* 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.
Synthesis of ethyl 4-iodobenzoate A mixture of 4-iodobenzoic acid, 25 ml ethyl alcohol and 20 ml solution of dry HCl in ethyl alcohol was refluxed for 2 hours. The solid was dissolved after 1 hour of boiling. The reaction solution was cooled to room temperature and evaporated under vacuum to a volume of 10 ml. A lower organic layer formed with the chemical conversion of the acid to the ester. The resulting mixture was cooled in an ice bath. To this mixture 80 ml of diethyl ether, dry sodium hydrogen carbonate (I gram) and 50 grams of ice were added. This solution was stirred, washed by dissolution of a saturated solution of sodium bicarbonate in 50 ml water and water, dried over sodium sulfate, and evaporated under vacuum, yielding ethyl 4-iodobenzoate as a liquid oil product (5.43 gram, 96.1percent yield) [1H-NMR (CDCl3): d7.8 (s, 1H), d7.79 (s, 1H), 7.6 (s, 1H), d4.4 (d, 2H, J=7.1 Hz), d1.4 (s, 3H)].
95.5%
for 5.5 h; Reflux
In a 250 mL three-necked flask,Iodobenzoic acid (20.0 g, 80.6 mmol) was dissolved in ethanol (100.0 mL)98percent concentrated sulfuric acid (8.7 g, 88.7 mmol) was slowly added,The reaction was refluxed for 5.5 h.The reaction is completed,The mixture was evaporated to dryness under reduced pressure and the residue was washed with water (20 mL × 2)Vacuum dried to give 4-iodobenzoate 21.3g,Yield 95.5percent.
85%
at 100℃; for 24 h;
General procedure: A mixture of acid (0.2 mmol), alcohol (0.6 mmol) and GO (50 wtpercent, calculated with the mass of acid) in ethyl alcohol or DCE (1 mL) was placed in a test tube equipped with a magnetic stirring bar. The mixture was stirred at 100 °C for 24 h. After the reaction was finished, filtered the GO, solvent was removed, and the residue was separated by column chromatography to give the pure sample.
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 10, p. 2278 - 2288
[2] Patent: US2016/97037, 2016, A1, . Location in patent: Paragraph 0438
[3] Dalton Transactions, 2015, vol. 44, # 19, p. 9269 - 9280
[4] Patent: CN106565761, 2017, A, . Location in patent: Paragraph 0029; 0030; 0053; 0054; 0069; 0070
[5] Synthesis, 2008, # 4, p. 605 - 609
[6] Synlett, 2017, vol. 28, # 8, p. 981 - 985
[7] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 11, p. 2663 - 2673
[8] Monatshefte fuer Chemie, 1946, vol. 76, p. 29
[9] Justus Liebigs Annalen der Chemie, 1881, vol. 207, p. 327
[10] Chemical & Pharmaceutical Bulletin, 1984, vol. 32, # 12, p. 5044 - 5047
[11] Journal of Medicinal Chemistry, 2004, vol. 47, # 24, p. 5937 - 5944
[12] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 9, p. 2079 - 2087
[13] Patent: US6344463, 2002, B1, . Location in patent: Page column 18
[14] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[15] Transition Metal Chemistry, 2015, vol. 40, # 6, p. 665 - 671
[16] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 355 - 360
[17] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
14
[ 619-58-9 ]
[ 51934-41-9 ]
Reference：
[1] Patent: US5877207, 1999, A,
[2] Patent: US5958954, 1999, A,
[3] Patent: US5919970, 1999, A,
[4] Patent: US6025388, 2000, A,
[5] Patent: US6037488, 2000, A,
[6] Patent: US5202471, 1993, A,
[7] Patent: US5489584, 1996, A,
[8] Patent: US5534641, 1996, A,
[9] Patent: US5616712, 1997, A,
[10] Patent: US5399561, 1995, A,
[11] Patent: US5688957, 1997, A,
[12] Patent: US4980369, 1990, A,
[13] Patent: US4739098, 1988, A,
[14] Patent: US4810804, 1989, A,
[15] Patent: EP290130, 1991, B1,
[16] Patent: US2004/102360, 2004, A1,
[17] Patent: US3957871, 1976, A,
Reference：
[1] European Journal of Organic Chemistry, 2013, # 26, p. 5886 - 5892
18
[ 619-58-9 ]
[ 16004-15-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3187 - 3200
19
[ 619-58-9 ]
[ 10602-00-3 ]
Reference：
[1] Chemical Communications, 2006, # 13, p. 1430 - 1432
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9562 - 9575
20
[ 619-58-9 ]
[ 5720-07-0 ]
[ 725-14-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With caesium carbonate In 1,2-dimethoxyethane; water at 80℃; for 6 h; Inert atmosphere
Method B.A solution of 4-methoxyphenyl boronic acid (1 g, 6.58 mmol), 4-iodobenzoic acid (1.63 g, 6.58 mmol) and cesium carbonate (5.36 g, 16.45 mmol) in 3:1 1,2- dimethoxyethane/water was deoxygenated with nitrogen for 15 minutes. Pd(PPtLs)4 (380 mg, 0.329 mmol) was then added and the solution was heated to 80° C for 6h. The reaction was allowed to cool and acidified with 2M HCl which caused a precipitate to form. The precipitate was filtered and the filtrate was extracted twice with dichloromethane. The organic layer was then dried over magnesium sulfate, filtered through diatomaceous earth filter aid (CELITE.(R).) and evaporated under reduced pressure to yield a combined 1.5O g (95percent). 1HNMR (DMSO): δ 7.99 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 3.80 (s, 3H). 13CNMR (DMSO): δ 167.17, 159.49, 143.90, 131.16, 129.91, 128.77, 128.09, 126.08, 114.45, 55.17.
89%
With Pd/C; potassium carbonate In water at 110℃; for 1 h;
General procedure: The Ni and Pd carbon aerogels were always sinked in water 24 h before their use as catalysts and kept in the same solvent.Catalytic reactions: In a 100 mL three necked round-bottom flask, arylboronic acid (15 mmol), aryl halide (10 mmol) and K2CO3 (2.76 g, 20 mmol) were dissolved in 20 mL of H2O. Then, Ni or Pd carbon aerogel (0.1 mmol, 1 mol percent) was added to the mixture and the reaction was carried out under reflux (110 °C), in the presence of air and mechanical stirring. Periodic sampling of the reaction media was made to analyze the reaction evolution by GC and 1H NMR measurements. The liquid phase was decanted and the carbon aerogel was washed with water. This water extracts and the reactive solution were mixed together and acidified until pH 1 to cause the precipitation of the final product. The solid was filtrated, washed with water and dried. The pieces of aerogel were washed with AcOEt, with water and were kept submerged in this solvent before reused.
Reference：
[1] Russian Chemical Bulletin, 2007, vol. 56, # 2, p. 369 - 370
[2] Green Chemistry, 2010, vol. 12, # 1, p. 150 - 158
[3] Patent: WO2009/146013, 2009, A1, . Location in patent: Page/Page column 52
[4] Green Chemistry, 2009, vol. 11, # 12, p. 1929 - 1932
[5] Tetrahedron, 2012, vol. 68, # 32, p. 6517 - 6520
[6] Green Chemistry, 2013, vol. 15, # 12, p. 3468 - 3473
[7] Tetrahedron Letters, 2006, vol. 47, # 25, p. 4225 - 4229
21
[ 619-58-9 ]
[ 725-14-4 ]
Reference：
[1] Green Chemistry, 2010, vol. 12, # 1, p. 150 - 158
22
[ 619-58-9 ]
[ 79-10-7 ]
[ 19675-63-9 ]
Yield
Reaction Conditions
Operation in experiment
73%
With tributyl-amine; potassium carbonate In N,N-dimethyl-formamideGreen chemistry
General procedure: In a typical reaction, aryl halides (9 mmol), phenylethylene (15 mmol) (or acrylic acid), tributylamine (30 mmol) and DMF (10 mL) were placed in a round-bottomed flask with 1.47 molpercent AOFs–Ni(0) as catalyst. The reaction was carried out in a temperature controlled oil bath. After completion of the reaction, the mixture was cooled to room temperature. Then the AOFs–Ni(0) was separated from the mixture by filtration and washed sequentially with hot ethanol and reused in thenext reaction. The filtrate was extracted with ethyl acetate (30 mL) and washed with distilled water (3 × 15 mL). The solvent was then removed by rotary evaporation to give a crude product. The crude product was purified by column chromatography on H 60-silica powder using mixed solvent (petroleum ether/ethyl acetate = 3/1). The pure products were characterised by melting point, 1H NMR, HRMS and GC-MS spectroscopy.#10;#10;
Reference：
[1] RSC Advances, 2016, vol. 6, # 20, p. 16115 - 16121
[2] Applied Organometallic Chemistry, 2012, vol. 26, # 1, p. 16 - 20
[3] Journal of Chemical Research, 2016, vol. 40, # 3, p. 164 - 166
23
[ 619-58-9 ]
[ 89976-27-2 ]
Reference：
[1] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 427 - 432
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 5, p. 1865 - 1877
[3] Dalton Transactions, 2015, vol. 44, # 5, p. 2047 - 2051
[4] Patent: US2016/333004, 2016, A1,
[5] Chemical Communications, 2017, vol. 53, # 55, p. 7808 - 7811
24
[ 619-58-9 ]
[ 39959-59-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3187 - 3200
25
[ 619-58-9 ]
[ 4334-88-7 ]
Reference：
[1] Patent: CN106565761, 2017, A,
[2] Patent: CN106565761, 2017, A,
26
[ 619-58-9 ]
[ 249647-25-4 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 47, p. 15467 - 15472
27
[ 619-58-9 ]
[ 865-47-4 ]
[ 120363-13-5 ]
Yield
Reaction Conditions
Operation in experiment
99.9%
Stage #1: at 75℃; for 1 h; Inert atmosphere Stage #2: at 0℃; for 0.5 h;
Thionyl chloride (2.30 ml, 32.30 mmol) and N,N-dimethylformamide (DMF) (0.02 ml, 0.20 mmol) were added to 4-iodobenzoic acid (1.00 g, 4.00 mmol), and then the reaction system was substituted with nitrogen, heated to 75 °C, refluxed, and then stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), and then a potassium tert-butoxide 1M solution in THF (4.5 ml) was slowly added at a sub-zero temperature, and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex:EA=9:1), thereby obtaining 2-(trimethylsilyl)ethyl 4-iodobenzoate (14.00 g, 99.9percent yield). 1H NMR (CDCl3, 400 MHz) δ 7.77 (2H, d, J = 7.5 Hz, aromatic), 7.69 (2H, d, J = 8.0 Hz, aromatic), 1.59 (9H, s, (CH3)3).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 415 - 420
31
[ 619-58-9 ]
[ 120363-13-5 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 10, p. 3585 - 3591
[2] Patent: JP2015/848, 2015, A,
32
[ 619-58-9 ]
[ 111291-97-5 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 10, p. 3585 - 3591
33
[ 619-58-9 ]
[ 100-39-0 ]
[ 136618-42-3 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.166667 h; Stage #2: at 20℃; for 6.25 h;
To 4-iodobenzoic acid (15.62g, 63mmol, 1.05eq) in dry DMF (6vol, 90ml) was added potassium carbonate (8.7g, 63mmol, 1.05eq) and the suspension was stirred for 10min. Benzyl bromide (10.25g, 7.13ml, 60mmol, 1 eq) was then added over ca. 1 min. and the resulting suspension was stirred at room temperature under nitrogen for 6.25hr. The mixture was partitioned between ether (200ml) and water (200ml). The aqueous phase was extracted with more ether, then the combined organics were washed with water, aqueous lithium chloride, brine, dried and then evaporated to give the title compound as a white crystalline solid after leaving under vacuum (18.38g, 86percent). LCMS; tRET = 3.81 min, 70percent ES +ve 376, 356 (+ artefact 1.48min. 28percent). <n="61"/>1H NMR (400 MHz, DMSOd6) δppm 7.92 (d, 2H) 7.74 (d, 2H) 7.46 (d, 2H) 7.35 - 7.42 (m, 3H) 5.34 (s, 2H).
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1842 - 1851
40
[ 619-58-9 ]
[ 128796-39-4 ]
[ 195457-71-7 ]
Yield
Reaction Conditions
Operation in experiment
86%
With Pd/C; potassium carbonate In water at 110℃; for 48 h;
General procedure: The Ni and Pd carbon aerogels were always sinked in water 24 h before their use as catalysts and kept in the same solvent.Catalytic reactions: In a 100 mL three necked round-bottom flask, arylboronic acid (15 mmol), aryl halide (10 mmol) and K2CO3 (2.76 g, 20 mmol) were dissolved in 20 mL of H2O. Then, Ni or Pd carbon aerogel (0.1 mmol, 1 mol percent) was added to the mixture and the reaction was carried out under reflux (110 °C), in the presence of air and mechanical stirring. Periodic sampling of the reaction media was made to analyze the reaction evolution by GC and 1H NMR measurements. The liquid phase was decanted and the carbon aerogel was washed with water. This water extracts and the reactive solution were mixed together and acidified until pH 1 to cause the precipitation of the final product. The solid was filtrated, washed with water and dried. The pieces of aerogel were washed with AcOEt, with water and were kept submerged in this solvent before reused.
Reference：
[1] Green Chemistry, 2010, vol. 12, # 1, p. 150 - 158
[2] Tetrahedron, 2012, vol. 68, # 32, p. 6517 - 6520
[3] Patent: WO2004/81005, 2004, A1, . Location in patent: Page 135-136
To a mixture of (p-iodobenzoic acid (250 mg, 1 mmol) and EDC (300 mg, 1.5 mmol) is added dry dichloromethane (500mu) and the mixture is stirred 30 min at 40 C and N2 atmosphere under reflux. After this time N-hydroxy succinimide (250 mg, 2.2 mmol) is added to the solution and the mixture is heated at reflux overnight under inert atmosphere. After the mixture cools, the sample is purified by chromatographic column in silica, with DCM (dichloromethane) as eluent, obtaining a white solid as product.
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃;
A mixture of 248.0 mg of 4-iodobenzoic acid was addedWith 268.0 mg of N, N'-dicyclohexylcarbodiimide (DCC)And 149.6 mg of N-hydroxysuccinimide (NHS) were dissolved in anhydrous tetrahydrofuran,After overnight reaction at room temperature,Filter to remove DCU,The solvent was removed by steaming,The product was separated from the column to react with iodobenzoic acid.
D. 4-Iodobenzoic acid tert-butyl ester 4-Iodobenzoic Acid (25 g, 0.10M) was suspended in 200 ml of anhydrous dioxane containing 14 ml of concentrated sulfuric acid. Isobutylene (200 ml) was condensed and added to the suspension. The reaction vessel was sealed and stirred at room temperature for 3 days, during which time most of the material dissolved. The reaction mixture was cautiously poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium carbonate, filtered and evaporated to a colorless oil (18 g, (60%). 1H NMR (CDCl3) delta 1.59 (s, 9H), 7.68 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H).
2d) 4-iodo-N-methylbenzenamide 41.2 g (0.166 mole) of 4-iodobenzoic acid was put in a flask, 28 ml of redistilled thionyl chloride and 30 ml of benzene was added, and mixture was heated gently for 5-6 hr. than SOCl2 and toluene was removed by the way of distillation. Hot residue was added with stirring to the mixture of a 10% aqueous sodium hydroxide, containing 7 g NaOH and 62 ml of 20% aqueous methylamine. The solution was stirred for 30 min, than it was cooled down with ice and the product was collected by filtration, washed with water, dried and crystallized from a water/ethanol (1:1). Yield 85 %.
In toluene; at 20 - 70℃; for 5.5h;Molecular sieve;
4-lodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70 C under a flow of nitrogen. A solution of lambda/,lambda/-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 mL) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, so the reaction cooled from 70 C to rt. The solution was heated to 70 C for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1 :1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCI (75 mL each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield light brown oil. HPLC-MS m/z: 327 (M+23).1H-NMR (CDCI3, 400 MHz) delta 7.77 (d, 2H), 7.69 (d, 2H), 1.58 (s, 9H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 18h;Heating / reflux;
25 g (0,088 mol) 4'-n-Pentoxy[1,1']biphenyl-4-boronsaeure und 21,8 g (0,088 mol) 4-lodbenzoesaeure werden unter Inertgasatmosphaere in einer Mischung aus 270 ml Ethanol, 750 ml Toluol und 132 ml einer 2M Sodaloesung suspendiert, mit 5,08 g (4,4 mmol) Tetrakis(triphenylphosphin)palladium versetzt und im Anschluss daran 18 Stunden unter Rueckfluss erhitzt. Die grau-braune Mischung wird abgekuehlt, angesaeuert und mit Ethylacetat extrahiert. Die organische Phase wird mit Wasser und gesaettigter Kochsalzloesung gewaschen, getrocknet (Natriumsulfat) und ueber Celite filtriert. Nach Entfernen der Loesungsmittel erhaelt man 1,2 g eines Feststoffes, der nach HPLC-Analyse (Vergleich mit Referenzsubstanz) jedoch keinerlei 4"-n-Pentoxy[1,1':4',1"]terphenyl-4-carbonsaeure enthaelt. Eine Bildung von 4-n-Pentoxy[1,1':4',1"]terphenyl-4-carbonsaeure hat auf dem in WO 94/25050 angegebenen Syntheseweg offensichtlich nicht stattgefunden.
B] 3'-Trifluoromethyl-biphenyl-4-carboxylic acid 3.0 g (12.1 mmol) of 4-iodo benzoic acid was dissolved in 40 ml of 1,2-dimethoxy-ethane, 20 ml of water was added, followed by 2.44 g (12.5 mmol) of 3-(trifluoromethyl)-benzeneboronic acid, 2.27 g (20.8 mmol) of sodium carbonate and 0.28 g (0.24 mmol) of tetrakis(triphenylphosphine)palladium. This mixture was stirred for 2 hours at 95 C., cooled down to RT and filtered. The pH of this solution was adjusted with HCl (1N) to pH 1-2, and it was then extracted twice with AcOEt. The organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated to give 3.58 g crude product, which was purified by chromatography over silica gel with a gradient of MeCl2 and MeOH to give 2.70 g of the title compound as light yellow solid. MS: 265.0 (M-H)-.
With caesium carbonate;tetrakis(triphenylphosphine)palladium (0); In methanol; water; toluene;
Step 1: 4-Chlorophenylboronic acid (501 mg) was combined with 4-iodobenzoic acid (795 mg), cesium carbonate (5.22 g), toluene (16 mL), water (8 mL) and n-butanol (4 mL). The mixture was degassed under vacuum with argon purging after which, tetrakis-triphenylphosphine palladium (40 mg) was added. The reaction was heated to 80 C. for 20 hours after which, it was cooled to room temperature and diluted with ethyl acetate (16 mL). The solids were collected on a Celite pad and washed with hot methanol. The methanol filtrate was concentrated to dryness giving 4'-chloro-4-biphenylcarboxylic acid (305 mg). Yield=41%
With caesium carbonate;tetrakis(triphenylphosphine)palladium (0); In water; ethyl acetate; toluene;
Step 1: 3-Methyl-4-methoxyphenylboronic acid (542 mg) was combined with 4-iodobenzoic acid (810 mg), cesium carbonate (5.32 g), toluene (16 mL), water (8 mL) and n-butanol (4 mL). The mixture was degassed under vacuum with argon purging after which, tetrakis-triphenylphosphine palladium (38 mg) was added. The reaction was heated to 80 C. for 20 hours after which, it was cooled to room temperature and diluted with ethyl acetate (16 mL). The layers were separated and the organics were concentrated to dryness. The residue was purified on silica gel (50% to 100% ethyl acetate/hexane over 40 minutes) giving 3'-methyl-4'-methoxy-4-biphenylcarboxylic acid (240 mg). Yield=30%
2'-methoxymethyl-biphenyl-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); at 90℃; for 19h;
Example 61 10-[2'-(METHOXYMETHYL)-1,1'-BIPHENYL-4-YL]CARBONYL}-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE Step A. 2'-Methoxymethyl-biphenyl-4-carboxylic acid; To a suspension of 4-iodobenzoic acid (0.82 g, 3.31 mmol) and <strong>[126617-98-9]2-methoxymethylphenylboronic acid</strong> (0.55 g, 3.31 mmol) in dry acetonitrile (30 mL) was added a 0.4 M aqueous sodium carbonate solution (30 mL) and the reaction mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) was then added and the reaction mixture heated to 90 C. for 19 hours. The hot reaction mixture was filtered through celite, concentrated in vacuo to remove acetonitrile and the resulting aqueous suspension washed with ethyl acetate (2×30 mL). The aqueous phase was acidified to pH 1 by the addition of concentrated hydrochloric acid, the resulting white suspension cooled to 4 C. for 1 hour and the solid product filtered. Recrystallization from dichloroethane gave the title compound (0.469 g, 59%) as a white solid, m.p. 164.5-165.5 C. MS [(-)ESI, m/z]: 241 [M-H]-
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 45℃;
Iminodiacetic dimethyl ester hydrochloride (624 mg, 3.24 mmol) was suspended in 5 mL of anhydrous DMF under nitrogen, and N-methylmorpholine (360 muL, 3.27 mmol) was added. After 5 minutes, 4-iodobenzoic acid (805 mg, 3.25 mmol) was added, followed by HOBt (450 mg, 3.33 mmol) and EDC (1.0 g, 5.28 mmol). The reaction was stirred overnight at 45 0C. The solvent was removed and the residue was dissolved in EtOAc (20 mL) and washed with 0.5 M HCl, sat. NaHCO3 and water. The organic phase was collected, the solvent removed and the mixture purified by column chromatography (silica; hexanes : EtOAc 90:10 - 65:45), yielding the product as a white solid. MS(ES+): Cal'd. 392.00 (MH+), exp. 391.98 (MH+).
To 4-iodobenzoic acid (15.62g, 63mmol, 1.05eq) in dry DMF (6vol, 90ml) was added potassium carbonate (8.7g, 63mmol, 1.05eq) and the suspension was stirred for 10min. Benzyl bromide (10.25g, 7.13ml, 60mmol, 1 eq) was then added over ca. 1 min. and the resulting suspension was stirred at room temperature under nitrogen for 6.25hr. The mixture was partitioned between ether (200ml) and water (200ml). The aqueous phase was extracted with more ether, then the combined organics were washed with water, aqueous lithium chloride, brine, dried and then evaporated to give the title compound as a white crystalline solid after leaving under vacuum (18.38g, 86%). LCMS; tRET = 3.81 min, 70% ES +ve 376, 356 (+ artefact 1.48min. 28%). <n="61"/>1H NMR (400 MHz, DMSOd6) deltappm 7.92 (d, 2H) 7.74 (d, 2H) 7.46 (d, 2H) 7.35 - 7.42 (m, 3H) 5.34 (s, 2H).
Intermediate 1 : Phenylmethyl 4-iodobenzoate; Potassium carbonate (8.7g, 63mmol) was added to 4-iodobenzoic acid (15.62g, 63mmol) in dry DMF (9OmL) and the suspension stirred for 10 min. Benzyl bromide (7.13ml_, 60mmol) was added over 1 min and the suspension was stirred at room temperature under nitrogen for 6 hours 15min and then partitioned between ether (ca. 20OmL) and water (ca. 20OmL). The aqueous phase was extracted once more with ether and the combined organic extracts were washed successively with water, aqueous lithium chloride and brine and then dried and evaporated to give, after drying under high vacuum, the title compound as a white crystalline solid (18.38g). LCMS (System A): tRET = 3.81; MNH4+ = 356
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
(a) N-Succinimidyl-4-iodobenzoate (2) To the solution of 4-iodobenzoic acid (1)(1.24 g, 5.0 mmol) and triethylamine (0.71 mL, 5.0 mmol) in DMF (30 mL) was added TSTU (1.51 g, 5.0 mmol). The solution was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% HCl (50 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to yield the title compound (2) as a white powder (1.42 g, 82%); m.p. 130-132 C.; vmax/cm-1(neat) 1769 (C=O, ester), 1719 (C=O, amide); (Found C, 38.40; H, 2.41; N, 4.15. C11H8INO4 requires C, 38.28; H, 2.34; N, 4.06%.); deltaH (300 MHz, CDCl3) 7.92 (2H, d, J 12.0 Hz, H2/6), 7.85 (2H, d, J 12.0 Hz, H3/5), 2.92 (4H, s, CH2); deltac (75 MHz, CDCl3) 169.0 (OCO), 162.0 (NCO), 138.7 (C2/6), 132.0(C3/5), 125.3 (C1), 103.3(C4), 26.0 (CH2); m/z (E.I.), 345 (M+, 5%), 231 (100%), 202 (20%), and 76 (48%); HRMS for C11H8INO4 requires 344.9493 found 344.9493.
4-Iodobenzoic acid (701 mg, 2.83 mmol) and K2CO3 (810 mg, 5.86 mmol) were succesively added each in one portion to a solution of <strong>[733757-89-6]6-tert-butoxycarbonyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine</strong> (D7, 657 mg, 2.77 mmol) copper (I) iodide (44.0 mg, 0.23 mmol), and N,N-dimethylglycine (52 mg, 0.50 mmol) in anhydrous DMSO (5 ml). This was diluted with more anhydrous DMSO (6 ml) and stirred at 130 C. for 4 hours. Upon cooling to room temperature, the mixture was partitioned between DCM (150 ml), and water (130 ml), and acidified (pH 3) with aqueous HCl (2N, 5.5 ml). The separated aqueous phase was further acidified (pH 0) with more aqueous HCl (2N, 5 ml) and extracted twice with DCM (125 ml then 50 ml). The combined organic phase was concentrated in vacuo using high vacuum, and partitioned between DCM (20 ml) and water (10 ml) to remove the residual DMSO. The organic phase was concentrated in vacuo giving a brown solid (1.09 g). An aliquot (100 mg) was dissolved in anhydrous DCM, pyrrolidine (100 mul, 1.21 mmol) and HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (118 mg, 0.31 mmol) were added, and the mixture stirred at room temperature for 5 hours. The resulting solution was concentrated in vacuo, dissolved in anhydrous DCM (5 ml), and TFA (200 mul, 2.70 mmol) was added in one portion. After stirring at room temperature for 2 hours 10 minutes, more TFA (500 mul, 6.75 mmol) was added in one portion and the mixture stirred at room temperature for a further 17 hours. The mixture was then concentrated in vacuo, purified by successive SCX column chromatography and high pH MDAP, dissolved in DCM, and ethereal HCl (1M) added. Further concentration in vacuo gave the title compound (22.9 mg, 62.8 mumol). LC/MS Retention time 1.74 mins/(ES+) 365 (M+H, C18H19F3N4O requires 364).
4-[5-(difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl}benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 22h;
General procedure: CuI (0.05 equiv), 1,10-phenanthroline (0.1 equiv) and K2CO3 (2 equiv) were placed in an oven-dried screw-capped test tube with Teflon-lined septum that was filled with nitrogen. About 2.5 mL of dry DMF was then added at room temperature. Now the corresponding aryl iodide (1.0 mmol) was added followed by MBI or FMBI (1.0 equiv) and the tube was placed in the preheated oil bath at 140 C and the reaction mixture was magnetically stirred for 22 h. After complete disappearance of iodobenzene (the progress of the reaction was followed by TLC), the reaction mixture was allowed to cool to room temperature. Then water was added and the reaction mixture was extracted with ethyl acetate. After removal of the solvent in vacuum, the crude residue was purified by column chromatography.5- (or 6-) (Difluoromethoxy)-2-(phenylsulfanyl)-1H-benzimidazole (1).
With tributyl-amine; potassium carbonate; In N,N-dimethyl-formamide;Green chemistry;
General procedure: In a typical reaction, aryl halides (9 mmol), phenylethylene (15 mmol) (or acrylic acid), tributylamine (30 mmol) and DMF (10 mL) were placed in a round-bottomed flask with 1.47 mol% AOFs-Ni(0) as catalyst. The reaction was carried out in a temperature controlled oil bath. After completion of the reaction, the mixture was cooled to room temperature. Then the AOFs-Ni(0) was separated from the mixture by filtration and washed sequentially with hot ethanol and reused in thenext reaction. The filtrate was extracted with ethyl acetate (30 mL) and washed with distilled water (3 × 15 mL). The solvent was then removed by rotary evaporation to give a crude product. The crude product was purified by column chromatography on H 60-silica powder using mixed solvent (petroleum ether/ethyl acetate = 3/1). The pure products were characterised by melting point, 1H NMR, HRMS and GC-MS spectroscopy.
To a solution of the compound 7(100mg, 0.071 mmol) in THF (5 mL) was added tetra-n-butylammonium fluoride (0.715 mL, 0.71 mmol) at RT. Prior to the addition of water, the mixture was stirred for 1 h. Then,the solution was extracted with methylene chloride. The green organic layer was collected, and the solvent was evaporated under reduced pressure to get the deprotected intermediate. To a solution of the deprotected intermediate in a degassed mixture of THF (20 mL) and NEt3(3 mL) was added 4-iodobenzoic acid (21.8 mg, 85 mumol), and compound 9(27 mg, 85 mumol), Pd2(dba)3(3.25 mg, 3.55 mumol), and AsPh3(43 mg, 142 mumol). The mixture was stirred at 85 °C for 5 h.The solvent was removed under vacuum and the residue was purified by column chromatography (silica gel) using CH2Cl2/CH3OH (19/1) as eluent. Recrystallization from CH2Cl2/CH3OH gave UI-5(29.7 mg, 30percent). 1H NMR (CDCl3, 400MHz) deltaH9.74 (d, J= 4.8 Hz, 4H), 8.90 (d, J= 4.8 Hz, 4H),8.05-8.02 (m, J= 8.4 Hz, 4H), 7.91-7.84 (m, J = 8.4 Hz,4H), 7.72 (t, J= 8.4 Hz, 2H), 7.53 (m, J= 8.4 Hz, 2H), 7.40(td, J= 8.4 Hz, 3H), 3.87 (t, J= 6.4 Hz, 8H), 1.26 (m, 6H),0.99 (m, 6H), 0.82 (m, 8H), 0.50 (m, 44H), MS (MALDITOF): m/z1398.9 [M+]; C90H100N4O6Zn (1397.7).
Thionyl chloride (2.30 ml, 32.30 mmol) and N,N-dimethylformamide (DMF) (0.02 ml, 0.20 mmol) were added to 4-iodobenzoic acid (1.00 g, 4.00 mmol), and then the reaction system was substituted with nitrogen, heated to 75 C, refluxed, and then stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (5 ml), and then a potassium tert-butoxide 1M solution in THF (4.5 ml) was slowly added at a sub-zero temperature, and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex:EA=9:1), thereby obtaining 2-(trimethylsilyl)ethyl 4-iodobenzoate (14.00 g, 99.9% yield). 1H NMR (CDCl3, 400 MHz) delta 7.77 (2H, d, J = 7.5 Hz, aromatic), 7.69 (2H, d, J = 8.0 Hz, aromatic), 1.59 (9H, s, (CH3)3).
4-iodo-N-methyl-N-( 1-methylpiperidin-4-yl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Step 2. To a mixture of 4-iodobenzoic acid (1.0 g, 4mmol) HATU (1.8 g, 4.8mmol) in DIVIF was added DIPEA (1.5 g, l2mmol) at 0°C and the mixture was stirred for 10mm, then methyl-(1-methyl-piperidin-4-yl)-amine (1.02 g, 8mmol) was added, andthe reaction mixture was stirred for 2h at r,t. The reaction mixture was poured into water and the mixture was extracted with EtOAc three times. The combined organic layer was washed with water and brine, dried (Na2504), the solvent was evaporated in vacuo to give 4-iodo-N-methyl-N-( 1 -methyl-piperidin-4-yl)-benzamide (1.2 g, 83percent of yield).
3-tert-butoxycarbonylamino-(2S)-2-(4-iodobenzoylamino)propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
DIEA (9.7ml, 55.1mmol) was added to a stirred solution of 4-iodo-benzoic acid (5.49g, 22.2mmol), HOAT (3.08g,22.6mmol), EDC (4.33g, 22.6mmol) in DMF (85ml). After 2 min., the H-DAP(Boc)-OMe (1) was added in one portion.After 12 hours, the reaction was found complete by LCMS. The reaction was diluted with EtOAc/hexane (1:1) (500ml).The organic phase was washed with 1N HCl (2x80ml), 1N NaOH (2x80ml), water (2x80ml), sat. brine (80ml), dried withNa2SO4, filtered and concentrated under reduced pressure to give crude product. The residue was filtered through afilter plug of silica eluting with EtOAc/hexane (1:1). The fractions with product were evaporated to give 9.3 g of product(3-tert-Butoxycarbonylamino-2-(4-iodo-benzoylamino)-propionic acid methyl ester) in 93% yield. This product was convertedto analogues in a similar manner as the aforementioned Examples.
With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); potassium methanolate; In N,N-dimethyl acetamide; at 70℃; for 24h;Schlenk technique; Sealed tube;
n the glove box, to a 50 mL Schlenk bottle with a stir bar was added <strong>[5122-99-6]4-iodophenylboronic acid</strong> (1 mmol, 247.8 mg), potassium methoxide (2 mmol, 2 equivalents, 140.2 mg), Cu(IPr)Cl (0.03 mmol, 0.03 equivalents, 14.6 mg) in this order. ), 5 mL of solvent N, N-dimethylacetamide. Remove the capped Schlenk bottle from the glove box, fully evacuate, fill the reaction system with carbon dioxide and seal it well, and then stir the reaction mixture at 70 C. for 24 hours. After cooling to room temperature, it was acidified by adding 1 mol / L hydrochloric acid, and extracted with ethyl acetate, and washed once with brine. The organic phase was collected and concentrated in vacuo. The liquid mixture was dropped on a silica gel column and purified by column chromatography. As petroleum ether / ethyl acetate, the desired product 4-iodobenzoic acid was obtained in a yield of 69%.
N-((4-(4-fluorobenzyl)morpholin-2-yl)methyl)-4-iodobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
To a 25-mL flask equipped with a stir bar was added 4-iodobenzoic acid (248 mg, 1 mmol),<strong>[112914-13-3](4-(4-fluorobenzyl)morpholin-2-yl)methanamine</strong> (246 mg, 1.1 mmol), HATU (420 mg,1.1 mmol,), and dichloromethane (10 mL). After stirring at room temperature for 5 min,pyridine (160 mg, 2 mmol) was added dropwise and the reaction mixture was allowed tostir for 12 h. The reaction mixture was then washed with aq. NaHCO3 (10 mL) andextracted with DCM (3×10 mL). The organic layers were combined and dried over Na2SO4,The product was purified by flash silica gel column chromatography using 30% EtOAc/hexas eluent and a white solid of N-((4-(4-fluorobenzyl)morpholin-2-yl)methyl)-4-iodobenzamide was obtained, 368 mg, 81% yield
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