Abstract: In this study, we developed a simple transition-metal-free borylation reaction of aryl bromides. Bis-boronic acid (BBA), was used, and the borylation reaction was performed using a simple procedure at a mild temperature. Under mild conditions, aryl bromides were converted to arylboronic acids directly without any deprotection steps and purified by conversion to trifluoroborate salts. The functional group tolerance was considerably high. The mechanism study suggested that this borylation reaction proceeds via a radical pathway.
* 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] Justus Liebigs Annalen der Chemie, 1956, vol. 600, p. 176,188
2
[ 99-90-1 ]
[ 100-47-0 ]
[ 58536-46-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With antimonypentachloride In dichloromethane at 0℃; Reflux Stage #2: With ammonium hydroxide In water at 0 - 20℃; for 3.5 h;
3.5 g (17.58 mmol) of 4-bromoacetophenone and 1.83 g (17.58 mmol) of benzonitrile were added to 49 mL of dichloromethane cooled at 0° C. by ice bath and stirred for 30 minutes. Then, 10.51 g (35.17 mmol) of antimony (V) chloride was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for about 1 hour and further stirred and refluxed overnight. The reaction mixture was cooled and filtered, and a collected yellow solid was washed with dichloromethane. The solid was slowly added to 75 mL of a 28percent ammonia solution cooled at 0° C. by ice bath and stirred for 30 minutes. Then the reaction mixture was stirred for 3 hours at room temperature. Subsequently, the mixture was filtered, and a white solid was collected. The white solid was then washed with water. Then the solvent was removed under vacuum, and 6.5 g (95percent) of Intermediate 1d was obtained as a white solid.
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 12, p. 2858 - 2866
[2] Patent: US10032992, 2018, B2,
4
[ 99-90-1 ]
[ 4637-24-5 ]
[ 60-34-4 ]
[ 73387-52-7 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: at 110℃; for 4 h; Stage #2: at 25℃;
4-bromoacetophenone (20.0 g; 0.10 mole) and N,N-dimethylformamide dimethylacetal (28.5 mL; 0.20 mole) were mixed together in DMF (12 mL) and heated to 1100C for 4 hours. The methanol and water that were generated during the reaction were distilled (6.2 mL). The mixture was cooled to 25°C. Methyl t-butyl ether (100 mL) and methylhydrazine (21.2 mL; 0.40 moles) <n="70"/>were added and the mixture was stirred over night. The reaction mixture was washed with 1 M aqueous ammonium chloride (3 x 40 ml_) and water (40 ml_). The organic phase was dried by azeotropic distillation using a Dean-Stark apparatus. As an alternative to distillation, the solution was dried through an anhydrous magnesium sulfate cartridge. The solution was filtered through a silica gel cartridge (60 g). The product was flushed from the cartridge with methyl t-butyl ether. The fraction(s) containing product were combined and concentrated to about 70 ml_ by distillation. Heptane (120 ml_) was added and distillation was continued until the pot temperature reached 98.4 0C. About 100 ml_ of distillate was collected. The mixture was cooled to 40 0C. The mixture was seeded and the temperature was maintained at 40 0C for 30 minutes while crystallization was initiated. The mixture was slowly chilled to 0 0C over 90 minutes. The mixture was held at 0 0C for 30 minutes. The mixture was filtered and the solid was washed (3 x) with chilled (00C) heptane. The solid was dried on the filter. A cream-colored, crystalline solid (16.3 g; 68percent yield) was obtained. The NMR data of the title compound are as per alternative 1
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1046 - 1051
7
[ 99-90-1 ]
[ 4637-24-5 ]
[ 73387-46-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: at 80℃; Stage #2: With hydrazine hydrate In ethanol at 80℃; for 2 h;
(1) 3-(4-bromophenyl)-1H-pyrazole 5 g (25.0 mmol) of 4-bromoacetophenone and 3.59 g (30.1 mmol) of 1,1-dimethoxy-N,N-dimethylmethanamine were added to 40 ml of DMF. The mixture was heated to 80° C. for overnight. After cooling, the mixture was poured to water (150 mL) and extracted with EA (100 mL*3). The combined organic phase was washed with brine, concentrated to give red liquid (6 g). The thus obtained product was redissolved in 50 ml of ethanol and treated with hydrazine monohydrate (3.5 ml, 75 mmol). After the reaction was stirred at 80° C. for 2 h, it was cooled to 23° C. and poured to ice-water. Solid was precipitated out of the solution and filtered, washed with water, and dried to give 3.6 g of compound 3-(4-bromophenyl)-1H-pyrazole as yellow solid (yield: 80percent). 1H NMR (400 MHz, CDCl3): δ=7.58-7.62 (m, 3H), 7.49-7.51 (m, 2H), 6.58 (d, J=2.4, 1H).
Stage #1: With sodium hydride In toluene; mineral oil at 0 - 20℃; for 2 h; Stage #2: Reflux
To a solution of NaH (80 g, 60percent mineral oil dispersion, 2 mol) in toluene (1.2 L) was added diethyl carbonate (295 g, 2.50 mol) at 0 °C. After stirring at rt for 2 hrs, the mixture was added drop wise to a solution of compound 15-1 (99 g, 0.50 mol) in toluene (400 mL) at reflux. After refluxing overnight, the reaction mixture was cooled to rt and sequentially treated with HOAc (140 mL) and aq. HC1 (2 M, 864 mL). The resulting mixture was extracted with EtOAc (400 mL x 3) and the combined organic extracts were washed with water (500 mL x 4) and brine (200 mL x 2) and dried with anhydrous Na2S04. The solvent was removed and the residue was dried in vacuo to give compound 15-2 (122 g, 90percent yield) as an oil. LC-MS (ESI): m/z 271.0 [M+H]+.
59%
With sodium hydride In tolueneInert atmosphere; Reflux
In around bottom flask, 8.04 g (200.96 mmol) of NaH were washed three times with cyclohexane; under argon, 100 ml of dry toluene and 30.4 ml (251.2 mmol) of diethyl carbonate were successively added. Slowly, 10 g (50.24 mmol) of 4'-bromoacetophenone were added and the resulting mixture was stirred one night under reflux. After cooling, 25 ml of acetic acid were added to the reaction mixture, then a solution of 15 ml of concentrated HC1 in 100 ml of cooled water. The mixture was extracted with ethyl acetate and the organic layer was treated with a solution of sodium bicarbonate then dried over MgS04, filtered and concentrated to give 17.4 g of orange oil. This oil was distilled under vacuum to give 8.07 g (yield 59percent) of Ethyl 3-(4-bromo-phenyl)-3-oxopropanoate. HPLC-MS: conditions D: tT = 8.03 min, (ES+) CnHnBrO;? requires 270/272; found 271/273 [M + H]. 1H NMR (300 MHz, CDC13).
37%
Stage #1: With sodium hydride In toluene; mineral oil at 0 - 20℃; for 2 h; Stage #2: at 110℃; for 12 h;
To a stirred solution of NaH (60percent, 4.2 g, 105.5 mmol) in toluene (100 mL) at 0°C, diethyl carbonate (8.9 g, 75.37 mmol) was added and the solution was stirred at rt for 2 h. To this solution, compound a (10 g, g, 50.25 mmol) was added at 110°C and the resulting reaction mixture was stirred at 110°C for 12 h. The progress of the reaction was monitored by TLC. Upon completion the reaction mixture was cooled to rt, diluted with iN HC1 andextracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure resulting in a crude compound which was purified by column chromatography to afford the compound b (5 g, 37percent).
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 31, p. 4543 - 4547
[2] Patent: WO2012/58125, 2012, A1, . Location in patent: Page/Page column 147
[3] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 1950 - 1956
[4] Archiv der Pharmazie, 2003, vol. 336, # 3, p. 181 - 190
[5] Molecules, 2004, vol. 9, # 3, p. 135 - 157
[6] Farmaco, Edizione Scientifica, 1985, vol. 40, # 4, p. 272 - 284
[7] Journal of the American Chemical Society, 2018, vol. 140, # 5, p. 1622 - 1626
[8] Patent: WO2014/147611, 2014, A1, . Location in patent: Page/Page column 56; 57
[9] Organic Letters, 2014, vol. 16, # 19, p. 5152 - 5155
[10] Patent: WO2015/35027, 2015, A1, . Location in patent: Page/Page column 122
[11] Patent: WO2005/40110, 2005, A1, . Location in patent: Page/Page column 255
[12] Patent: US6329408, 2001, B1,
[13] Polymer, 2010, vol. 51, # 26, p. 6107 - 6114
[14] Angewandte Chemie - International Edition, 2011, vol. 50, # 32, p. 7304 - 7307
[15] Patent: US2011/263559, 2011, A1, . Location in patent: Page/Page column 51
[16] Patent: WO2012/3164, 2012, A1, . Location in patent: Page/Page column 21
[17] Angewandte Chemie - International Edition, 2012, vol. 51, # 34, p. 8661 - 8664
[18] Journal of the American Chemical Society, 2013, vol. 135, # 32, p. 11692 - 11695
[19] Organic Process Research and Development, 2006, vol. 10, # 5, p. 899 - 904
[20] Organic Letters, 2016, vol. 18, # 20, p. 5408 - 5411
[21] Organic Letters, 2017, vol. 19, # 23, p. 6344 - 6347
[22] Organic and Biomolecular Chemistry, 2018, vol. 16, # 25, p. 4683 - 4687
[23] RSC Advances, 2018, vol. 8, # 53, p. 30201 - 30206
10
[ 623-53-0 ]
[ 99-90-1 ]
[ 26510-95-2 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 39, p. 11143 - 11145
11
[ 67-56-1 ]
[ 99-90-1 ]
[ 57699-28-2 ]
Reference：
[1] Tetrahedron, 2009, vol. 65, # 47, p. 9797 - 9800
[2] Chemistry - A European Journal, 2013, vol. 19, # 52, p. 17711 - 17714
12
[ 99-90-1 ]
[ 586-61-8 ]
Reference：
[1] Green Chemistry, 2015, vol. 17, # 3, p. 1408 - 1413
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 13, p. 3585 - 3589[3] Angew. Chem., 2017, vol. 129, # 13, p. 3639 - 3643,5
13
[ 99-90-1 ]
[ 3972-65-4 ]
Reference：
[1] Patent: US5049570, 1991, A,
14
[ 109-67-1 ]
[ 99-90-1 ]
[ 37593-02-5 ]
Yield
Reaction Conditions
Operation in experiment
72%
With sodium hydroxide; potassium phosphate; dihydrogen peroxide In tetrahydrofuran
4-Pentylacetophenone (11) To a solution of 9-BBN (0.5 M in THF) (90.0 ml, 45.0 mmol) at 23° C., 1-pentene (4.93 ml, 45.0 mmol) was added. After 12 h, the solution was diluted with anhydrous dioxane (150 ml) and then 4-bromoacetophenone (5.97 g, 30.0 mmol) K3PO4 (9.55 g, 45.0 mmol), Pd(PPh3)4 (0.867 g, 0.750 mmol) were added. After deoxygenating the solution with N2 for 20 min, the solution was refluxed for 12 h. After cooling to ambient temperature, 3N NaOH (40 ml) and 30percent H2O2 (40 ml) were added dropwise followed by dilution with hexanes (200 ml). After separation of layers, the organic layer was washed with brine (200 ml), dried, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluding with 10percent EtOAc/hexanes, to afford 4.09 g of 11 as an oil (72percent). 1H NMR (CDCl3) δ 0.88 (t, J=6.9 Hz, 3H), 1.23-1.36 (m, 4H), 1.55-1.69 (m, 2H), 2.58 (s, 3 H), 2.66 (t, J=7.7 Hz, 2H), 7.25 (d, J=1.9 Hz, 2H), 7.86 (d, J=1.9 Hz, 2H); 13C NMR (CDCl3) δ 14.09, 22.58, 26.65, 30.89, 31.51, 36.04, 128.55, 128.68, 134.97, 148.92, 197.98.
Stage #1: at -50 - 20℃; Stage #2: With ammonium chloride In tetrahydrofuran; diethyl ether
l-(4-Bromophenyl)ethanone (9.25 g,46.5 mmol) was dissolved in tetrahydrofuran (200 mL). The solution was cooled in a -50 0C bath. Methylmagnesium bromide (3M in ether, 46.5 mL, 139 mmol) was added over a 15 min period. The reaction was allowed to warm to room temperature and then stirred for 20 h. The reaction was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an oil. The oil was purified on a silica gel column (0-20 percent ethyl acetate in hexanes) to give the product a colorless oil (9.1 g, 46.2 mmol, 91 percent yield). MS (ESI) m/z 197.1 [M]+, 199.1 [M+2]+.
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 17, p. 3368 - 3383
[2] Patent: WO2010/62571, 2010, A1, . Location in patent: Page/Page column 92
[3] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 15, p. 2169 - 2174
[4] Journal of the American Chemical Society, 1971, vol. 93, p. 6877 - 6887
[5] Journal of the American Chemical Society, 1999, vol. 121, # 14, p. 3557 - 3558
[6] Patent: WO2005/61491, 2005, A2, . Location in patent: Page/Page column 54-55
[7] Patent: WO2015/42397, 2015, A1, . Location in patent: Paragraph 0001243
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5323 - 5333
[9] Patent: WO2006/133559, 2006, A1, . Location in patent: Page/Page column 42
20
[ 917-54-4 ]
[ 99-90-1 ]
[ 2077-19-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2007, # 28, p. 4642 - 4645
[2] Patent: EP1894911, 2008, A1, . Location in patent: Page/Page column 42
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 662 - 667
[2] Journal of the American Chemical Society, 1982, vol. 104, # 15, p. 4173 - 4179
[3] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 20, p. 2583 - 2587
[4] Synlett, 2004, # 10, p. 1723 - 1726
With potassium phosphate tribasic heptahydrate; C45H53ClFeNO2PPd In water; toluene at 100℃; for 8 h; Inert atmosphere
General procedure: Potassium phosphate (0.75 mmol) and IIe (1 mol percent) was added to the solution of aryl halides (0.25 mmol) and cyclopropylboronic acid (0.5 mmol) in toluene (2.0 mL) and water (100 μL). The mixture was heated to 100 °C for a proper time under nitrogen atmosphere and cooled to room temperature. Water (10 mL) was added and the mixture was extracted with EtOAc (3.x.15 mL), evaporated and purified by chromatography on silica gel.
1.0 g
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In water; dimethyl sulfoxide at 100℃; for 48 h;
To a solution of 1-(4-bromophenyl)ethanone (3.Og, 0.0150 mmol) in mixture of DMSO: water (3:1, 30 mL) was added tripotassium phosphate (9.5 g, 0.045 mmol), 1,1 ‘-bi s(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.200 g,0.245 mmol) and cyclopropylboronic acid (1.9 g, 0.022 mmol). The reactionmixture was heated at 100 °C for 48 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer were washed with water and brine, dried over Na2504 and concentrated. The obtained solid was purified by column chromatography on silica gel to afford 1.0 g of the title product. ‘H NIVIR (300 IVIFIz, DMSO d6): 7.86-7.83 (d, J = 7.8 Hz, 2H), 7.13.7.10 (d, J = 7.8 Hz, 2H), 2.57 (s,3H), 1.94 (m, 1H), 1.07-1.05 (q, J= 7.2 Hz, 2H),0.79-0.77 (d, J= 4.8 Hz, 2H).
Reference：
[1] Tetrahedron, 2012, vol. 68, # 3, p. 900 - 905
[2] Synthetic Communications, 2006, vol. 36, # 1, p. 121 - 128
[3] Patent: WO2015/59618, 2015, A1, . Location in patent: Page/Page column 42
[4] Journal of the American Chemical Society, 2016, vol. 138, # 20, p. 6598 - 6609
[5] Patent: WO2016/201168, 2016, A1, . Location in patent: Paragraph 0662
26
[ 99-90-1 ]
[ 6921-45-5 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #2: With potassium phosphate In MeTHF; water; toluene at 100℃; for 3 h; Inert atmosphere
Example 3: Use of cyclopropyldioxazaborocane in the Suzuki coupling reaction; The boronic acid coupling products were obtained under the conditions recorded in the table below, by applying procedures 3a) and 3b).+ catalyst + ligand + K3PO4 solvent SIMes : 1 ,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylideneThe Suzuki coupling process has many advantages. The first is that the conditions are extremely simple to implement using catalysts which are readily available and usable (u n l i ke the rare model s issu ing from the l iteratu re relating to cyclopropylboronic acid) [19, 11]. The particularly short reaction times are also an element that simplifies the implementation of the process. Finally, it has been possible to carry out Suzuki couplings both with brominated derivatives and with chlorinated derivatives.Example 3a): Coupling with brominated derivatives: Procedure:Cyclopropyldioxazaborocane (1.5 eq.) is dissolved in a solution of 1 N HCI/NaClsat (1 ml/mmol of dioxazaborocane); boronic acid is then extracted with MeTHF (1.5 ml/mmol of dioxazaborocane). It is added to a solution containing aryl bromide (1 eq .), PdCI2dppf (0.5 eq.), PPh3 (0.1 eq.) and K3PO4 (2 eq .) in toluene (1.5 ml/mmol), anhydrous. The mixture is then heated at 1000C for 3 hours, under argon. After cooling, the organic phase is washed with water and then dried over MgSO4 and evaporated. The residue is then purified by flash chromatography (eluant: pure DCM). The fractions containing the product are then combined and evaporated.4-cyclopropylacetophenone:Yellowish liquid (41 1 mg, 2.57 mmol, 99percent). 1H NMR (CDCI3, 300 MHz), δ = 7.87 (d, 3JHH = 8.5 Hz, 2H, H5), 7.14 (d, 3JHH = 8.5 Hz, 2H, H4), 2.58 (s, 3H, H8), 1 .96 (tt, 3JHH = 8.4 Hz, 3JHH = 5.0 Hz, 1 H, H1), 1 .08 (ddd, 3JHH = 8.4 Hz, 3JHH = 5.0 Hz, 2Jgem = 6.6 Hz, 2H, H2), 0.80 (td, 3JHH = 4.8 Hz, 2Jgem = 6.7 Hz, 1 H, H2). 13C NMR (CDCI3, 75.5 MHz), δ = 197.7 (C7), 150.4 (C6), 134.6 (C3), 128.5 (C5), 125.5 (C4), 26.5 (Ce), 15.8 (CO, 10.4 (C2). Rf = 0.30 (DCM/EP 70 :30).
With sulfuryl dichloride In methyl t-butyl ether at 20℃; for 1 h;
[0371] [TABLE-US-00002] (18) acetophenone derivative R13 R14 1 NO2 H 2 NO2 Cl 3 H Br 4 H H [0372] An acetophenone (2.00 g) as shown by the formula (18) was dissolved or suspended in a solvent as shown in Table 2 (M representing the molarity based on the acetophenone derivative), and sulfuryl chloride in an amount as shown in Table 2 was added all at once under stirring. The temperature and reaction time were as shown in Table 2. [TABLE-US-00003] TABLE 2 Acetophenone SO2Cl2 Time Yield Ex. Solvent (M) derivative (equivalent) Temp. (hr) (percent) 42 MTBE(0.5) 1 3.0 r.t. 4.5 50.8 43 MTBE(1) 1 1.65 reflux 7.0 70.1 44 IPE(1) 1 3.0 r.t. 3.0 77.8 45 DME(1) 1 1.65 r.t. 4.0 71.4 46 MTBE(1) 3 3.0 r.t. 1.0 50.3 47 MTBE(1) 4 1.1 r.t. 7.0 78.9 MTBE: methyl t-butyl ether; IPE: diisopropyl ether; DME: 1,2-dimethoxyethane
35%
With Oxone; ammonium chloride In methanol at 20℃; for 24 h;
General procedure: A typical procedure for the α-chlorination of ketone:acetophenone 1a (0.5 mmol), Oxone® (0.6 mmol) and NH4Cl (1.0 mmol) were added in MeOH (2 mL). The mixture was stirred at room temperature for 24 h and then separated on a silica gel plate using (4:1 hexane-ethyl acetate) as eluant to give α-chloroacetophenone 2a in 85percent of yield. White solid, mp 52–54 °C; 1H NMR (500 MHz, CDCl3): δ 7.97 (d, 2 H, J = 8.4 Hz), 7.64–7.61 (m, 1H), 7.53–7.50 (m, 2H), 4.73 (s, 2H); 13C NMR (125 MHz, CDCl3): δ 193.35, 137.53, 134.46, 128.75, 127.13, 48.14.
Reference：
[1] Synthesis, 1988, # 7, p. 545 - 546
[2] Synthetic Communications, 2006, vol. 36, # 2, p. 255 - 258
[3] Green Chemistry, 2009, vol. 11, # 2, p. 275 - 278
[4] Synthetic Communications, 2011, vol. 41, # 10, p. 1508 - 1513
[5] Tetrahedron Letters, 2004, vol. 45, # 1, p. 191 - 193
[6] European Journal of Organic Chemistry, 2017, vol. 2017, # 43, p. 6390 - 6400
[7] Synthetic Communications, 2006, vol. 36, # 6, p. 777 - 780
[8] Advanced Synthesis and Catalysis, 2017, vol. 359, # 23, p. 4177 - 4183
[9] Patent: US2003/225289, 2003, A1, . Location in patent: Page 28
[10] Chinese Chemical Letters, 2012, vol. 23, # 11, p. 1213 - 1216,4
[11] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1985, vol. 24, # 4, p. 300 - 303
[12] Journal of the American Chemical Society, 1952, vol. 74, p. 3333,3337
[13] Magnetic Resonance in Chemistry, 1987, vol. 25, p. 179 - 180
[14] Bulletin des Societes Chimiques Belges, 1964, vol. 73, p. 579 - 584
[15] Chemistry Letters, 2012, vol. 41, # 4, p. 432 - 434
[16] Tetrahedron, 2013, vol. 69, # 31, p. 6392 - 6398
[17] Organic and Biomolecular Chemistry, 2016, vol. 14, # 17, p. 4129 - 4135
[18] Advanced Synthesis and Catalysis, 2018, vol. 360, # 11, p. 2119 - 2124
30
[ 99-90-1 ]
[ 7716-86-1 ]
[ 4209-02-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 23, p. 4177 - 4183
[2] Journal of the Chinese Chemical Society (Taipei, Taiwan), 1997, vol. 44, # 3, p. 309 - 312
Reference：
[1] Journal of Chemical Research, Miniprint, 1983, # 9, p. 2127 - 2155
35
[ 99-90-1 ]
[ 1553-60-2 ]
Reference：
[1] Organic Process Research and Development, 2006, vol. 10, # 5, p. 1076 - 1079
36
[ 99-90-1 ]
[ 18640-58-9 ]
Yield
Reaction Conditions
Operation in experiment
37%
With nitric acid In water at 5 - 10℃; for 0.5 h;
To fuming nitric acid (200 mL), l-(4- bromophenyl)-l-propanone (1-1) (40 g, 0.20 mol) was added while keeping the inside temperature of mixture at 5 to 10 0C. The reaction solution was stirred at this temperature for 30 minutes and then poured into ice. The precipitate was collected by filtration, washed with distilled water (25 mL x 2) and re-crystallized from methanol to give 1-2 (18 g, 37percent yield). 1H NMR (500 MHz, CDCl3) δ 8.38 (IH, d, J= 2.0 Hz), 7.99 (IH, dd, J= 8.2 Hz, 2.0 Hz), 7.86 (IH, d, J= 8.2Hz), 3.01 (2H, q, J= 7.1Hz), 1.25 (3H, t, J= 7.1Hz) ppm; LC-MS (ESI): m/z 244.0 (M+H)+.
37%
at 5 - 10℃; for 0.5 h;
Example 1. Synthesis of 1-12, dimethyl (2S. 2,S)-l.l ,-((2S.2,S)-2.2,-(5.5,-(2.2'-bis(2- methoxyethoxy)biphenyl-4,4'-diyl)bis(lH-imidazole-5,2-diyl))bis(pyrrolidine-2,l- diyl))bis(3-methyl-l-oxobutane-2,l-diyl)dicarbamate as shown in Scheme 1[00185] Step 1. Preparation of 1-2. To fuming nitric acid (200 mL), l-(4- bromophenyl)-l-propanone (1-1) (40 g, 0.20 mol) was added while keeping the inside temperature of mixture at 5 to 10 °C. The reaction solution was stirred at this temperature for 30 minutes and then poured into ice. The precipitate was collected by filtration, washed with distilled water (25 mL x 2) and re-crystallized from methanol to give 1-2 (18 g, 37percent yield). 1H NMR (500 MHz, CDC13): δ 8.38 (1H, d, J= 2.0 Hz), 7.99 (1H, dd, J= 8.2 Hz, 2.0 Hz), 7.86 (1H, d, J= 8.2Hz), 3.01 (2H, q, J= 7.1Hz), 1.25 (3H, t, J= 7.1Hz) ppm; LC-MS (ESI): m/z 244.0 [M+H]+.
Reference：
[1] Patent: WO2010/111673, 2010, A1, . Location in patent: Page/Page column 37-38
[2] Patent: WO2012/40389, 2012, A2, . Location in patent: Page/Page column 61-62
[3] Chemische Berichte, 1916, vol. 49, p. 2230
[4] Journal of the Chemical Society, 1932, p. 1988,1991
[5] Journal of the Chemical Society, 1942, p. 500,503
[6] Journal of the Chemical Society, 1931, p. 2388,2406
[7] Il Farmaco; edizione scientifica, 1972, vol. 27, # 4, p. 333 - 342
[8] Justus Liebigs Annalen der Chemie, 1961, vol. 641, p. 81 - 94
[9] Organic Letters, 2008, vol. 10, # 23, p. 5417 - 5420
[10] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 21, p. 3441 - 3445
37
[ 99-90-1 ]
[ 4654-39-1 ]
Reference：
[1] Organic Process Research and Development, 2006, vol. 10, # 5, p. 1076 - 1079
38
[ 67-56-1 ]
[ 99-90-1 ]
[ 49660-93-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 21, p. 3373 - 3380
[2] Organic Letters, 2017, vol. 19, # 18, p. 4750 - 4753
[3] Organic Letters, 2017, vol. 19, # 19, p. 5228 - 5231
Reference：
[1] Australian Journal of Chemistry, 2015, vol. 68, # 8, p. 1221 - 1227
41
[ 3144-09-0 ]
[ 99-90-1 ]
[ 5317-89-5 ]
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 43, p. 7295 - 7298
[2] Organic Letters, 2011, vol. 13, # 10, p. 2564 - 2567
[3] Green Chemistry, 2014, vol. 16, # 3, p. 1480 - 1488
42
[ 99-90-1 ]
[ 7511-49-1 ]
Yield
Reaction Conditions
Operation in experiment
84%
With sulfated tungstate In neat (no solvent) at 130℃; for 10 h;
General procedure: In round bottom flask equipped with condenser a mixture of aryl alkyl ketones (3mmol) and sulfated tungstate (20 wt. percent) were stirred at 130 C, the progress of the reaction was monitored by TLC. After disapperance of the aryl alkyl ketones and the reaction was continued for additional time of 2 h. The reaction mixture was cooled, diluted with 30 mL of ethyl acetate and filtered to recover the catalyst. The filtrate was washed with 10 mL of water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel ( 60-120) with (PE:EA=9:1) as eluent to get pure 1,3,5-arylenzenes.
76%
With para-dodecylbenzenesulfonic acid In neat (no solvent) at 130℃; for 4 h; Green chemistry
General procedure: A mixture of acetophenone (3 mmol) and DBSA (0.6 mmol) was heated at 130 °C in a preheated oil bath for 3–8 hours. After completion of the reaction as indicated by thin layer chromatography (TLC), the reaction mixture was cooled to room temperature and diluted with equal volumes of saturated solution of NaHCO3 and brine (5 mL + 5 mL). The resulting solution was extracted with ethyl acetate (10 mL × 3) and the organic layers were combined, dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The crude product obtained was purified by silica gel (60–120 mesh size) column chromatography using 1–2percent ethyl acetate in heptane as the eluent to afford the desired products in pure form.
69%
With ethylenediamine; trifluoroacetic acid In nitromethane for 48 h; Reflux
General procedure: To a solution of aryl methyl ketone (1, 1.5mmol) in dry nitromethane (1.5mL) was added trifluoroacetic acid (0.045 mL, 0.6mmol) and ethylenediamine (0.020 mL, 0.3mmol). The mixture was stirred at reflux and detected by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated NH4Cl, extracted with Ethyl acetate. Combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give product 2.
Reference：
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[2] RSC Advances, 2015, vol. 5, # 27, p. 21206 - 21214
[3] Journal of the Iranian Chemical Society, 2012, vol. 9, # 5, p. 791 - 798
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 14, p. 2907 - 2916
[5] Synthetic Communications, 2005, vol. 35, # 24, p. 3167 - 3171
[6] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 12, p. 2781 - 2783
[7] Chemistry - A European Journal, 2012, vol. 18, # 20, p. 6172 - 6182
[8] RSC Advances, 2016, vol. 6, # 60, p. 55319 - 55326
[9] Polyhedron, 2012, vol. 31, # 1, p. 721 - 728
[10] Tetrahedron Letters, 2017, vol. 58, # 31, p. 3032 - 3036
[11] Chemical Communications, 2018, vol. 54, # 81, p. 11475 - 11478
[12] Synthetic Communications, 2012, vol. 42, # 24, p. 3569 - 3578
[13] RSC Advances, 2015, vol. 5, # 15, p. 10869 - 10877
[14] Journal of the American Chemical Society, 2017, vol. 139, # 5, p. 2053 - 2059
[15] Journal of Materials Chemistry, 2002, vol. 12, # 2, p. 206 - 212
[16] Green Chemistry, 2010, vol. 12, # 8, p. 1370 - 1372
[17] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 16, p. 2695 - 2701
[18] Journal of Chemical Research, 2007, # 12, p. 720 - 721
[19] New Journal of Chemistry, 2002, vol. 26, # 3, p. 291 - 297
[20] Advanced Synthesis and Catalysis, 2013, vol. 355, # 5, p. 957 - 972
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[23] Tetrahedron Letters, 1991, vol. 32, # 33, p. 4175 - 4176
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[30] RSC Advances, 2013, vol. 3, # 6, p. 1902 - 1915
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[32] Tetrahedron Letters, 2018, vol. 59, # 11, p. 1023 - 1027
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[35] Macromolecules, 2003, vol. 36, # 22, p. 8353 - 8360
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[38] Journal of Organic Chemistry, 2004, vol. 69, # 18, p. 6050 - 6058
[39] Chemistry of Materials, 2017, vol. 29, # 24, p. 10469 - 10477
[40] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 1251 - 1258
[41] Journal of the American Chemical Society, 1953, vol. 75, p. 5959
[42] Tetrahedron Letters, 2005, vol. 46, # 46, p. 7871 - 7875
[43] Journal of Materials Chemistry, 2011, vol. 21, # 34, p. 12958 - 12963
[44] Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2011, vol. 71, # 1-2, p. 113 - 120
[45] Journal of Materials Chemistry, 2012, vol. 22, # 10, p. 4502 - 4510
[46] Patent: EP2586766, 2013, A1, . Location in patent: Paragraph 0085
[47] CrystEngComm, 2016, vol. 18, # 42, p. 8147 - 8150
[48] Angewandte Chemie - International Edition, 2016, vol. 55, # 47, p. 14614 - 14617[49] Angew. Chem., 2016, vol. 128, p. 14834 - 14837,4
[50] Chemistry - A European Journal, 2018, vol. 24, # 18, p. 4547 - 4551
43
[ 99-90-1 ]
[ 122-51-0 ]
[ 7511-49-1 ]
Yield
Reaction Conditions
Operation in experiment
43.6%
With hydrogenchloride In benzene at 20℃; for 3 h;
4-Bromoacetophenone (7.962 g, 40 mmol) and ethyl orthoformate ester (8 mL, 48 mmol) were dissolved in benzene (24 mL) in a flask. Gaseous hydrogen chloride was bubbled through the solution at room temperature and under stirring for 3 h. The solution became brownish-red colored and the precipitate formation began during the first hour. The resulting precipitate was filtered off, washed with acetone and methanol, and dried. The yield of product recrystallized from chloroform was 43.6percent. The 1H NMR spectrum of synthesized product (see Fig. 1) was completely corresponded to that of 1,3,5-tris(4-bromophenyl)benzene. 1H NMR (500 MHz), δ: 7.68 (s, 3 H); 7.60 (d, 6 H, J = 8.5 Hz); 7.53 (d, 6 H, J = 8.5 Hz).
Reference：
[1] Russian Chemical Bulletin, 2018, vol. 67, # 8, p. 1433 - 1439[2] Izv. Akad. Nauk, Ser. Khim., 2018, # 8, p. 1433 - 1439,7
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 2, p. 502 - 506[2] Angew. Chem., 2014, vol. 126, # 2, p. 512 - 516,5
[3] Organic Letters, 2018, vol. 20, # 9, p. 2711 - 2715
[4] Advanced Synthesis and Catalysis, 2017, vol. 359, # 20, p. 3665 - 3673
[5] Bulletin de la Societe Chimique de France, 1899, vol. <3> 21, p. 67
[6] Journal of the American Chemical Society, 2010, vol. 132, # 34, p. 11898 - 11899
[7] Chemical Communications, 2013, vol. 49, # 9, p. 925 - 927
[8] Advanced Synthesis and Catalysis, 2013, vol. 355, # 4, p. 667 - 672
[9] Chemical Communications, 2013, vol. 49, # 35, p. 3640 - 3642
[10] Chemical Communications, 2013, vol. 49, # 23, p. 2368 - 2370
[11] Advanced Synthesis and Catalysis, 2013, vol. 355, # 8, p. 1517 - 1522
[12] Advanced Synthesis and Catalysis, 2018, vol. 360, # 17, p. 3345 - 3355
[13] Chemistry - A European Journal, 2014, vol. 20, # 24, p. 7241 - 7244
[14] Chemical Communications, 2015, vol. 51, # 21, p. 4372 - 4375
[15] Chemical Communications, 2015, vol. 51, # 52, p. 10524 - 10527
[16] Advanced Synthesis and Catalysis, 2015, vol. 357, # 11, p. 2437 - 2441
[17] Synlett, 2015, vol. 26, # 17, p. 2442 - 2446
[18] Tetrahedron Letters, 2016, vol. 57, # 23, p. 2511 - 2514
[19] Organic Letters, 2016, vol. 18, # 13, p. 3114 - 3117
[20] Organic and Biomolecular Chemistry, 2016, vol. 14, # 42, p. 9970 - 9973
[21] Organic and Biomolecular Chemistry, 2017, vol. 15, # 20, p. 4320 - 4327
[22] European Journal of Organic Chemistry, 2017, vol. 2017, # 26, p. 3830 - 3836
[23] Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2390 - 2395
[24] Organic and Biomolecular Chemistry, 2017, vol. 15, # 31, p. 6592 - 6603
[25] Advanced Synthesis and Catalysis, 2017, vol. 359, # 16, p. 2729 - 2734
56
[ 99-90-1 ]
[ 74-88-4 ]
[ 30314-45-5 ]
Reference：
[1] Liebigs Annalen der Chemie, 1987, p. 263 - 264
57
[ 99-90-1 ]
[ 24358-62-1 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 120 - 180℃; for 7 h; Large scale
In a 5L reaction flask, p-bromoacetophenone 1000g, ammonium formate 1445g, slowly heated to 120 degrees, the two materials slowly dissolved into a liquid state, stirring was turned on, maintaining 120 degrees for 2 hours.The reaction temperature was then raised to 180 degrees and incubated for 5 hours.Stop the reaction. After cooling, add water, methylene chloride, separate the layers, and concentrate the organic phase. Add 670 ml of concentrated hydrochloric acid and 1000 mM.Precipitation, reflux, 1-2 hours,The reactants were solid first, followed by clarification, and a large amount of solids precipitated. After the reaction was completed and slightly cold, another 1000 ml of toluene was added and the mixture was cooled to room temperature with stirring. After filtration, the solid was washed twice more with toluene, and the solid was dried to obtain the hydrochloride salt of the product, which was neutralized with sodium hydroxide, extracted with dichloromethane, dried and concentrated, and distilled under reduced pressure to obtain pure product (814 g). 81percent.
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 245 - 252
[2] Patent: CN106957255, 2017, A, . Location in patent: Paragraph 0055-0058; 0069-0072; 0083-0086
[3] Chirality, 2018, vol. 30, # 7, p. 900 - 906
[4] Bulletin des Societes Chimiques Belges, 1963, vol. 72, p. 202 - 207
[5] Tetrahedron Asymmetry, 2006, vol. 17, # 6, p. 967 - 974
[6] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 7, p. 1339 - 1347
[7] RSC Advances, 2014, vol. 4, # 66, p. 34764 - 34767
[8] Molecules, 2014, vol. 19, # 12, p. 21386 - 21397
[9] Organic Letters, 2015, vol. 17, # 6, p. 1469 - 1472
[10] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5393 - 5401
58
[ 99-90-1 ]
[ 77287-34-4 ]
[ 24358-62-1 ]
Reference：
[1] Journal of the American Chemical Society, 1936, vol. 58, p. 1808,1810[2] Organic Syntheses, 1943, vol. Coll. Vol. II, p. 503,505
59
[ 99-90-1 ]
[ 149-73-5 ]
[ 41841-16-1 ]
Reference：
[1] Journal of Chemical Research, 2004, # 6, p. 392 - 393
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1433 - 1436
60
[ 67-56-1 ]
[ 99-90-1 ]
[ 41841-16-1 ]
[ 97728-73-9 ]
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 17, p. 3003 - 3007
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 3, p. 1097 - 1103
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 235 - 242
63
[ 99-90-1 ]
[ 62-53-3 ]
[ 23600-83-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; C40H43BN2P(1-)*C16H32LiO4(1+); potassium <i>tert</i>-butylate In tolueneInert atmosphere; Schlenk technique
General procedure: Typically, [Pd(cinnamyl)Cl]2 (0.0031 g, 0.006 mmol), ligand 1 (0.0107 mg, 0.012 mmol), and KO(t-Bu) (0.081 g, 0.72 mmol) were loaded into a Schlenk tube. If a solid aryl bromide or amine was used, it was also added at this time. To the mixture of solids, the aryl bromide (0.6 mmol) and amine (0.72 mmol) were added via syringe (if liquid), followed by toluene (2 mL). The resulting mixture was stirred at room temperature for 1 min., then placed in a pre-heated, 80 °C oil bath and allowed to react for 12 h. After this time, the mixture was removed from the bath and cooled to room temperature, diluted with EtOAc (5 mL), and filtered through silica (1 × 4 cm column, ~10 mL), eluting with EtOAc (20 mL) or until the filtrate ran clear. The volatiles were removed from the filtrate via rotary evaporation and the resulting residue was subjected to flash chromatography on silica gel (8 × 2 cm column, ~25 mL silica). Specific details related to the synthesis, yield and characterization of each coupled product are described below in Section 4.8.
84%
With potassium phosphate; copper(l) iodide In diethylene glycol at 70℃; for 14 h; Sealed tube
General procedure: A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), PSAP (30 mg,0.05 mmol, > 100 mesh), K3PO4 (424 mg, 2 mmol), aryl bromides (1mmol), amines (1.5 mmol), DEG (2 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into a preheated oil batchat 70 °C. The reaction mixture was held at this temperature for 14 hours. After cooling to r.t., the reaction mixture was filtered, and the precipitates were thoroughly washed with water and EtOAc (3 × 20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Theresidue was purified using flash column chromatography on silica gel(eluting with petroleum ether/EtOAc) to afford the desired products.
82%
With copper(l) iodide; tetrabutylammomium bromide; potassium hydroxide In water at 70℃; for 16 h; Green chemistry
General procedure: A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90 μM), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides (0.5 mmol), arylamine (2.0 mmol), H2O (1.0 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into an oil bath, which was preheated to 70 °C (90 °C for alkyl amine, 120 °C for imidazole). The reaction mixture was stirred for another 16 h (8 h for imidazole). After allowing the mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates were washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3×25 mL). The combined organic phases was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel to afford the desired products.
80%
With C21H17N3O; copper; potassium hydroxide In propan-1-ol at 80℃; for 5 h; Sealed tube
The 198 mg (1mmol) 4 - bromophenylmethyl, 279 mg (3mmol) aniline, 64 mg (1mmol) Cu, 65.4 mg (0.2mmol) ligand L6, 56mg (1mmol) KOH, 2 ml propanol, adding 10 ml reaction tube, sealing, 80 °C reaction under the condition of 5h. After the stop of the reaction, water, extracted with ethyl acetate, washing, saturated salt water washing, after drying with anhydrous sodium sulfate, filtered, the filtrate is distilled under reduced pressure, purification by silica gel chromatography separation column column, shall be 1 - (4 - (phenylamino) phenyl) b one 169 mg, yield 80percent.
75%
With C104H96N16O8Pd2(4+)*4NO3(1-); sodium t-butanolate In toluene at 110℃; for 18 h;
General procedure: In a 50 mL round bottom flask, the mixture of iodobenzene (2 mmol), amine (2.4 mmol), t-BuONa (3 mmol), and 1 as catalyst (0.05 mol percent) was taken in toluene (10 mL). The reaction mixture was then heated to 110°C and continued for 12–18 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction the aqueous reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on silica gel which afforded corresponding coupling products (yield 75–96percent).
53%
at 90℃; for 12 h; Sealed tube
General procedure: To a 10 mL sealed vial was added Cu(OAc)2·H2O (10 mg, 0.05mmol), N-methoxy-1H-pyrrole-2-carboxamide (7 mg, 0.05 mmol), aryl bromide (1.0 mmol), amine (3.0 mmol), K3PO4 (318 mg, 1.5 mmol),PEG-100 (2.0 g) and a magnetic stir bar. The reaction mixture was stirred in an oil bath preheated to 90 °C for 12 h. After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 25 mL) and water (20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product.
82 %Chromat.
at 150℃; for 12 h;
General procedure: In a typical run, an oven-dried 10 ml round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 ml). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 ml) was added, and extraction with ether (4×10 ml) was done. The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in acetonitrile and analyzed by GC–MS.
Reference：
[1] Journal of Organometallic Chemistry, 2017, vol. 841, p. 57 - 61
[2] Chemical Communications, 1998, # 15, p. 1509 - 1510
[3] Applied Organometallic Chemistry, 2011, vol. 25, # 5, p. 341 - 347
[4] Synthesis (Germany), 2018, vol. 50, # 19, p. 3911 - 3920
[5] Tetrahedron, 2013, vol. 69, # 42, p. 8974 - 8977
[6] Patent: CN106883132, 2017, A, . Location in patent: Paragraph 0053-0055
[7] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[8] European Journal of Organic Chemistry, 2010, # 17, p. 3219 - 3223
[9] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1532 - 1536
[10] European Journal of Organic Chemistry, 2009, # 5, p. 635 - 642
[11] Angewandte Chemie - International Edition, 2016, vol. 55, # 42, p. 13219 - 13223[12] Angew. Chem., 2016, vol. 128, # 42, p. 13413 - 13417,5
[13] Russian Chemical Bulletin, 2012, vol. 61, # 5, p. 1009 - 1013[14] Izv. Akad. Nauk, Ser. Khim., 2012, vol. 61, # 5, p. 1004 - 1008,5
[15] Synthesis (Germany), 2014, vol. 46, # 24, p. 3356 - 3364
[16] Russian Journal of General Chemistry, 2005, vol. 75, # 2, p. 207 - 211
[17] Inorganica Chimica Acta, 2019, vol. 486, p. 232 - 239
64
[ 99-90-1 ]
[ 23600-83-1 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1969, p. 2342 - 2355
Reference：
[1] Quarterly Journal of Pharmacy and Pharmacology, 1936, vol. 9, p. 75,102
[2] Patent: CN106588806, 2017, A,
70
[ 99-90-1 ]
[ 24358-62-1 ]
[ 27298-97-1 ]
Reference：
[1] Angewandte Chemie - International Edition, 2003, vol. 42, # 44, p. 5472 - 5474
[2] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 7, p. 1339 - 1347
71
[ 99-90-1 ]
[ 27298-97-1 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5314 - 5327
[2] Organic Process Research and Development, 2014, vol. 18, # 6, p. 788 - 792
72
[ 99-90-1 ]
[ 27298-97-1 ]
[ 177750-53-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 24, p. 5393 - 5401
73
[ 99-90-1 ]
[ 71866-86-9 ]
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 51, p. 18576 - 18579
74
[ 99-90-1 ]
[ 118621-30-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 1005 - 1010
75
[ 99-90-1 ]
[ 149104-90-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2000, # 23, p. 3825 - 3834
[2] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11667 - 11673
[3] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
76
[ 13675-18-8 ]
[ 99-90-1 ]
[ 149104-90-5 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
[2] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1842 - 1851
77
[ 99-90-1 ]
[ 3114-31-6 ]
Yield
Reaction Conditions
Operation in experiment
57%
With chlorine In dichloromethane
PREPARATION 13 4-Bromo-3-chloroacetophenone, compound Va.3 (Va.3); X=3-Cl; Y=H; Z=Br A solution of 100 g of 4-bromoacetophenone in 250 ml of dichloromethane is added dropwise at 0° C. to 133.34 g of aluminium chloride in 600 ml of dichloromethane. After stirring for 2 hours at 0° C., 28.3 ml of prefrozen (-75° C.) chlorine are bubbled through the medium at 0° C. The reaction mixture is stirred at room temperature for 12 hours and then hydrolyzed. The phases are separated after settling has taken place, the aqueous phase is extracted with dichloromethane, the organic phases are dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is recrystallized from hexane; yield=57percent; m.p.=80° C.
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 13, p. 5489 - 5494
80
[ 99-90-1 ]
[ 1000994-95-5 ]
Yield
Reaction Conditions
Operation in experiment
77%
With diethylamino-sulfur trifluoride In dichloromethane at 50℃; Inert atmosphere
Example 63A1-Bromo-4-(1,1-difluoroethyl)benzene; Under argon, 3.0 g (15.07 mmol) of 1-(4-bromophenyl)ethanone were initially charged in 30 ml of dichloromethane, and 15.9 ml (120.57 mmol) of [ethyl(trifluoro-λ4-sulphanyl)amino]ethane (DAST) were added slowly. The reaction solution was then slowly warmed to 50° C. and stirred at this temperature overnight. After the reaction had ended, the reaction solution was slowly poured into ice-water. The organic phase was then separated off, and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase petroleum ether/dichloromethane 4:1). This gave 2.56 g (11.58 mmol, 77percent of theory) of the title compound as a yellowish liquid.GC-MS (Method 1): Rt=2.84 min; m/z=220/222 (M)+.
76%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In tetrahydrofuran; methanol for 96 h; Reflux
Example 48A 1-Bromo-4-(1,1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50percent in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for 4 days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76percent of theory) 1H NMR (400 MHz, DMSO-d6): δ=7.70 (d, 2H), 7.52 (d, 2H), 1.96 (t, 3H).
76%
With methanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride In tetrahydrofuran for 96 h; Reflux
Example 68A1-Bromo-4-(1,1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50percent in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for four days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76percent of theory)1H NMR (400 MHz, DMSO-d6): δ=7.70 (d, 2H), 7.52 (d, 2H), 1.96 (t, 3H).
59%
at 85℃; for 15 h;
Deoxo-Fluor (registered trademark) (22.2 g) was added to 1-(4-bromophenyl)ethanone (20.0 g) and the mixturewas stirred at 85°C for 15 hours. Under icecooling, ice water and an aqueous solution of potassium carbonate wereadded to the reaction solution, followed by extraction with chloroform. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound(13.0 g, yield 59percent) as a yellow oil.1H NMR (600 MHz, CDCl3) δ ppm 1.91 (t, J=18.2 Hz, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H).
25%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane; toluene at 20 - 85℃; for 20 h; Ionic liquid; Sealed tube
Step A: Preparation of l-bromo-4-(l,l-difluoroethyl)benzene. [00211] To a vial equipped with a magnetic stir bar were added a solution of l-(4- bromophenyl)ethanone (295 mg, 1.48 mmol) in anhydrous DCM (3.0 mL) followed by a 50percent solution of Deoxofluor® in toluene (1.6 mL, 4.45 mmol) at room temperature under N2 and the vial was sealed. The reaction mixture was stirred for approximately 15 h at room temperature, but little conversion had taken place. The mixture was concentrated, treated with additional Deoxofluor® solution (0.66 mL, 1.79 mmol),and warmed to and stirred at 85 °C under N2 for 5 h. The reaction mixture was cooled to 0 °C and carefully quenched by adding sat'd aq NaHC03 dropwise until gas evolution ceased. The bi-phasic mixture was extracted with DCM (2 x 5 mL), and the combined extracts were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography (Si02, 0-^50 EtOAc in hexanes) to afford the title compound (83 mg, 25percent)as a clear liquid: 1H NMR (400 MHz, CDC13) δ 7.58 - 7.53 (m, 2H), 7.41 - 7.35 (m, 2H), 1.90 (t, J = 18.1 Hz, 3H); 19F NMR (376 MHz, CDC13) δ -87.86; IR (Thin Film) 1599, 1294, 1089 cm"1; EIMS mlz 220/221.
17.26 g
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In chloroform at 50℃; for 35 h; Inert atmosphere
Under argon atmosphere, into a 500-ml reaction vessel made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulfur trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50°C for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid. [0134] The properties of Compound (4-1) were as follows. 1H-NMR (400MHz, CDCl3, 8 (ppm)); 1.90 (3H, t, J=18.1Hz), 7.54 (2H, d, J=2.3Hz), 7.57 (2H, d, J=2.4Hz) CI-MS; 222 (M+2)
17.26 g
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In chloroform at 50℃; for 35 h; Inert atmosphere
Under argon atmosphere, into a 500-ml reaction vessel 30 made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulthr trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50° C. for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid.The properties of Compound (4-1) were as follows. ‘H-NMR (400 MHz, CDC13, ö (ppm)); 1.90 (3H, t, J=18. 1 Hz), 7.54 (2H, d, J=2.3 Hz), 7.57 (2H, d, J=2.4 Hz)CI-MS; 222 (M+2)4045
With sulfuryl dichloride; In methyl t-butyl ether; at 20℃; for 1h;Conversion of starting material;
[0371] [TABLE-US-00002] (18) acetophenone derivative R13 R14 1 NO2 H 2 NO2 Cl 3 H Br 4 H H [0372] An acetophenone (2.00 g) as shown by the formula (18) was dissolved or suspended in a solvent as shown in Table 2 (M representing the molarity based on the acetophenone derivative), and sulfuryl chloride in an amount as shown in Table 2 was added all at once under stirring. The temperature and reaction time were as shown in Table 2. [TABLE-US-00003] TABLE 2 Acetophenone SO2Cl2 Time Yield Ex. Solvent (M) derivative (equivalent) Temp. (hr) (%) 42 MTBE(0.5) 1 3.0 r.t. 4.5 50.8 43 MTBE(1) 1 1.65 reflux 7.0 70.1 44 IPE(1) 1 3.0 r.t. 3.0 77.8 45 DME(1) 1 1.65 r.t. 4.0 71.4 46 MTBE(1) 3 3.0 r.t. 1.0 50.3 47 MTBE(1) 4 1.1 r.t. 7.0 78.9 MTBE: methyl t-butyl ether; IPE: diisopropyl ether; DME: 1,2-dimethoxyethane
35%
With Oxone; ammonium chloride; In methanol; at 20℃; for 24h;
General procedure: A typical procedure for the alpha-chlorination of ketone:acetophenone 1a (0.5 mmol), Oxone (0.6 mmol) and NH4Cl (1.0 mmol) were added in MeOH (2 mL). The mixture was stirred at room temperature for 24 h and then separated on a silica gel plate using (4:1 hexane-ethyl acetate) as eluant to give alpha-chloroacetophenone 2a in 85% of yield. White solid, mp 52-54 C; 1H NMR (500 MHz, CDCl3): delta 7.97 (d, 2 H, J = 8.4 Hz), 7.64-7.61 (m, 1H), 7.53-7.50 (m, 2H), 4.73 (s, 2H); 13C NMR (125 MHz, CDCl3): delta 193.35, 137.53, 134.46, 128.75, 127.13, 48.14.
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; acetic acid; for 3h;Irradiation; Inert atmosphere;
General procedure: Into a flask charged with the respective alpha-haloketone 2 (1 mmol) and ethidine (Hantzsch's ester, 1a; 1.2 mmol), was added the solvent as per Tables 2-4 (2.5 mL). The flask was then attached to a balloon filled with N2 and irradiated with 3 W blue LED at a distance of 5 cm. The workup was followed when TLC showed that ethidine or the haloketone was consumed. When AcOH was used as the solvent, the reaction was worked up as follows: the reaction mixture was partitioned between EtOAc (40 mL) and H2O (10 mL), then the organic phase was washed with sat. aq NaHCO3 (3 15 mL) and brine (15 mL), and dried (anhyd Na2SO4). After concentration under reduced pressure, the residue was subjected to flash chromatography for purification eluting with petroleum ether (PE) and CH2Cl2. When aprotic polar solvents were used, the reaction mixture was diluted with EtOAc (40 mL) and the organic layer was washed with H2O (3 15 mL) and brine (15 mL), and dried (anhyd Na2SO4). When volatile solvents were used, the mixture was concentrated under reduced pressure and the residue was subjected to flash chromatography for purification.
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 7h;
To a mixture of 4'-bromoacetophenone (300 mg, 1.51 mmol) and1,4-dioxane (4ml) were added water (0.4ml), cesium carbonate (1.48 g, 4.54 mmol), <strong>[910251-11-5]potassium methoxymethyl trifluoroborate</strong> (459 mg, 3.02 mmol) and 1',1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (110 mg, 0.151 mmol). Then, the reaction mixture was stirred at 100C (external temperature) for 7 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain the title compound (76 mg, 31%). 1H-NMR Spectrum (CDCl3) delta (ppm).: 2.61 (3H, s), 3.42 (3H, s), 4.52(2H, s), 7.41-7.45(2H, m), 7.93-7.97 (2H, m).
With chlorine;aluminium chloride; In dichloromethane;
PREPARATION 13 4-Bromo-3-chloroacetophenone, compound Va.3 (Va.3); X=3-Cl; Y=H; Z=Br A solution of 100 g of 4-bromoacetophenone in 250 ml of dichloromethane is added dropwise at 0 C. to 133.34 g of aluminium chloride in 600 ml of dichloromethane. After stirring for 2 hours at 0 C., 28.3 ml of prefrozen (-75 C.) chlorine are bubbled through the medium at 0 C. The reaction mixture is stirred at room temperature for 12 hours and then hydrolyzed. The phases are separated after settling has taken place, the aqueous phase is extracted with dichloromethane, the organic phases are dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is recrystallized from hexane; yield=57%; m.p.=80 C.
palladium diacetate; In tetrahydrofuran; nitrogen; toluene;
EXAMPLE 45 Synthesis of 4-acetylbiphenyl from an aryl bromoide utilizing 0.000001 mol percent Pd An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with phenylboronic acid (228 mg, 1.5 mmol), and potassium phosphate (425 mg, 2.0 mmol), and 4-bromoacetophenone (199 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and toluene (1.5 mL) was added through a rubber septum. In a separate flask in a nitrogen filled glovebox, palladium acetate (4.5 mg, 0.02 mmol) and 2-(di-tert-butylphosphino)biphenyl (12.0 mg, 0.04 mmol) were dissolved in 20 ml, THF under argon. A portion of this solution (10 muL, 0.00001 mmol Pd, 0.001 mol percent Pd) was added to a second flask contaninig 10 mL THF). A portion of this second solution (10 muL, 0.00000001 mmol Pd, 0.000001 mol percent Pd) was added to the reaction mixture, followed by additional toluene (1.5 mL) through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was heated to 100° C. with stirring until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 176 mg (90percent) of the title compound.
176 mg (90%)
palladium diacetate; In tetrahydrofuran; nitrogen; toluene;
Example 45 Synthesis of 4-acetylbiphenyl from an aryl bromoide Utilizing 0.000001 mol percent Pd An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with phenylboronic acid (228 mg, 1.5 mmol), and potassium phosphate (425 mg, 2.0 mmol), and 4-bromoacetophenone (199 mg, 1.0 mmol). The tube was evacuated and backfilled with argon, and toluene (1.5 mL) was added through a rubber septum. In a separate flask in a nitrogen filled glovebox, palladium acetate (4.5 mg, 0.02 mmol) and 2-(di-tert-butylphosphino)biphenyl (12.0 mg, 0.04 mmol) were dissolved in 20 mL THF under argon. A portion of this solution (10 muL, 0.00001 mmol Pd, 0.001 mol percent Pd) was added to a second flask contaninig 10 mL THF). A portion of this second solution (10 muL, 0.00000001 mmol Pd, 0.000001 mol percent Pd) was added to the reaction mixture, followed by additional toluene (1.5 mL) through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was heated to 100° C. with stirring until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL) and poured into a separatory funnel. The mixture was washed with water (20 mL), and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 176 mg (90percent) of the title compound.
1-(4-bromophenyl)-3-(3-thiazolidinyl)propan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; formaldehyd; In ethanol; acetone;
EXAMPLE 58 Preparation of 1-(4-bromophenyl)-3-(3-thiazolidinyl)propan-1-one 12.56 g (0.1 mol) of <strong>[14446-47-0]thiazolidine hydrochloride</strong>, 19.9 g (0.1 mol) of 4-bromoacetophenone, 12 ml of 36% formaldehyde solution (0.144 mol), 30 ml of ethanol and 5 drops of concentrated hydrochloric acid are mixed and then heated. After a short reflux period, a homogeneous solution is formed. After a 7-hour boiling, the solution is evaporated, the oily residue is poured into 1000 ml of acetone under stirring and the precipitated starting material is filtered off. After evaporating the filtrate, the residue is recrystallized from ethanol or methanol to give the hydrochloride of the title compound, m.p.: 170 C.
With hydrogenchloride; formaldehyd; In ethanol; acetone;
Example 58 1-(4-bromophenyl)-3-(3-thiazolidinyl)propan-1-one 12.56 g (0.1 mol) of <strong>[14446-47-0]thiazolidine hydrochloride</strong>, 19.9 (0.1 mol) of 4-bromoacetophenone, 12 ml of 36% formaldehyde solution (0.144 mol), 30 ml of ethanol and 5 drops of concentrated hydrochloric acid are mixed and then heated. After a short reflux period, a homogenous solution is formed. After 7 hours boiling, the solution is evaporated, the oily residue is poured into 1000 ml of acetone under stirring and the precipitated starting material is filtered off. After evaporating the filtrate, the residue is recrystallized from ethanol or methanol to give the hydrochloride salt of the title compound, m.p.: 170C.
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 115℃;
In a sealed tube, dissolve benzyl 3-oxopiperazine-l-carboxylate (500 mg, 2.13 mmol), A- bromo-acetophenone (425 mg, 2.13 mmol), Cs2CO3 (1.4 g, 4.26 mmol), Pd2dba3 (195 mg, 0.213 mmol) and xantphos (124 mg, 0.213 mmol) in dry dioxane (10 mL). Degas the mixture with Argon and heat at 115 0C overnight. Cool and dilute with EtOAc (25 mL). Filter the solution through Ce lite and evaporate the filtrate. Chromatograph the crude product on silica eluting with hexane/acetone (2: 1) to yield the title compound. LC-MS (M+l): 353.14
With tetrabutylammomium bromide; potassium carbonate;palladium diacetate; In ethanol; water; at 150℃; for 0.166667h;Irradiation;
l-(3'-ChIoro-4'-hydroxy-biphenyl-4-yl)-ethanone 84. To a mixture of 4'-bromoacetophenone (0.10Og, 0.5 mmol), 3-chloro-4- hydroxyphenylboronic acid 83 (0.103 g, 0.6 mmol), K2CO3 (0.173 g5 1.25 mmol) and Bu4NBr (0.161 g, 0.5 mmol) in EtOH (1.2 mL) and water (2.8 mL) was added Pd(OAc)2 (catalytic) and the reaction was micro waved at 15O0C for 10 min. Water (10 mL) was added and the organics extracted into EtOAc (10 mL). Flash chromatography using an elution gradient of hexane to 30percent EtOAc in hexane gave the product in a mixture. This was dissolved in EtOAc and extracted with base. The aqueous layer was acidified and organics extracted into EtOAc then concentrated under reduced pressure. Flash chromatography using DCM as eluent gave the product as the first fraction: 1H NMR delta (270 MHz5 CDCl3) 2.62 (3H, s), 5.86 (IH5 s), 7.11 (IH5 d5 J= 8.4 Hz), 7.44 (IH, dd, J= 8.4, 2.2 Hz), 7.57-7.62 (3H, m), 8.00 (2H5 d, J= 8.7 Hz); HPLC > 92percent (Rt 3.98, 90percent MeCN in H2O); ES-ve MS (M-H)- 245.22 m/z
With potassium fluoride; copper(l) iodide; palladium diacetate; catacxium A; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;
2-Trimethylsilylpyridine (1) , 4-bromoacetophenone (199mg, 1.00mmol) (2), the palladium source, the ligand (if required), CuI and KF (128mg, 2.20mmol) were combined in a reacti-vial and the vial was evacuated and backfilled with nitrogen three times. Degassed DMF was added via syringe. The vial was again evaporated and backfilled with nitrogen three times. The resulting suspension was stirred at 90 oC overnight.
4-bromoacetophenone (20.0 g; 0.10 mole) and N,N-dimethylformamide dimethylacetal (28.5 mL; 0.20 mole) were mixed together in DMF (12 mL) and heated to 1100C for 4 hours. The methanol and water that were generated during the reaction were distilled (6.2 mL). The mixture was cooled to 25C. Methyl t-butyl ether (100 mL) and methylhydrazine (21.2 mL; 0.40 moles) <n="70"/>were added and the mixture was stirred over night. The reaction mixture was washed with 1 M aqueous ammonium chloride (3 x 40 ml_) and water (40 ml_). The organic phase was dried by azeotropic distillation using a Dean-Stark apparatus. As an alternative to distillation, the solution was dried through an anhydrous magnesium sulfate cartridge. The solution was filtered through a silica gel cartridge (60 g). The product was flushed from the cartridge with methyl t-butyl ether. The fraction(s) containing product were combined and concentrated to about 70 ml_ by distillation. Heptane (120 ml_) was added and distillation was continued until the pot temperature reached 98.4 0C. About 100 ml_ of distillate was collected. The mixture was cooled to 40 0C. The mixture was seeded and the temperature was maintained at 40 0C for 30 minutes while crystallization was initiated. The mixture was slowly chilled to 0 0C over 90 minutes. The mixture was held at 0 0C for 30 minutes. The mixture was filtered and the solid was washed (3 x) with chilled (00C) heptane. The solid was dried on the filter. A cream-colored, crystalline solid (16.3 g; 68% yield) was obtained. The NMR data of the title compound are as per alternative 1
A N,N'-dimethylformamide (15 mL) solution of 4-bromoacetophenone (10.60 g, 53.25 mmols) and N,N'-dimethylformamide dimethyl acetal (2.5 equivalents) was heated at 125 degrees Celcius for 3 hours. The dark red solution was cooled to room temperature. The volatiles were removed by rotary evaporation providing a red viscous oil. To this substance was added anhydrous N,N'-dimethylformamide (15 mL) and methyl hydrazine (7.6 g, 160 mmols, 3 equivalents). The mixture was stirred at room temperature for 1 hour and then heated at 75 degrees Celcius for 4 hours. The volatiles were removed by rotary evaporation and the crude residue was taken up in a small volume of methylene chloride. This red solution was applied to a cartridge of silica gel. The cartridge was eluted with a 20:80 mixture of ethyl acetate and hexanes, respectively. The appropriate fractions were combined and concentrated to produce 12.5 g of a white solid. 1 H NMR (400 MHz, CHLOROFORM-c/) delta ppm 3.87 - 3.95 (m, J=2.22 Hz, 3 H) 6.29 - 6.36 (m, 1 H) 7.31 (dd, J=8.36 Hz, 2 H) 7.52 - 7.56 (m, 1 H) 7.62 (dd, J=2.05 Hz, 2 H).
General procedure for the synthesis of NiTo a stirred solution of 1-(4-bromophenyl)ethan-1-one (30.0 g, 150 mmol) in DMF (18 mL) was added DMFDMA (43.5 mL, 300 mmol), the resulting mixture was stirred at 110 C for 4 hours. After cooling to room temperature, MTBE (150 mL) was added to the mixture, then MeNHNH2 (78.9 g, 600 mmol) was added into above mixture, the resulting mixture was stirred at 25 C for 17 hours. The mixture was diluted with EtOAc (100 mL), filtered and the filter cake was washed with EtOAc (150 mL). The combined organic layer was washed with water (200 mLx3) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography (eluted: PE/EtOAc=8/1 to 4/1) to afford Ni.
With PdCl(C3H5)(1,4-bis(diphenylphosphino)butane); potassium acetate; at 125℃; for 6h;Inert atmosphere; Green chemistry;Catalytic behavior;
General procedure: The reaction of 4-bromoacetophenone (0.100 g, 0.5 mmol), heteroaromatic (0.75 mmol) and KOAc (0.098 g, 1 mmol) at 125-150 C (see tables) in the presence of PdCl(C3H5)(dppb) or Pd(OAc)2 (see tables) in the appropriate solvent under argon affords the coupling product after filtration on silica gel (pentane/ether).
With potassium hydroxide; In ethanol; at 80℃; for 2h;
Compound B weighed (400mg, 3.7mmol) was added to a 100mL round bottom flask,Dissolved in anhydrous ethanol Compound B was dissolved,Weigh 4_ bromoacetophenone (736mg, 3.7mmol),K0H (20.7 mg, 0.37 mmol, 0. leq)Sequentially added (4-bromoacetophenone dissolved,Then slowly added Kappa0Eta) reaction solution,At 80 C heated to reflux 2h,The reaction was followed by TLC until the starting material, compound B, reacted completely.The reaction solution was evaporated to dryness with a vacuum rotary evaporator,The crude product was purified by silica gel column chromatography (200-300 mesh)The final white solid, Compound C (378 mg, 94.5%) 0 was obtained
With sodium hydroxide; In ethanol;Reflux;
7.6 g (50 mmol) of o-nitrobenzaldehyde was added to a round bottom flask and 170 mL of absolute ethanol was added. After stirring, 20 g (357 mmol) of iron powder was added,Acetic acid 170mL and distilled water 85mL, and finally add a drop of concentrated hydrochloric acid,Reflux 15min (TLC monitoring reaction completely) to stop the reaction,The filtrate was washed with 100 mL of water and the filtrate was extracted with CH2Cl2. The combined organic layers were washed with aqueous NaHCO3 and distilled water, dried over anhydrous MgSO4 and concentrated to give a yellow oil.7.8 mmol of o-aminobenzaldehyde and 7.8 mmol of p-bromoacetophenone were added to 30 mL of absolute ethanol and a saturated NaOH solution was added. The reaction mixture was heated and refluxed overnight, cooled and filtered, and the resulting crude product was recrystallized from ethanol to give white needle-like crystals to p-bromoquinoline.All the glass instruments were dried at 180 C for 5 hours and then cooled in a vacuum state. A solution of p-bromoquinoline (0.50 g, 1.76 mmol) and 18 mL of THF was added to a 50 ml reaction flask. The reaction system was cooled to -78 C with a liquid nitrogen-acetone cold bath and 1.32 mL of 1.6 M n-butyllithium in n-hexane was added to the syringe.At -78 C for about 1 hour. A solution of 2.11 mmol of triphenylchlorosilane in THF was rapidly injected into the reaction flask under nitrogen with a syringe. The mixture was naturally warmed to room temperature with stirring and the reaction was continued for 18 hours.The above reaction is carried out under dry nitrogen protection. After completion of the reaction, the mixture was carefully poured into 50 mL of distilled water, hydrolyzed three times with dichloromethane, dried over anhydrous sodium sulfate and concentrated,And purified by column chromatography to give the target compound Sipq. White solid, yield 22%
With potassium carbonate; L-proline;copper(l) iodide; In dimethyl sulfoxide; at 95℃; for 72h;
The reaction is carried out under protective gas (argon). A mixture of 2.39 g (12 mmol) 1-(4-bromophenyl)ethanone, 0.99 mL (8 mmol) <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong>, 2.21 g (16 mmol) potassium carbonate, 150 mg (0.8 mmol) copper iodide and 180 mg (1.6 mmol) L-proline in 12 mL DMSO was stirred for 72 hours at 95 C. The reaction mixture was added to water, mixed with a little ammonia extracted twice with tert-butyl-methylether. The combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether+30% ethyl acetate). The product was further reacted directly.Yield: 33% of theoryC15H13F2NO2 (277.27)Rt=1.98 min. method 1
With diethylamino-sulfur trifluoride; In dichloromethane; at 50℃;Inert atmosphere;
Example 63A1-Bromo-4-(1,1-difluoroethyl)benzene; Under argon, 3.0 g (15.07 mmol) of 1-(4-bromophenyl)ethanone were initially charged in 30 ml of dichloromethane, and 15.9 ml (120.57 mmol) of [ethyl(trifluoro-lambda4-sulphanyl)amino]ethane (DAST) were added slowly. The reaction solution was then slowly warmed to 50 C. and stirred at this temperature overnight. After the reaction had ended, the reaction solution was slowly poured into ice-water. The organic phase was then separated off, and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase petroleum ether/dichloromethane 4:1). This gave 2.56 g (11.58 mmol, 77% of theory) of the title compound as a yellowish liquid.GC-MS (Method 1): Rt=2.84 min; m/z=220/222 (M)+.
76%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In tetrahydrofuran; methanol; for 96h;Reflux;
Example 48A 1-Bromo-4-(1,1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50% in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for 4 days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76% of theory) 1H NMR (400 MHz, DMSO-d6): delta=7.70 (d, 2H), 7.52 (d, 2H), 1.96 (t, 3H).
76%
With methanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride; In tetrahydrofuran; for 96h;Reflux;
Example 68A1-Bromo-4-(1,1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50% in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for four days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76% of theory)1H NMR (400 MHz, DMSO-d6): delta=7.70 (d, 2H), 7.52 (d, 2H), 1.96 (t, 3H).
59%
With diethylamino-sulfur trifluoride; at 85℃; for 15h;
Deoxo-Fluor (registered trademark) (22.2 g) was added to 1-(4-bromophenyl)ethanone (20.0 g) and the mixturewas stirred at 85C for 15 hours. Under icecooling, ice water and an aqueous solution of potassium carbonate wereadded to the reaction solution, followed by extraction with chloroform. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound(13.0 g, yield 59%) as a yellow oil.1H NMR (600 MHz, CDCl3) delta ppm 1.91 (t, J=18.2 Hz, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H).
25%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; toluene; at 20 - 85℃; for 20h;Ionic liquid; Sealed tube;
Step A: Preparation of l-bromo-4-(l,l-difluoroethyl)benzene. [00211] To a vial equipped with a magnetic stir bar were added a solution of l-(4- bromophenyl)ethanone (295 mg, 1.48 mmol) in anhydrous DCM (3.0 mL) followed by a 50% solution of Deoxofluor in toluene (1.6 mL, 4.45 mmol) at room temperature under N2 and the vial was sealed. The reaction mixture was stirred for approximately 15 h at room temperature, but little conversion had taken place. The mixture was concentrated, treated with additional Deoxofluor solution (0.66 mL, 1.79 mmol),and warmed to and stirred at 85 C under N2 for 5 h. The reaction mixture was cooled to 0 C and carefully quenched by adding sat'd aq NaHC03 dropwise until gas evolution ceased. The bi-phasic mixture was extracted with DCM (2 x 5 mL), and the combined extracts were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography (Si02, 0-^50 EtOAc in hexanes) to afford the title compound (83 mg, 25%)as a clear liquid: 1H NMR (400 MHz, CDC13) delta 7.58 - 7.53 (m, 2H), 7.41 - 7.35 (m, 2H), 1.90 (t, J = 18.1 Hz, 3H); 19F NMR (376 MHz, CDC13) delta -87.86; IR (Thin Film) 1599, 1294, 1089 cm"1; EIMS mlz 220/221.
17.26 g
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In chloroform; at 50℃; for 35h;Inert atmosphere;
Under argon atmosphere, into a 500-ml reaction vessel made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulfur trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50C for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol%), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid. [0134] The properties of Compound (4-1) were as follows. 1H-NMR (400MHz, CDCl3, 8 (ppm)); 1.90 (3H, t, J=18.1Hz), 7.54 (2H, d, J=2.3Hz), 7.57 (2H, d, J=2.4Hz) CI-MS; 222 (M+2)
17.26 g
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In chloroform; at 50℃; for 35h;Inert atmosphere;
Under argon atmosphere, into a 500-ml reaction vessel 30 made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulthr trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50 C. for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol %), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid.The properties of Compound (4-1) were as follows. ?H-NMR (400 MHz, CDC13, oe (ppm)); 1.90 (3H, t, J=18. 1 Hz), 7.54 (2H, d, J=2.3 Hz), 7.57 (2H, d, J=2.4 Hz)CI-MS; 222 (M+2)4045
With [(eta5-C5Me5)Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)]OTf2; potassium hydroxide; In water; for 12h;Reflux; Green chemistry;
Bromoacetophenone (239 mg, 1.2 mmol),[Cp * Ir (6,6 '- (OH) 2bpy) (H2O)] [OTf] 2 (8.3 mg,0.01 mmol, 1 mol%), potassium hydroxide (56 mg, 1.0 mmol, 1.0 equiv.),Aminobenzyl alcohol (123 mg, 1.0 mmol) and water (1 mL) were sequentially added to a 5 mL round bottom flask. It was extracted with ethyl acetate and the reaction mixture was refluxed in air for 12 hours and then cooled to room temperature.Extraction with ethyl acetate, removal of the solvent by rotary evaporation followed by column chromatography (developing solvent: petroleum ether / ethyl acetate) gave the pure target compound in a yield of 86%
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: The chalcones were prepared through an aldol condensation reaction between acetophenones (1.0 mmol) and the corresponding aldehydes (1.0 mmol), in methanol (15 mL), KOH (50 % v/v), at room temperature with magnetic stirring for 24 h.14 Distilled water and 10% hydrochloric acid were added to the reaction for total precipitation of the compounds, which were then obtained by vacuum filtration and later recrystallized from hot ethanol. The purity of the synthesized compounds was analyzed by thin-layer chromatography (TLC) using Merck silica pre-coated aluminum plates of 200 mum thickness, with several solvent systems of different polarities. Compounds were visualized with ultraviolet light (l = 254 and 360 nm) and using sulfuric anisaldehyde solution followed by heat application as the developing agent.
With potassium hydroxide; In methanol; at 20℃; for 24h;
General procedure: The novel chalcones (1-8)were prepared by magnetic stirring with acetophenone (1 mmol), methanol (30 ml), KOH 50% w/v (5 ml) and <strong>[130345-50-5]quinoxaline-6-carbaldehyde</strong> (12) (1 mmol), at room temperature for 24 h. Distilled water and chloridric acid 10% were added in the reaction for total precipitation of the compounds. The compounds were then obtained by vacuum filtration and later recrystallized in dichloromethane/hexane. The purified chalcones were obtained with yields between 41% and 93%.
With potassium tert-butylate; In water; at 120℃; for 24h;Inert atmosphere;
General procedure: 2-nitrobenzyl alcohol (0.5 mmol), t-BuOK (1 mmol), ketone (1 mmol) and a magnetic stir bar were placed in a pressure tube and water (3 mL) was then injected. The mixture was bubbled with argon for 15 min at r.t. then stirred at 120 oC for 24 h. The mixture was cooled to r.t., extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (PE-EtOAc).
With copper(l) iodide; ethylenediamine; sodium t-butanolate; In toluene; at 100℃; for 5.0h;
General procedure: CuI (10mol%) and EDA (10mol%) were added to a mixtureof O-alkyl carbamate (1mmol), NaOtBu (1.5mmol) and aryl halide (1mmol) in 2mL toluene and the mixture wasstirred for the appropriate time, which was determined byTLC monitoring, at 100C. After completion of the reaction,the catalyst was removed by filtration and 20mL H2Owas added to the filtrate. The resultant mixture was extractedwith CHCl3.Then the organic phase was washed with water(2 × 10mL) and dried over anhydrous Na2SO4.After evaporationof CHCl3under reduced pressure, the correspondingcrude product was purified by flash chromatography to givethe desired pure cross-coupling product in good to excellentyield. In the case of using arylboronic acids as couplingpartners, Cu(OAc)2 was employed instead of CuI.
With copper(I) oxide; tetrakis(triphenylphosphine) palladium(0); lithium carbonate; In N,N-dimethyl acetamide; at 160℃; for 24h;Molecular sieve; Inert atmosphere;
General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added <strong>[2164-61-6]pyridazine-3-carboxylic acid</strong> (0.6 mmol, 1.0 eq), aryl- and heteroaryl-bromides (1.2 mmol, 2.0 eq), Pd(PPh3)4 (35 mg, 0.03 mmol, 5.0 mol %), Cu2O (84 mg, 0.6 mmol, 1.0 eq), Li2CO3 (107 mg, 1.8 mmol, 3.0 eq), 3A MS (200 mg) and DMA (4.0 mL). The mixture was stirred at 160 C for 24 h under N2. After the reaction was complete, the mixture was washed with brine and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/1), the eluent need bubbled NH3 five seconds. The eluent of TLC (ethyl acetate / petroleum ether 1:1) need bubbled NH3 two seconds.
General procedure: To a solution of the appropriate acetophenone (0.04 mol) in 20 mLethanol, 4-methanesulfonyl phenyl hydrazine hydrochloride (6a,0.04 mol) was added. The resulting solution was heated under reflux for12 h. The precipitated hydrazones was filtered and washed with sufficientamount of ethanol and recrystallized from ethanol to afford hydrazones8a, 8b and 8f. Physical and spectral data are listed below:
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 80℃;
4-Bromoacetophenone (10 g, 50.23 mmole) and <strong>[86-58-8]quinolin-8-ylboronic acid</strong> (9.12 g, 52.75 mmole) were placed in a reaction tank.Add 120 ml of toluene,And potassium carbonate (18.05 g, 130.6 mmole) was dissolved in 70 ml of deionized water and added to the reaction tank.Simultaneously add tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (1.74g, 1.507mmole) and 30ml of ethanol, and turn on heating and stirring.Heat to 80 C and react overnight. After the reaction was completed, 300 ml of deionized water was added, and after stirring for 30 minutes, the stirring was stopped and allowed to stand for stratification.After removing the water layer,Purified by silica gel chromatography,After concentration to a thick state, 300 ml of hexane was added to precipitate.The organic layers were combined solid was filtered to give a light yellow solid A (about 8 grams).
General procedure: A mixture of acetophenone 2a (18.88 mmol), Quinoline aldehyde 1 (17.16 mmol) andKOH (25.74 mmol) was refluxed in methanol (75 mL) for 4 hrs. Completion of the reactionwas evidenced by TLC analysis. After completion of the reaction, the reaction mixturewas cooled to 0 C. The resulting solid filtered and the solid recrystallized frommethanol. Obtained as an off - white solid (5.745 g) in 85% yield.
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