstituted phenyl)-3-hydroxynaphthalene-2-carboxamides 1-24
General procedure: 3-Hydroxynaphthalene-2-carboxylic acid (0.5 g, 2.65 mM) was suspended in drychlorobenzene (20 mL) at ambient temperature and phosphorus trichloride (0.12 mL,1.35 mM), and the corresponding substituted aniline (2.65 mM) was added dropwise.The reaction mixture was transferred to the microwave reactor, where the synthesis wasperformed (1st phase: 10 min, 100 C; 2nd phase: 15 min, 120 C; 3rd phase: 20 min, 130 C;max 500 W). The mixture was then cooled to 60 C, and the solvent was removed underreduced pressure. The residue was washed sequentially with hydrochloric acid and water,and the crude product was recrystallized from EtOH. All the compounds are presented inTable 1.
Stage #1: 3,5-difluoroaniline With 5,10-dihydro-6,9-dioxa-7,8-dithia-dibenzo[<i>a</i>,<i>c</i>]cyclodecene; tris(pentafluorophenyl)borate In 1,4-dioxane at 20℃; for 12h;
Stage #2: 1-Adamantanethiol With lithium carbonate In 1,4-dioxane at 20℃; for 8h;
48 Synthesis of compound 3y:
Add 3,5-difluoroaniline (12.9mg, 0.1mmol, 1.0equiv), 5 (29.0mg, 0.105mmol, 1.05equiv), B(C6F5)3 (0.5mg, 0.001mmol, 1mol%) to the reaction tube And redistilled 1,4-dioxane (0.25mL), stirred at room temperature for 12 hours, and then added 1-adamantanethiol (20.1mg, 0.12mmol, 1.2equiv) and lithium carbonate (7.4mg, 0.1mmol, 1.0 equiv), stirring at room temperature for 8 hours, removing the solvent, and column chromatography to obtain a bright yellow liquid 3y (25.1 mg, 70%).
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