* 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] Patent: JP2005/120047, 2005, A, . Location in patent: Page/Page column 129
2
[ 767-00-0 ]
[ 2315-86-8 ]
Yield
Reaction Conditions
Operation in experiment
93%
at -15 - 10℃;
Example 1; 3-Bromo-4-hydroxybenzonitrile (IV)4-Cyanophenol (III) (5.0 g, 0.042 mol) was dissolved in acetonitrile (50 mL), under a nitrogen atmosphere. The mixture was cooled to -15°C, and CF3SO3H was added (3.7 mL, 6.3 g, 0.042 mol). The temperature was kept under 100C and NBS (8.2 g, 0.046 mol) was added in 6 portions. The reaction mixture was brought at room temperature and was stirred for 4 hours under a nitrogen atmosphere, monitoring by TLC (Hexane/EtOAc 75:25, UV, KMnψ4). When the starting material was completely consumed, the mixture was diluted with an aqueous solution OfNa2CO3 and extracted with MTBE (3 x 50 mL). The combined organic layers were dried over sodium sulphate and the solvent was removed under reduced pressure to afford the title compound, as a white solid (7.7 g, 93percent).1H NMR (DMSO, 300 MHz, 300 K): δ= 8.04 ppm (d, J=2.2 Hz, IH), 7.63 (dd, J=2.2 Hz, J=8.5 Hz, IH), 7.04 (d, J=8.5, IH).
89.1%
Stage #1: With iodine In dichloromethane at -5℃; for 0.166667 h; Stage #2: With bromine In dichloromethane at 20℃; for 24 h;
Intermediate 13-bromo-4-hydroxy benzonitrile preparation For 1000 ml in three-necked bottle, adding 50g (0.420mol) to p-hydroxybenzonitrile, 1.5g (0.006mol) iodine, 200 ml dichloromethane, -5 ° C of the lower mechanical stirring 10 min. The 43.4 ml (0.840mol) bromine and 200 ml methylene chloride mixed solution into the above-mentioned reaction solution, the drop finishes, room temperature reaction 24h. the response finishes, the above-mentioned reaction solution slowly poured into 550 ml (16percent) in aqueous solution of sodium bisulfite, stirring 30 min then, filtering, washing, drying, the white solid obtained 74.1g, yield: 89.1percent
Reference：
[1] Patent: US9181298, 2015, B2, . Location in patent: Page/Page column 33; Sheet 8
[2] Journal of Organic Chemistry, 2005, vol. 70, # 11, p. 4267 - 4271
[3] Patent: WO2010/142653, 2010, A1, . Location in patent: Page/Page column 14
[4] Patent: CN103333134, 2016, B, . Location in patent: Paragraph 0101; 0102
[5] RSC Advances, 2014, vol. 4, # 49, p. 25898 - 25903
[6] Tetrahedron Letters, 2015, vol. 56, # 41, p. 5646 - 5650
[7] Synthetic Communications, 2011, vol. 41, # 1, p. 147 - 155
[8] Journal of the Chemical Society, 1949, p. 642,645
[9] Patent: WO2010/92043, 2010, A1, . Location in patent: Page/Page column 78-79
[10] Patent: WO2011/141933, 2011, A2, . Location in patent: Page/Page column 44
[11] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 7867 - 7877
3
[ 2973-78-6 ]
[ 2315-86-8 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 105 - 110℃; for 5 h;
Step-1: Preparation of 3-bromo-4-hydroxy-benzonitrile (XVII)Into a 3L round bottomed flask formic acid(98percent, 0.7L) and 3-bromo-4-hydroxy- benzaldehyde (l OOg) were charged and stirred for 15 minutes. Sodium formate(59g) and hydroxylamine hydrochloride(38.4g) were charged and the reaction mixture was heated to 105 -1 10°C. Reaction mass was maintained at the same temperature for 5 hours and brought to room temperature. Water(2.3L) was added and the reaction mass was stirred for 2hours. Reaction mass was filtered and washed with water(500ml). Dried in tray drier at 60-65°CYield: 69g(70percent)Purity by HPLC: 97percentMelting range: 150-158°C
70%
Stage #1: With formic acid In water for 0.25 h; Stage #2: at 105 - 110℃; for 5 h;
Step-1: Preparation of 3-bromo-4-hydroxy-benzonitrile (XVII) Into a 3 L round bottomed flask formic acid (98percent, 0.7 L) and 3-bromo-4-hydroxy-benzaldehyde (100 g) were charged and stirred for 15 minutes. Sodium formate (59 g) and hydroxylamine hydrochloride (38.4 g) were charged and the reaction mixture was heated to 105-110° C. Reaction mass was maintained at the same temperature for 5 hours and brought to room temperature. Water (2.3 L) was added and the reaction mass was stirred for 2 hours. Reaction mass was filtered and washed with water (500 ml). Dried in tray drier at 60-65° C. Yield: 69 g (70percent) Purity by HPLC: 97percent Melting range: 150-158° C.
With oxalyl dichloride; Triphenylphosphine oxide In chloroform at 20℃; for 1 h;
General procedure: To a solution of triphenylphosphine oxide (14 mg, 0.050 mmol) in either CHCl3, CDCl3 or EtOAc (3.0 mL) was added oxalyl chloride (102 μL, 1.21 mmol) and the reaction mixture was stirred for 5 min. The appropriate oxime (1.00 equiv) was then added in one portion and the reaction mixture was stirred for 1.0 h at room temperature after which the solvent was removed in vacuo. Purification by flash chromatography (silica, 10-100percent Et2O/pet. ether) gave the pure nitriles.
Reference：
[1] Chemical Communications, 2013, vol. 49, # 30, p. 3146 - 3148
6
[ 1689-84-5 ]
[ 2315-86-8 ]
[ 767-00-0 ]
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 365, p. 151 - 156
7
[ 1689-84-5 ]
[ 17345-61-8 ]
[ 2315-86-8 ]
[ 767-00-0 ]
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 365, p. 151 - 156
8
[ 767-00-0 ]
[ 2315-86-8 ]
[ 1689-84-5 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[3] Journal of the Chemical Society, 1949, p. 642,645
[4] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
9
[ 78338-69-9 ]
[ 2315-86-8 ]
Reference：
[1] Chemische Berichte, 1896, vol. 29, p. 2357
10
[ 2315-86-8 ]
[ 74-88-4 ]
[ 117572-79-9 ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In acetonitrile at 25℃; for 6 h;
A mixture of 3-bromo-4-hydroxybenzonitrile (5.0 g, 25.3 mmol), potassium carbonate (7.0 g, 50.1 mmol) and iodomethane (3.9 g, 2,7.8 mmol) in acetonitriie (20 ml) was stirred at 25°C for 6 hours. TLC showed the reaction was complete. The mixture was paititioned between etliyl acetate (100 mi) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted 30percent ethyl acetate in hexane) to afford 3-bromo-4-methoxybenzonitrile (4.8 g, 22.6 mmol, yield 89percent).
With N-Bromosuccinimide; trifluorormethanesulfonic acid In acetonitrile
93%
With 1,1'-(ethane-1,2-diyl)dipyridinium bistribromide at 20℃; for 0.5h;
93%
With N-Bromosuccinimide; trifluorormethanesulfonic acid at -15 - 10℃;
1
Example 1; 3-Bromo-4-hydroxybenzonitrile (IV)4-Cyanophenol (III) (5.0 g, 0.042 mol) was dissolved in acetonitrile (50 mL), under a nitrogen atmosphere. The mixture was cooled to -15°C, and CF3SO3H was added (3.7 mL, 6.3 g, 0.042 mol). The temperature was kept under 100C and NBS (8.2 g, 0.046 mol) was added in 6 portions. The reaction mixture was brought at room temperature and was stirred for 4 hours under a nitrogen atmosphere, monitoring by TLC (Hexane/EtOAc 75:25, UV, KMnθ4). When the starting material was completely consumed, the mixture was diluted with an aqueous solution OfNa2CO3 and extracted with MTBE (3 x 50 mL). The combined organic layers were dried over sodium sulphate and the solvent was removed under reduced pressure to afford the title compound, as a white solid (7.7 g, 93%).1H NMR (DMSO, 300 MHz, 300 K): δ= 8.04 ppm (d, J=2.2 Hz, IH), 7.63 (dd, J=2.2 Hz, J=8.5 Hz, IH), 7.04 (d, J=8.5, IH).
89.1%
Stage #1: 4-cyanophenol With iodine In dichloromethane at -5℃; for 0.166667h;
Stage #2: With bromine In dichloromethane at 20℃; for 24h;
Intermediate 13-bromo-4-hydroxy benzonitrile preparation
Intermediate 13-bromo-4-hydroxy benzonitrile preparationFor 1000 ml in three-necked bottle, adding 50g (0.420mol) to p-hydroxybenzonitrile, 1.5g (0.006mol) iodine, 200 ml dichloromethane, -5 ° C of the lower mechanical stirring 10 min. The 43.4 ml (0.840mol) bromine and 200 ml methylene chloride mixed solution into the above-mentioned reaction solution, the drop finishes, room temperature reaction 24h. the response finishes, the above-mentioned reaction solution slowly poured into 550 ml (16%) in aqueous solution of sodium bisulfite, stirring 30 min then, filtering, washing, drying, the white solid obtained 74.1g, yield: 89.1%
88%
With 1,4-bis(3-methylimidazolium-1-yl)butane ditribromide In acetonitrile at 20℃; for 0.25h; Green chemistry; regioselective reaction;
88%
With hexamethonium bis(tribromide) In neat (no solvent) for 0.333333h; Green chemistry; regioselective reaction;
61%
With ethyl triphenylphosphonium tribromide In acetonitrile at 20℃; for 0.25h;
With chloroform; bromine
With N-Bromosuccinimide In acetic acid at 20℃; for 18h;
43
A solution of 4-cyanophenol (30.0 g, 252 mmol) in acetic acid (450 ml) was treated with Λ/-bromosuccinimide (44.8 g, 252 mmol). The reaction mixture was stirred at RT for 18h, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica) eluting with chloroform and methanol (99:1 ) to afford the title compound as a brown solid.1H NMR (300MHz, DMSOd6) δ [ppm] 11.54 (1 H, s), 8.04 (1 H, d, J= 2.0), 7.66 (1 H, dd, J= 2.0, J= 8.5), 7.06 (1 H, d, J=8.5).
With N-Bromosuccinimide; trifluorormethanesulfonic acid In acetonitrile at -15 - 30℃;
5
Trifluoromethane sulfonic acid (12.6 g) was added to a solution of 4-cyano phenol compound of formula-8 (10 g) in acetonitrile (40 ml) at -15 to -20°C and the temperature of reaction mixture was raised to 10°C. N-bromo succinamide (16.4 g) was added to the reaction mixture by lot- wise. The temperature of the reaction mixture was raised to 25- 30°C and then stirred for 4 hours. After completion of the reaction, sodium carbonate solution (50 ml) was added to the reaction mixture. The reaction mixture was extracted with dichloromethane, dried with sodium sulfate and distilled off the solvent under reduced pressure. Cyclohexane was added (50 ml) to the obtained residue and then cooled to 25-30°C. Filtered the obtained solid, washed with cyclohexane and dried to get the title compound. Yield: 14.5 grams.
With N-Bromosuccinimide; trifluorormethanesulfonic acid In acetonitrile at -20℃; for 5h; Inert atmosphere;
With potassium carbonate; In acetonitrile; at 25℃; for 6h;
A mixture of 3-bromo-4-hydroxybenzonitrile (5.0 g, 25.3 mmol), potassium carbonate (7.0 g, 50.1 mmol) and iodomethane (3.9 g, 2,7.8 mmol) in acetonitriie (20 ml) was stirred at 25C for 6 hours. TLC showed the reaction was complete. The mixture was paititioned between etliyl acetate (100 mi) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted 30% ethyl acetate in hexane) to afford 3-bromo-4-methoxybenzonitrile (4.8 g, 22.6 mmol, yield 89%).
In DMF (N,N-dimethyl-formamide); at 20℃; for 3 - 12h;
The tetrazole of the present example was prepared by dissolving 4-hydroxy-3-bromo-4-hydroxy-benzonitrile in DMF and adding methyl iodide and stirring at RT for 3-12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic phase was then dried over Na2SO4 and concentrated in vacuo to yield the 3-bromo4-methoxy-benzonitrile. This compound then was used to form the corresponding tetrazole via the method described in Example 3.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 72h;
Example 16; N-r(2Z)-5-tert-butyl-3-isobutyl-L3-thiazol-2(3H)-ylidenel-5-cvano-2- (cyclobutyloxv)benzamide; Example 16A; 3-bromo-4-cvclobutoxybenzonitrile; <strong>[4399-47-7]<strong>[4399-47-7]Bromocyclobutan</strong>e</strong> (2.7 g, 20.2 mmol), 3-bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of dimethylformamide and reacted at 60 0C for 72 hours. The mixture was diluted with ethyl acetate, washed with water, brine, dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed (SiO2) using a gradient from hexane to 30% ethyl acetate in hexane over 500 mL to afford the title compound. (2.2 g, 8.7 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) delta ppm 1.69 - 1.82 (m, 1 H), 1.87 - 2.00 (m, 1 H), 2.21 - 2.35 (m, 2 H), 2.45 - 2.57 (m, 2 H), 4.69 - 4.79 (m, 1 H), 6.76 (d, J=8.48 Hz, 1 H), 7.53 (dd, J=8.48, 2.03 Hz, 1 H), 7.82 (d, J=2.03 Hz, 1 H). MS (DCI/NH3) m/z 251.9 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 72h;
Example 64A 3-bromo-4-cyclobutoxybenzonitrile 3-Bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), bromocyclobutane (2.7 g, 20.2 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of DMF and heated at 60 C. for 72 hours. The reaction was diluted with EtOAc washed with water, brine dried with MgSO4 and the solvent was removed. The product was purified by flash chromatography using a gradient from 0 to 30% EtOAc in hexane to provide the title compound. 1H NMR (300 MHz, CHLOROFORM-D) delta ppm 1.69-1.82 (m, 1H) 1.87-2.00 (m, 1H) 2.21-2.35 (m, 2H) 2.45-2.57 (m, 2H) 4.69-4.79 (m, 1H) 6.76 (d, J=8.48 Hz, 1H) 7.53 (dd, J=8.48, 2.03 Hz, 1H) 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+.
With 1-butyl-3-methylimidazolium hydrogen sulfate; water at 60 - 65℃; for 2.25h; Green chemistry;
General procedure for the synthesis of carboxylic acids from nitriles
General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO4 and the reaction mixture was heated at 60-65 °C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90%) in all cases. All final products obtained were found sufficiently pure so it didn’t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95% ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity.
2,2-difluoro-5-cyano-1,3-benzoxathiolane-7-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium fluoride; In acetonitrile; at 100.0℃; for 16.0h;Industrial scale;
Place a polytetrafluoroethylene magnet in a 25 mL reaction tube and add 0.30 mmol of 3-bromo-4-hydroxybenzonitrile, 0.36 mmol of copper (bpy) CuSCF3, 0.339 mmol of potassium fluoride and 2.5 mL of acetonitrile , The reaction was stirred at 100 in a closed system for 16 h, extracted three times with n-pentane,The organic phases were combined, washed with water and then evaporated to remove the organic solvent. The obtained crude product was purified by silica gel column chromatography using n-pentane and diethyl ether (10: 1, v / v)2,2-difluoro-5-cyano-1,3-benzoxasulfide (85% yield).
With potassium carbonate In N,N-dimethyl-formamide at 0 - 40℃; for 16h;
101.1 Step 1: Preparation of 3-bromo-4-ethoxybenzonitrile.
To a stirred solution of 3-bromo-4-hydroxybenzonitrile (1 .0 g, 5.05 mmol) in N,N30 dimethylformamide (10 mL) was added iodoethane (945 mg, 6.06 mmol, 484 liL) and potassium carbonate (1 .40 g, 10.1 mmol) at 0 °C. The reaction was warmed at 40 °C for 16 h. The reaction mixture was quenched by addition of water (15 mL), then the mixture was extracted with ethyl acetate (40 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-bromo-4-ethoxybenzonitrile (1 .20 g) as a yellow solid. 1 NMR (400 MHz, ODd3) O 7.80 (d, J2.0 Hz, 1 H), 7.55 (dd, J2.0, 8.6 Hz, 1H), 6.89 (d, J8.6 Hz, 1H), 4.14 (q, J7.0 Hz, 2H), 1.49 (t, J6.9 Hz, 3H).
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