4-Amino-2-(trifluoromethyl)benzonitrile

Off-White Solid

General procedure: A mixture of compound 3a or 3b (19 mmol) and CuCN (29 mmol, 1.5 eq) in DMF (20 ml) was heated at 145 °C under nitrogen overnight. The reaction mixture was cooled to room temperature and then poured into ice water (50 ml). Ethyl acetate (100 ml) was added and the insoluble solid was filtered off (washed with ethyl acetate [2 x 30 ml]). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated aqueous NaHCO3 solution (1 x 150 ml), brine (3 x 100 ml) and dried over Na2SO4. The resulting material was concentrated and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate, 10:1) to afford the title compound (4a or 4b) as a gray solid (60–65 percent yield). 4-Amino-2-(trifluoromethyl) benzonitrile (4a) Yield: 65 percent; mp 143–145 °C, Gray Powder; IR (KBr) ν max: 3485–3362 (N–Hstretch), 2219 (C:N), 1627 (N–Hbend), 1615 1566, 1509, 1467 (C=Caroma), 1361, 1185, 1121, 1044 (C–Hbend), 1276, 550 (CF3) cm-1; 1H NMR (CDCl3, 400 MHz, ppm): δ 7.46 (d, J = 3.6 Hz, 1H, C6-H), 7.01 (d, J = 2 Hz, 1H, C3-H), 6.82 (dd, J = 2.4 Hz, J = 5.2 Hz, 1H, C5-H), 6.12 (br s, 2H, –NH2); 13C NMR (100 MHz, CDCl3, ppm): δ 152.6 (C4), 135.1 (C6), 132.7 (C2), 123.3 (C5), 120.5 (CF3), 116.7 (C3), 114.9 (CN), 110.7 (C1); HRMS (ESI): m/z calculated for C8H5F3N2 [M–H]-: 185.03321; Found: 185.03133.Under a nitrogen atmosphere, copper acetate (20 molpercent, 4.6 mg) and a magnet were added to a previously baked 10 mL glass pressure tube. Then, N, N-dimethylformamide (0.5 mL), 4-iodo-3-trifluoromethylaniline (0.125 mmol, 1.0 equiv., 35.9 mg) was added. The pressure tube was sealed and the air inside the tube was removed and filled with carbon dioxide (5.0 equiv., 15 mL), ammonia (5.0 equiv., 15 mL) and hydrogen (5.0 equiv., 15 mL). After adding, place the pressure tube of the glass in advance to warm up In a 160°C metal module, stir for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature and pressure was slowly released. Using dodecane as an internal standard, the yield of the gas chromatography was determined to be 74percent.4-Amino-2-trifluoromethyl-benzonitrile (20.44 g, 109.79 mmoles) and p-toluenesulfonic acid monohydrate (1.05 g, 5.52 mmoles) were dissolved methanol (200 mL) and THF (200 mL), and the reaction mixture was stirred under a nitrogen atmosphere. The reaction vessel was wrapped in aluminium foil, while the solution was stirred for 20 min., then N-iodosuccinimide (30.41 g, 135.17 mmoles) was added and the reaction was allowed to stir overnight (16 hrs). The reaction mixture was concentrated in vacuo, triturated with hexanes (3*400 mL) and concentrated to dryness. The crude solid was dissolved in diethyl ether (400 mL), washed with water (3*), the organic extracts were diluted with hexanes (400 mL) and a white solid precipitated. The solid was filtered and dried in a vacuum oven (35 C. a762 Torr) overnight to yield the title compound. 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), delta 7.00 (s, 1H), delta 4.83 (br s, 2H) MS calculated for C8H4F3IN2: 312.03, found 311 (M-H).EXAMPLE 81 4-Amino-5-iodo-2-trifluoromethyl-benzonitrile 4-Amino-2-trifluoromethyl-benzonitrile (20.44 g, 109.79 mmoles) and p-toluenesulfonic acid monohydrate (1.05 g, 5.52 mmoles) were dissolved methanol (200 mL) and THF (200 mL), and the reaction mixture was stirred under a nitrogen atmosphere. The reaction vessel was wrapped in aluminium foil, while the solution was stirred for 20 min., then N-iodosuccinimide (30.41 g, 135.17 mmoles) was added and the reaction was allowed to stir overnight (16 hrs). The reaction mixture was concentrated in vacuo, triturated with hexanes (3*400 mL) and concentrated to dryness. The crude solid was dissolved in diethyl ether (400 mL), washed with water (3*), the organic extracts were diluted with hexanes (400 mL) and a white solid precipitated. The solid was filtered and dried in a vacuum oven (35 C. a 762 Torr) overnight to yield the title compound. 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), delta 7.00 (s, 1H), delta 4.83 (br s, 2H) MS calculated for C8H4F3IN2: 312.03, found 311 (M-H).EXAMPLE 81 4-Amino-5-iodo-2-trifluoromethyl-benzonitrile 4-Amino-2-trifluoromethyl-benzonitrile (20.44 g, 109.79 mmoles) and p-toluenesulfonic acid monohydrate (1.05 g, 5.52 mmoles) were dissolved methanol (200 mL) and THF (200 mL), and the reaction mixture was stirred under a nitrogen atmosphere. The reaction vessel was wrapped in aluminium foil, while the solution was stirred for 20 min., then N-iodosuccinimide (30.41 g, 135.17 mmoles) was added and the reaction was allowed to stir overnight (16 hrs). The reaction mixture was concentrated in vacuo, triturated with hexanes (3*400 mL) and concentrated to dryness. The crude solid was dissolved in diethyl ether (400 mL), washed with water (3*), the organic extracts were diluted with hexanes (400 mL) and a white solid precipitated. The solid was filtered and dried in a vacuum oven (35 C. a 762 Torr) overnight to yield the title compound. 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), delta 7.00 (s, 1H), delta 4.83 (br s, 2H) MS calculated for C8H4F3IN2: 312.03, found 311 (M-H).4-Bromo-2-trifluoromethylbenzonitrile: In a round bottom flask, 4-cyano-3-trifluoromethylaniline (20 g, 107.5 mmol) was solubilized in 300 mL of 47% aq HBr. This solution was cooled to 0 C. in an ice bath and NaNO2 (22.2 g, 322 mmol) was added slowly. Then CuBr (46.3 g, 322.5 mmol) was added slowly. After the addition, the ice bath was removed and the mixture was stirred at 20 C. for 3 hr. The mixture was cooled to 0 C. in an ice bath and 500 mL of water were added to get a yellow precipitate. Solid was filtered and washed successively with 10% aq. HCl (50 mL) and water (100 mL), and dried to give the product (23.5 g, 87%), 1H NMR (300 MHz, Acetone-d6)delta: 8.19 (s, 1H, C3-H), 8.16 (d, 1H, J=8 Hz, C6-H), 8.05 (d, 1H, J=8 Hz, C5-H).To a solution of 4-amino-2-(trifluoromethyl)benzonitrile 29 (1.02 g, 5.48 mmol) in acetonitrile (30 mL) was added tert-butyl nitrite (0.95 mL, 7.19 mmol) dropwise at 0 C. After stirring at 0 C for 0.5 h, copper (II) bromide (1.39 g, 6.22 mmol) was added and the mixture was warmed to room temperature. The mixture was stirred at room temperature for 14 h, poured into brine, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 30 (1.13 g, 82%) as a yellow oil. 1H NMR (200 MHz, CDCl3) delta: 7.60-8.10 (3H, m).General procedure: 4-Cyano-3-(substituted) aniline 4a or 4b (38 mmol) was dissolved in conc. HCl (27 ml). After cooling to 0 C, sodium nitrite (39 mmol, 1.5 eq) was added very slowly to the stirred solution with the temperature being kept within (0 and 5 C). This diazonium salt solution was then poured into a flask containing CuBr (53 mmol, 1.4 eq) and 22 ml of conc. HCl. The solution was stirred for 2 h, and then, the reaction mixture was poured into ice water (50 ml) extracted with Ethyl acetate (100 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with saturated aqueous NaHCO3 solution (1 x 150 ml), brine (3 x 100 ml) and dried over Na2SO4. The resulting material was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate, 10:1) to afford the title compound (5a or 5b) as white solid (72-75 % yield). 4-Bromo-2-(trifluoromethyl) benzonitrile (5a) Yield 75 %; White Solid; IR (KBr) nu max: 3101, 3040 (C-Harom), 2924, 2853 (C-Halk), 2235 (C:N), 1594, 1558, 1542, 1508, 1484, 1405 (C=Carom), 1182, 1142, 1057 (C-Hbend), 1304, 1270, 551 (C-CF3) cm-1; 1H NMR (400 MHz, CDCl3, ppm): delta 7.96 (s, 1H, H-2), d 7.87 (d, J = 8.0 Hz, 1H, H-6), 7.74 (d, J = 8.0 Hz, 1H, H-5); 13C NMR (100 MHz, CDCl3, ppm): delta 135.8 (C6), 134.4, 133.8 (q, J = 65.5 Hz, C2), 130.3 (q, CF3), 128.2 (d, J = 26 Hz, C5), 122.9 (C3), 120.2 (C4), 114.8 (CN), 108.9 (C1); HRMS (ESI): m/z Calcd for C8H3 79BrF3N [M'H]?: 249. 94737 Found: 249.94696; Calcd for C8H3 81BrF3N [M'H]?: 251.94520; Found: 251.94479.Examples 1 and 2; 4-bromo-2-(trifluoromethyl) benzonitrileIntermediate lb; To a solution of 4-amino-2-(trifluoromethyl) benzonitrile (la) (5.0 g, 26.9 mmol) in CH3CN (50 mL), cooled to 0C, Isoamyl nitrite (6mL, 40.9 mmol) was added and stirred for 30 min. Then CuBr2 (7.1 g, 32.0 mmol) was added portion wise to the reaction mixture maintaining the temperature at 0C. The reaction mixture was slowly warmed to room temperature and stirred for further 4 h. After completion of reaction (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (3 x 70 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to provide the crude residue which was purified by column chromatography to afford the bromo lb (5 g, 74%) as a syrup.TLC: 30% EtOAc/Hexane (Rf: 0.8)'H NMR (500MHZ, CDC13, delta in ppm): 7.95 (s, 1H), 7.85 (d, J= 8.5 Hz, 1H), 7.71 (d, J= 8.5 Hz, 1H).4-Bromo-2-trifluoromethyl-benzonitrile (74) is prepared from 4-cyano-3-trifiuoromethyl-aniline (47) via diazotization. 4-Bromo-2-trifluoromethyl-benzonitrile (74) is reacted with BuLi to yield Li- derivative (75). 3-Bromo-benzonitrile is reacted with BuLi to yield the Li derivative (77). Alkylation of Li-derivative (77) with (2-bromo-ethoxy)-rerr-butyl-dimethyl-silane (78) yields derivative (79) which is converted to acetophenone (80) by MeMgI. Following deprotection and Mitsunobu reaction with /7-CN-phenol forms acetophenone (82). Addition of Li-derivative (75) followed by dehydration yields compound XL VHI, as presented in Figure 3.Reference Example 8 Production of 4-bromo-2-(trifluoromethyl)benzonitrile To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (1.02 g) in acetonitrile (30 ml) was added dropwise tert-butyl nitrite (0.95 ml) at 0 C. The reaction mixture was stirred at the same temperature for 0.5 hour.. To the reaction mixture was added copper bromide (II) (1.39 g) little by little.. The temperature of the reaction mixture was raised up to room temperature, and the reaction mixture was stirred further for 14 hours.. The reaction mixture was poured into a saturated solution of sodium chloride, extracted with ethyl acetate, and the ethyl acetate layer was dried over magnesium sulfate and concentrated.. The residue was purified by column chromatography (carrier: silicagel, eluant: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to obtain the titled compound (1.13 g) as pale yellow oily substance.1H-NMR (CDCl3) delta 7.71 (1H, d, J=8.2 Hz), 7.8-7.9 (1H, m), 7.95 (1H, s).To the cooled and vigorously stirred suspension of 4-amino-2-(trifluoro- methyl)benzonitrile (5.00 g, 26.8 mmol) in 25 ml of concentrated hydrogen bromide a solution of sodium nitrite (1.85 g, 26.8 mmol) in 10 ml of water was added drop- wise while keeping the temperature below 5 C during the addition. This mixture was then poured into a solution of copper(I)bromide (3.85 g, 26.8 mmol) in 30 ml of concentrated hydrogen bromide and stirred at RT for two hours. The reaction mixture was then poured into an ice- water (300 ml) mixture and extracted four times with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and water, dried and evaporated to dryness. Combiflash purification using heptane/ethyl acetate as eluent system afforded 5.1 g of the title product. -NMR (400MHz; d6-DMSO): delta 8.13 (d, 1H), 8.18 (d, 1H), 8.27 (s, 1H)Synthesis of N-(4-Cyano-3-trifluoromethyl-phenyl)-2-oxo-propionamide Pyruvic acid (3.0 mL; 43 mmol) and thionyl chloride (3.1 mL; 43 mmol) were added simultaneously via syringes to a stirring solution of

Used for the preparation of benzene derivatives as non-steroidal androgen receptor modulators.

Molecular Weight:186.13
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Exact Mass:186.04048265
Monoisotopic Mass:186.04048265
Topological Polar Surface Area:49.8
Heavy Atom Count:13
Complexity:227
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes