| 90% |
With sulfuric acid; dihydrogen peroxide; potassium iodide In methanol at 60℃; for 3h; |
|
| 89% |
With N-iodo-succinimide; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) In 1,2-dichloro-ethane; toluene at 85℃; for 14h; |
General Procedure:
General procedure: To a stirred solution of the substrate (1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added Ph3PAuNTf2 (0.025 mmol, 19 mg; complex Ph3PAuNTf2 toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248 mg). The resulting solution was stirred at r.t. or under reflux until complete conversion of the starting material. After removal of the solvent under reduced pressure, the crude material was purified by flash column chromatography using different gradients of hexanes and EtOAc to obtain the pure desired products. |
| 84% |
With iodine; silver sulfate In ethanol at 25℃; Darkness; |
|
| 75% |
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate In methanol; dichloromethane at 20℃; for 24h; |
4
PREPARATION 4; 2-Iodo-4-(trifluoromethyl)aniline; A solution of 5 g (31 mM) of 4-(trifluoromethyl)aniline in 90 ml of methanol and 30 ml of dichloromethane is prepared and 3.56 g (35.6 mM) of calcium carbonate are added. 14.9 g (42.7 mM) of trimethylbenzylammonium dichloroiodide are then added in portions at room temperature, with stirring. The reaction medium is stirred for 24 hours at room temperature and then filtered to remove the mineral salts. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 6.65 g of the expected compound in the form of an orange oil (yield=75%).1H NMR (CDCl3, 300 MHz) δ=5.0 (s, 2H), 6.82 (d, J=5.5 Hz, 1H), 7.38 (dd, J=5.5 Hz, 1.3 Hz, 1H), 7.79 (d, J=1.3 Hz, 1H). |
| 72% |
With sulfuric acid; dihydrogen peroxide; potassium iodide In methanol; water at 60℃; for 3h; Inert atmosphere; |
|
| 70% |
With Iodine monochloride In methanol; dichloromethane at 20℃; |
B5.1
To a solution of 4-(trifluoromethyl)benzenamine (10.0 g, 0.0617 mol) in dry methanol (200 ml) was added iodine monochloride (10.49 g, 0.148 mol) in dry MDC (40 ml) at RT slowly. Reaction mixture was stirred at RT over night. The reaction mixture was concentrated, water was added and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water, brine (2×50 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 6% ethyl acetate in pet-ether to get 2-iodo-4-(trifluoromethyl)benzenamine (12.5 g, 70%) as pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 4.42 (bs, 2H), 6.75 (d, 1H), 7.38 (d, 1H), 7.87 (s, 1H). |
| 61% |
With Iodine monochloride In water; acetic acid for 0.5h; heated 90 deg C then 25 deg C; |
|
| 61% |
With iodine; silver sulfate In ethanol at 20℃; for 18h; |
A.10; A.D.I
Method DSynthesis of substituted 2-(1 H-indol-3-yl)ethanamineStep I: substituted 2-iodo-aniline Iodine (1 eq) was added to a stirred mixture of silver sulphate (1 eq) and an aniline (1 eql) in ethanol (6.21 mL/mmol). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulphate. The organic layer was washed with brine, dried with magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to yield a substituted 2-iodo-aniline; INTERMEDIATE 10 - PREPARATION of 2-iodo-4-(trifluoromethyl)aniline. 2-iodo-4-(trifluoromethyl)aniline was prepared according to method D Step I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40 % ethyl acetate in heptane) to afford 1.08 g (61 %) of 2-iodo-4-(trifluoromethyl)aniline as a red oil.1 H NMR (DMSO-d6) δ 7.80 (s, 1 H), 7.38 (d, 1 H), 6.82 (d, 2H), 5.93 (s, 2H). |
| 61% |
With iodine; silver sulfate In ethanol at 20℃; for 18h; |
A.40
INTERMEDIATE 40 - PREPARATION of 2-lodo-4-(trifluoromethyl)aniline. Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40 % ethyl acetate in heptane) to afford 1.08 g (61 %) of the title compound as a red oil.1 H NMR (DMSO-d6) δ 7.80 (s, 1 H), 7.38 (d, 1 H), 6.82 (d, 2H), 5.93 (s, 2H). |
| 61% |
With iodine; silver sulfate In ethanol at 20℃; for 18h; |
Intermediate 40 PREPARATION of 2-iodo-4-(trifluoromethyl)aniline
Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 1.08 g (61%) of the title compound as a red oil. [0628] 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.38 (d, 1H), 6.82 (d, 2H), 5.93 (s, 2H). |
| 61% |
With iodine; silver sulfate In ethanol at 20℃; for 18h; |
D.I Intermediate 10-Preparation of 2-iodo-4-(trifluoromethyl)aniline
Iodine (1 eq) was added to a stirred mixture of silver sulphate (1 eq) and an aniline (1 eql) in ethanol (6.21 mL/mmol). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulphate. The organic layer was washed with brine, dried with magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to yield a substituted 2-iodo-aniline. 2-iodo-4-(trifluoromethyl)aniline was prepared according to method D Step I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 1.08 g (61%) of 2-iodo-4-(trifluoromethyl)aniline as a red oil. [0533] 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.38 (d, 1H), 6.82 (d, 2H), 5.93 (s, 2H). |
| 61% |
With iodine; silver sulfate In ethanol at 20℃; for 18h; |
132
INTERMEDIATE 132 - PREPARATION of 2-iodo-4-(trifluoromethyl)aniline; Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 ml 6.21 mmol) in ethanol (40 ml_). The reaction mixture was then stirred at room temperature for 18 hours and filtered through celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulphate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40 % ethyl acetate in heptane) to afford 1.08 g (61 %) of 2-iodo-4-(trifluoromethyl)aniline as a red oil. 1H NMR (DMSO-de) δ 7.80 (s, 1 H), 7.38 (d, 1 H), 6.82 (d, 2H), 5.93 (s, 2H) |
| 546 g |
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate In methanol; dichloromethane for 30h; |
|
|
With iodine; silver sulfate In ethanol at 20℃; for 16h; |
|
|
With N-iodo-succinimide In tetrahydrofuran; methanol |
|
|
With Iodine monochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; |
|
|
With iodine; sodium hydrogencarbonate In water |
|
|
With hydrogenchloride; potassium iodate; potassium iodide In methanol; water for 3.75h; |
|
|
With iodine; silver sulfate In ethanol for 2h; |
10
To a mixture of iodine (3.9 g, 15.5 mmol) and silver sulfate (4.8 g, 15.5 mmol) in ethanol (150 ml) was added 4-trifluoromethylaniline (2.5 g, 15.5 mmol). The mixture was stirred for 2 h, filtered, the solids washed well with EtOAc and the filtrate concentrated in vacuo. The residue was take up in DCM (100 ml) washed with 5% aqueous sodium hydroxide (50 ml), water (40 ml), brine (30 ml), dried (MGS04), filtered and evaporated. The crude 2-iodo-4-trifluoromethylaniline was purified by flash chromatography eluting with 4: 1HEXANE/DCM to give an orange solid (3.1 g). To the 2-iodo-4-trifluoromethylaniline from the foregoing step (900 mg, 3.14 mmol) in dry DMF (2 ml) were added ethyl 2-cyclohexanoneacetate (0.62 ml, 3.5 mmol), p- toluenesulfonic acid (20 mg), and tetraethoxysilane (0.9 ml, 4.1 mmol). The mixture was heated at 130°C for 5 h, allowed to cool to 110°C and more DMF (5 ml) was added followed by Hunig's base (2 ml) and palladium acetate (30 mg, 5 mol%). Reaction heated at 110°C for 15 h. After cooling, the reaction was diluted with EtOAc (100 ml), washed with water (2 x 30 ml), 2M aqueous HC1 (30 ml), brine (30 ml), dried (MGS04), filtered and evaporated. The crude ethyl ({6-TRIFLUOROMETHYL}-2, 3,4, 9- TETRAHYDRO-L-CARBAZOL-L-YL) acetate was purified by flash chromatography eluting with 'hexane to 10: 1HEXANE/ETHER to give a yellow oil (260 mg) which was BENZYLATED under the conditions of Example 1, Step 2. The resultant ethyl (6-trifluoromethyl-9- {4- (TRIFLUOROMETHYL) BENZYL}-2, 3,4, 9-TETRAHYDRO-1 H-CARBAZOL-1-YL) acetate was hydrolysed using the procedure of Example 1, Step 3 to give the desired (6- trifluoromethyl-9- {4- (TRIFLUOROMETHYL) BENZYL}-2, 3,4, 9-TETRAHYDRO-1 H-carbazol-1- yl) acetic acid a white solid (40 mg). H NMR (MEOD) 7.76 (1H, s), 7.55 (2H, d, J = 8. 2 HZ), 7.32 (2H, M), 7.07 (2H, d, J = 8.2 Hz), 5.58 (1H, d, J=17.7 Hz, ), 5.48 (1H, d, J= 17.7 Hz), 3.31 (1H, M), 2.92-2. 81 (1H, M), 2.72-2. 62 (1H, M), 2.48 (2H, M), 1.99-1. 81 (4H, M). m/z = 456 [MH] + |
|
With iodine; sodium hydrogencarbonate In water at 5 - 10℃; for 12h; |
General procedure: Step A: A suspension of appropriately substituted aniline (0.045 mol) in aqueous solution (50.0 mL) of sodium bicarbonate (0.045 mol) was stirred for 0.5 h. Then iodine (0.040 mol) was added at 5-10 °C and the mixture was stirred for 12.0 h. After completion, the reaction mixture was diluted with ethyl acetate (250 mL) and extracted with ethyl acetate (3 × 250 mL). The organic layers were collected, combined, washed with saturated aqueous sodium thiosulfate solution (2 × 125 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using 3:1, hexane-ethyl acetate to afford the desired o-iodo derivative. |
| 2.3 g |
With iodine; silver sulfate In ethanol at 20℃; for 1h; |
5.1
A mixture of 2.5 g of 4-trifluoromethylaniline, 3.9 g of iodine, 4.8 g of silver (I) sulfate, and 300 ml of ethanol was stirred for 1 hour at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 2.3 g of 2-iodo-4-trifluoromethylaniline.1H-NMR (CDC13) ö: 7.88-7.85 (m, 1H), 7.40-7.35 (m, 1H), 6.74 (d, 1H, J=8.3 Hz), 4.42 (br s, 2H) |
|
With iodine; sodium hydrogencarbonate In water; toluene at 20℃; Inert atmosphere; |
|
| 574 mg |
With N-iodo-succinimide; trifluoroacetic acid at 20℃; Cooling with ice; |
12.12.1 12.1 Synthesis of 2-iodo-4-trifluoromethylaniline
12.1 Synthesis of 2-iodo-4-trifluoromethylaniline A single-necked flask was charged with 4-trifluoromethylaniline (374 mg), and TFA (5 mL) was added to dissolve the former. The mixture was cooled in an ice bath, and N-iodosuccinimide (522 mg) was added in portions. The mixture was stirred at room temperature overnight. A small amount of the raw materials remained as detected by TLC, and the target product was detected by LCMS. Post-treatment: 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate (20ml) three times. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was allowed to pass through a column, so as to obtain 574 mg of 2-iodo-4-trifluoromethylaniline. LC-MS 287.8 (M + 1). |
|
With iodine; sodium hydrogencarbonate In water; toluene at 18 - 20℃; for 24h; |
10
Weigh (37.9mmol 6.1g) of compound 10-a in the equation in a flask, then 3mL of toluene and 100mL of water, then place the reaction at 18°C, add (60mmol 5g) sodium bicarbonate and (30 mmol 7.6g) Iodine, the reaction is left at room temperature for 24 hours, and after the reaction is over, it is quenched with sodium thiosulfate, extracted with the second organic solvent ethyl acetate, the solvent is removed under reduced pressure, and separated by a chromatographic column to obtain 10-b |
|
With N-iodo-succinimide; acetic acid at 20℃; for 1h; |
|
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