* 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.
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 16 h; Inert atmosphere
General procedure: Method B: to a solution of compound 4a (1.65 g, 9.94 mmol) inanhydrous CH2Cl2 (100 mL) stirred at 0 C under argon was addedDess-Martin reagent (5.06 g,11.93 mmol). The mixture was allowedto warm to room temperature after 10 min and stirred for 16 h. Thereaction was quenched with a saturated sodium bicarbonate solution and salts were filtered off. The filtrate was extracted withCH2Cl2. The combined organic layers were dried over MgSO4,filtered and evaporated under reduced pressure. Purification bysilica column chromatography using CH2Cl2 as eluent gave thedesired ketone 5a (1.42 g, 87percent) as a pale yellow solid.
81%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 1,4-dioxane at 80℃; Schlenk technique
General procedure: In an oven dried Schlenk tube, were added alcohol 1 (69.0–199.5 mg, 0.5 mmol), CuI (10 molpercent)and 1,10-Phenanthroline (20 molpercent) and K3PO4 (2 mmol) followed by the addition of dioxane (2mL) at room temperature under open air atmosphere. The stirred reaction mixture was heated inan oil bath at 80 C for 7–48 h. Progress of the reaction was monitored by TLC till the reaction iscompleted. Then, the reaction mixture was cooled to room temperature, quenched with aqueousNH4Cl solution and then extracted with CH2Cl2 (3 10 mL). The organic layer was washed withsaturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the solvent under reducedpressure and purification of the crude material by silica gel column chromatography (petroleumether/ethyl acetate) furnished the aldehyde/ketone 2 (61–97percent).
Reference：
[1] Synthesis, 1980, # 9, p. 691 - 694
[2] European Journal of Medicinal Chemistry, 2015, vol. 105, p. 80 - 105
[3] Synthetic Communications, 2014, vol. 44, # 14, p. 2076 - 2087
[4] Tetrahedron Letters, 2000, vol. 41, # 42, p. 8131 - 8135
[5] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4775 - 4782
[6] Chemische Berichte, 1903, vol. 36, p. 3595
[7] Gazzetta Chimica Italiana, 1904, vol. 34 I, p. 358[8] Gazzetta Chimica Italiana, 1904, vol. 34 II, p. 170
[9] Gazzetta Chimica Italiana, 1904, vol. 34 I, p. 358[10] Gazzetta Chimica Italiana, 1904, vol. 34 II, p. 170
[11] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 9, p. 3024 - 3038
[12] Heterocycles, 1984, vol. 21, # 2, p. 711
[13] Journal of the American Chemical Society, 2004, vol. 126, # 36, p. 11152 - 11153
[14] Organic Letters, 2009, vol. 11, # 21, p. 4846 - 4848
2
[ 274-09-9 ]
[ 75-36-5 ]
[ 3162-29-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
With indium(III) tosylate In dodecane; nitromethane for 2.5 h; Schlenk technique; Reflux
General procedure: Into a Schlenk flask were introduced 20 mL of nitromethane,2 mmol of 1,3-dimethoxybenzene, 10 mol percent of catalyst and4 mmol of acetyl chloride, with 0.5 mmol of dodecane for GC monitoring. The solutions were heated at reflux. The reactionswere followed by gas chromatography, by analysis of aliquots.The products were obtained after extraction by diethyl ether andpurification by column chromatography. All products are knowncompounds.
94%
With 10percent AlCl3 on polystyrene In dichloromethane at 45℃;
In a 1 L three-opening in the bottle, by adding dichloromethane 500 ml, aluminum chloride/polystyrene (66.5 g, loading 10 wt percent), stirring slowly under the condition into the acetyl chloride (42.9 g, 5.5 µM), the completion of the dropping, then gradually dripped into the pepper link (61.0 g, 0.5 µM, dissolved in 100 ml dichloromethane); after dropping, slow heating to 45 °C stirring reaction, until the pepper ring reaction finishes, cooling, filtering to obtain aluminum chloride/polystyrene catalyst; the reaction liquid layered extraction, the combined organic layer, evaporating the solvent under reduced pressure, drying to obtain products 77.2 g, yield 94percent.
Reference：
[1] Tetrahedron, 2015, vol. 71, # 38, p. 6813 - 6817
[2] Patent: CN107434798, 2017, A, . Location in patent: Paragraph 0031; 0032
[3] Monatshefte fuer Chemie, 1929, vol. 53/54, p. 435
[4] Archiv der Pharmazie (Weinheim, Germany), 1927, p. 390,400[5] Chem. Zentralbl., 1924, vol. 95, # II, p. 1404
3
[ 274-09-9 ]
[ 108-24-7 ]
[ 3162-29-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 1.5 h;
General procedure: An oven-dried vial was charged with anisole 1a (0.75 mmol, 1.0 equiv), acetic anhydride 2a (1.5 mmol, 2.0 equiv) and TFA (0.8 mL). The reaction mixture was stirred at room temperature and monitored by TLC or GC-MS. The reaction typically took 1.5 h to complete. Upon completion, aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography to afford ketone product 3a. Alternatively, the product can also be obtained without workup: upon completion, the solvent was removed under reduced pressure and the residue was subjected to silica gel flash column chromatography.
90%
at 120℃;
In a 1 L three-opening in the bottle, adding trifluoromethylbenzene 500 ml, zinc chloride/three-alumina (272.6 g, loading 10 wt percent), stirring slowly under the condition into the acetic anhydride (56.1 g, 0 . 55 µM), the completion of the dropping, then gradually dripped into the pepper link (61.0 g, 0.5 µM, dissolved in 100 ml trifluoromethylbenzene); after dropping, slow heating to 120 °C stirring reaction, until the pepper ring reaction finishes, cooling, filtering to obtain the zinc chloride/three-alumina catalyst; the reaction liquid layered extraction, the combined organic layer, evaporating the solvent under reduced pressure, drying to obtain products 73.9 g, yield 90percent.
Reference：
[1] Tetrahedron Letters, 2018, vol. 59, # 10, p. 869 - 872
[2] Patent: CN107434798, 2017, A, . Location in patent: Paragraph 0033-0034
[3] Organic Letters, 2001, vol. 3, # 3, p. 417 - 420
[4] Journal of the American Chemical Society, 1957, vol. 79, p. 3582,3585
[5] Journal of Organic Chemistry, 1953, vol. 18, p. 9,13
[6] Medicinal Chemistry Research, 2014, vol. 23, # 8, p. 3744 - 3751
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 13, p. 2668 - 2674
4
[ 274-09-9 ]
[ 64-19-7 ]
[ 3162-29-6 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 80℃;
In a 1 L three-opening in the bottle, to join the nitrobenzene 500 ml, aluminum chloride/silicon dioxide (166.3 g, loading 10 wt percent), stirring slowly into the acetic acid under the condition (33.0 g, 0 . 55 µM), the completion of the dropping, then gradually dripped into the pepper link (61.0 g, 0.5 µM, dissolved in 100 ml of nitrobenzene); after dropping, slow heating to 80 °C stirring reaction, until the pepper ring reaction finishes, cooling, filtering to obtain aluminum chloride/silicon dioxide catalyst; the reaction liquid layered extraction, the combined organic layer, evaporating the solvent under reduced pressure, drying to obtain products 78.8 g, yield 96percent.
Reference：
[1] Patent: CN107434798, 2017, A, . Location in patent: Paragraph 0035-0042
5
[ 75-16-1 ]
[ 147030-72-6 ]
[ 3162-29-6 ]
Yield
Reaction Conditions
Operation in experiment
85%
With benzotriazol-1-ol In tetrahydrofuran; diethyl ether at 0℃; for 1 h;
N-methoxy-N-methylbenzo[d][1,3]dioxole-5-carboxamide. To a solution of acid 290 40 (1.0g, 6.01mmol) in dry 196 DCM (20mL), EDCI (1382mg, 7.21mmol), 291 HOBt (974mg, 7.21mmol) and 76 N,N-DIPEA (2mL, 12.01mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 30min, then 292 N,O-dimethylhydroxylamine hydrochloride (703mg, 7.21mmol) and N,N-DIPEA (1.00mL, 6.01mmol) were added. The reaction mixture was stirred at 25°C for 12h, then quenched with saturated aqueous NaHCO3. The reaction was extracted with DCM (3×20mL) and the combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (100percent chloroform) to afford the 293 title compound as a colorless oil (73percent yield). 1H NMR (300MHz, CDCl3), δ 7.30 (dd, 1H, J1=0.9Hz, J2=0.9Hz), 7.22 (s, 1H), 6.81 (d, 1H, J=8.7Hz), 6.00 (s, 2H), 3.55 (s, 3H), 3.34 (s, 3H); ESI-MS m/z 210.0 [M+H]+, 231.9 [M+Na]+, 425.0 [2M+H]+, 440.9 [2M+Na]+. To a solution of N-methoxy-N-methylbenzo[d][1,3]dioxole-5-carboxamide (920mg, 4.40mmol) in dry THF (20mL) MeMgBr (3M solution in Et2O, 2.2mL, 6.60mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1h, and then quenched with saturated aqueous NH4Cl. THF was evaporated under reduced pressure and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM (3×30mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was submitted to the next step without further purification (85percent yield). 1H NMR (300MHz, CDCl3) δ 7.53 (dd, 1H, J1=1.8Hz, J2=8.1Hz), 7.41 (s, 1H), 6.83 (d, 2H, J=8.4Hz), 6.02 (s, 1H), 2.52 (s, 3H); ESI-MS m/z 165.0 [M+H]+.
Reference：
[1] European Journal of Medicinal Chemistry, 2019, p. 290 - 320
6
[ 69672-52-2 ]
[ 94839-07-3 ]
[ 3162-29-6 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 51, p. 15734 - 15735
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 29, p. 8444 - 8447[2] Angew. Chem., 2016, vol. 128, # 29, p. 8584 - 8587,4
15
[ 6329-73-3 ]
[ 3162-29-6 ]
[ 179237-91-3 ]
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 47, p. 12978 - 12992
16
[ 81581-27-3 ]
[ 3162-29-6 ]
Reference：
[1] Yakugaku Zasshi, 1953, vol. 73, p. 681,684[2] Chem.Abstr., 1954, p. 8788
[3] Journal of the American Chemical Society, 1929, vol. 51, p. 1269
[4] Journal fuer Praktische Chemie (Leipzig), 1927, vol. <2> 116, p. 323
Reference：
[1] European Journal of Medicinal Chemistry, 2019, p. 290 - 320
27
[ 676-58-4 ]
[ 147030-72-6 ]
[ 3162-29-6 ]
Reference：
[1] Synlett, 1999, # 7, p. 1091 - 1093
28
[ 25054-53-9 ]
[ 3162-29-6 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 4760,4764
29
[ 62681-68-9 ]
[ 3162-29-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1912, vol. 389, p. 36,111
30
[ 495-76-1 ]
[ 3162-29-6 ]
Reference：
[1] Journal of the Chinese Chemical Society, 1997, vol. 44, # 1, p. 65 - 69
31
[ 186581-53-3 ]
[ 120-57-0 ]
[ 3162-29-6 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1392,1394[2] Chemische Berichte, 1929, vol. 62, p. 1276
32
[ 120-57-0 ]
[ 74-88-4 ]
[ 3162-29-6 ]
Reference：
[1] Journal of the Chinese Chemical Society, 1997, vol. 44, # 1, p. 65 - 69
33
[ 88775-41-1 ]
[ 3162-29-6 ]
[ 88775-49-9 ]
[ 88775-29-5 ]
[ 118-41-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 9, p. 3039 - 3055
[2] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 9, p. 3039 - 3055
[3] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 9, p. 3039 - 3055
34
[ 7664-93-9 ]
[ 81581-27-3 ]
[ 3162-29-6 ]
Reference：
[1] Journal of the American Chemical Society, 1929, vol. 51, p. 1269
[2] Journal fuer Praktische Chemie (Leipzig), vol. <2> 166, p. 322
35
[ 274-09-9 ]
[ 75-36-5 ]
[ 3162-29-6 ]
[ 75-11-6 ]
[ 635-67-6 ]
[ 72712-21-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 311 - 314
36
[ 75-15-0 ]
[ 274-09-9 ]
[ 7446-70-0 ]
[ 75-36-5 ]
[ 3162-29-6 ]
Reference：
[1] Monatshefte fuer Chemie, 1929, vol. 53/54, p. 435
37
[ 7647-01-0 ]
[ 57134-53-9 ]
[ 3162-29-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1913, vol. 399, p. 150
38
[ 3162-29-6 ]
[ 105-58-8 ]
[ 81581-27-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 14-15, p. 3076 - 3080
[2] Organic Letters, 2016, vol. 18, # 20, p. 5408 - 5411
[3] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 244 - 258
39
[ 3162-29-6 ]
[ 10328-92-4 ]
[ 485-61-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 727 - 731
40
[ 3162-29-6 ]
[ 24316-19-6 ]
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 32, p. 10370 - 10371
[2] Patent: WO2009/148654, 2009, A2,
41
[ 3162-29-6 ]
[ 124-41-4 ]
[ 6100-74-9 ]
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1982, vol. 30, # 5, p. 1567 - 1573
[2] Chemical & Pharmaceutical Bulletin, 1982, vol. 30, # 5, p. 1567 - 1573
42
[ 3162-29-6 ]
[ 159873-64-0 ]
Reference：
[1] Helvetica Chimica Acta, 2001, vol. 84, # 12, p. 3735 - 3741
[2] Journal of the American Chemical Society, 1997, vol. 119, # 22, p. 5081 - 5090
Conditions A (used in Table 3, top)
General procedure: An oven-dried vial was charged with anisole 1a (0.75 mmol, 1.0 equiv), acetic anhydride 2a (1.5 mmol, 2.0 equiv) and TFA (0.8 mL). The reaction mixture was stirred at room temperature and monitored by TLC or GC-MS. The reaction typically took 1.5 h to complete. Upon completion, aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography to afford ketone product 3a. Alternatively, the product can also be obtained without workup: upon completion, the solvent was removed under reduced pressure and the residue was subjected to silica gel flash column chromatography.
90%
at 120℃;
2 Embodiment 2
In a 1 L three-opening in the bottle, adding trifluoromethylbenzene 500 ml, zinc chloride/three-alumina (272.6 g, loading 10 wt %), stirring slowly under the condition into the acetic anhydride (56.1 g, 0 . 55 µM), the completion of the dropping, then gradually dripped into the pepper link (61.0 g, 0.5 µM, dissolved in 100 ml trifluoromethylbenzene); after dropping, slow heating to 120 °C stirring reaction, until the pepper ring reaction finishes, cooling, filtering to obtain the zinc chloride/three-alumina catalyst; the reaction liquid layered extraction, the combined organic layer, evaporating the solvent under reduced pressure, drying to obtain products 73.9 g, yield 90%.
90.3%
With diatomite-solid acid catalyst In 1,2-dichloro-ethane at 80℃; for 6h;
1.1; 1.2; 4.1; 4.2; 5.1; 5.2; 6.1; 6.2; 7.1; 7.2; 8.1; 8.2 Example 1
(1) Take commercial diatomite (30g, 303 mmol) and bake at 120 ° C for 7 h to remove water from the diatomite,Add the dried diatomite to the reaction kettle, and slowly add chlorosulfonic acid (15g, 128 mmol) under mechanical stirring at room temperature.After 45 minutes of reaction, it can be used directly as a catalyst for the Friedel-Crafts acylation reaction and not used for further processing.(2) Add 3.9 g of diatomite-solid acid catalyst, 200 mL of dichloroethane, pepper ring (30 g, 246 mmol), and acetic anhydride (50 g, 492 mmol) in sequence to the reaction kettle.The reaction was carried out at 80 ° C, TLC detection, and the raw material reaction was complete after 6h. Filter while hot to remove the solid acid catalyst,The excess acetic anhydride and acetic acid were distilled off under reduced pressure, and the organic layer was extracted with dichloroethane,The combined organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a solid.The solid was recrystallized from ethanol / water = 20: 1 to obtain 36.4g of white solid 3,4-methylenedioxyacetophenone, melting point 89 ° C, yield 90.3%.
61%
In dichloromethane Heating;
With sodium perchlorate; acetic acid; acetyl chloride
With zinc(II) chloride
With zinc(II) chloride at 20℃; for 12h;
With aluminum (III) chloride; carbonic acid dimethyl ester at 20℃;
With zinc(II) chloride at 70℃; for 5h;
1.1; 2.1; 3.1; 4.1; 5.1; 6.1; 6.1
S1, 40g (0.301mol) anhydrous zinc chloride,Add 300g (2.941mol) of acetic anhydride and 450g (3.685mol) of pepper ring into a three-necked flask,Turn on stirring, heat up to 70°C, react for 5h,After the reaction is completed, wash twice with 200g of water,After washing the material, vacuum distillation to recover the pepper ring,The acylation intermediate 3,4-methylenedioxyacetophenone is obtained;
With indium(III) tosylate In dodecane; nitromethane for 2.5h; Schlenk technique; Reflux;
4.2. Acylation reactions, general procedure
General procedure: Into a Schlenk flask were introduced 20 mL of nitromethane,2 mmol of 1,3-dimethoxybenzene, 10 mol % of catalyst and4 mmol of acetyl chloride, with 0.5 mmol of dodecane for GC monitoring. The solutions were heated at reflux. The reactionswere followed by gas chromatography, by analysis of aliquots.The products were obtained after extraction by diethyl ether andpurification by column chromatography. All products are knowncompounds.
94%
With 10percent AlCl3 on polystyrene In dichloromethane at 45℃;
1 Embodiment 1
In a 1 L three-opening in the bottle, by adding dichloromethane 500 ml, aluminum chloride/polystyrene (66.5 g, loading 10 wt %), stirring slowly under the condition into the acetyl chloride (42.9 g, 5.5 µM), the completion of the dropping, then gradually dripped into the pepper link (61.0 g, 0.5 µM, dissolved in 100 ml dichloromethane); after dropping, slow heating to 45 °C stirring reaction, until the pepper ring reaction finishes, cooling, filtering to obtain aluminum chloride/polystyrene catalyst; the reaction liquid layered extraction, the combined organic layer, evaporating the solvent under reduced pressure, drying to obtain products 77.2 g, yield 94%.
71.5%
With diatomite-solid acid catalyst In 1,2-dichloro-ethane at 80℃; for 6h;
3.1; 3.2 Example 3
(1) Take commercial diatomite (30g, 303 mmol) and bake at 120 ° C for 7 h to remove water from the diatomite,Add the dried diatomite to the reaction kettle, and slowly add chlorosulfonic acid (15g, 128 mmol) under mechanical stirring at room temperature.After 45 ~ 60min of reaction, it can be directly used as a catalyst for Friedel-crafts acylation reaction, and not used for further processing.(2) Use the above diatomite solid acid catalyst 3.9g, dichloroethane 200mL, pepper ring (30g, 246mmol),Acetyl chloride (38.6g, 492 mmol), reacted at 80 ,TLC detection showed that the raw material reaction was complete after 6h.Filter while hot to remove the solid acid catalyst, extract the organic layer with dichloroethane,The combined organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate.Concentrate under reduced pressure to obtain a solid, which is recrystallized from ethanol / water = 20: 1. 28.6g of white solid 3,4-methylenedioxyacetophenone was obtained, melting point 89oC, yield 71.5%.
With carbon disulfide; aluminium trichloride at -15℃;
With aluminum (III) chloride In dichloromethane at -50℃; for 2h; Sealed tube; Inert atmosphere;
Typical Procedure for Transformation of Arenes 1 into 5-Alkyl-1-aryltetrazoles 3:
General procedure: To a solution ofcumene 1A (1.0 mmol, 120.0 mg) in CH2Cl2 (2.0 mL) in a 30 mL sealed tube was added acetyl chloride(1.2 mmol, 85.4 μL) at 0 °C. After flash with argon gas, the mixture was stirred for a few minutes.Anhydrous AlCl3 (1.2 mmol, 161.0 mg) was added and the obtained mixture was stirred for 2 h at 0 °C.Then, the reaction mixture was quenched with cooled water (1.0 mL) and stirred for 0.5 h. Afterremoval of the solvent under reduced pressure, MeOH (3.0 mL), NH2OHHCl (1.5 mmol, 107.0 mg), andK2CO3 (1.5 mmol, 207.0 mg) were added. After flash with argon gas, the obtained mixture was stirredfor 16 h at rt. After removal of the solvent under reduced pressure, toluene (3.0 mL), DPPA (2.5 mmol,0.54 mL), and DBU (3.5 mmol, 0.53 mL) were added to the residue. After flash with argon gas, themixture was warmed at 120 °C for 16 h. The mixture was cooled to rt and then, sat. NaHCO3 aq. (15.0mL) was added. The mixture was filtered through Celite, and the filtrate was extracted with AcOEt(20.0 mL ×3). The organic layer was dried over Na2SO4. After removal of the solvent under reducedpressure, the residue was purified by short column chromatography on silica gel (n-hexane/AcOEt,3:1-1:3) to afford 1-(4’-isopropylphenyl)-5-methyl-1H-tetrazole 3Aa in 60% yield (121.1 mg).
With zinc(II) oxide; zinc(II) chloride In dichloromethane at 0 - 5℃; for 5h;
9.9A Preparation of 5-Acetyl-l,3-benzodioxole (using 0.5 moles of Zinc Oxide and 0.05 moles of zinc chloride per mole of acyl chloride using dichloromethane as solvent)
488 g of 1,3-benzodioxole and 1000 g of dichloromethane were charged into a 5 litre reaction flask and the reaction mixture was cooled to 0°C under stirring. Add 160 g of zinc oxide and 28 g of zinc chloride to the above mixture under constant stirring. Later, 316 g of acetyl chloride was added in 4 hours maintaining the temperature of the reaction medium between 0°C and 5°C under stirring. The reaction medium was stirred for another 1 hour till the complete acylation occurred. The reaction mass was subjected to aqueous workup and the organic layer was separated and distilled to recover 261 g of unreacted 1,3-benzodioxole and 278 g of 5-Acetyl- 1,3-benzodioxole with a yield of 122.5% (wt./wt.) and purity of > 99% by GC analysis.
With nitric acid In nitromethane at 20℃; for 2.5h;
XIV
Example XIV; Synthesis of 2-(3,4-methylenedioxy-6-nitrophenyl)-propoxycarbonyl piperidine (FIG. 4A, eq. 4, R=101); Preparation of 3,4-(methylenedioxy)-6-nitroacetophenone. To 3,4-(methylenedioxy)-acetophenone (2.70 g, 17.5 mmol) in 30 mL CH3NO2 at r.t. was added HNO3 (6.9 mL, 105 mmol) dropwise in 30 min. The solution was stirred for additional 2 h. The reaction mixture was carefully neutralized by the addition of saturated aqueous NaHCO3 solution and then extracted with DCM. The combined organic phase was dried overnight over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluant: AcOEt/Hex, 1/2, v/v) to afford 3,4-(methylenedioxy)-6-nitroacetophenone (2.80 g, 82%) as light yellow solid. 1H-NMR (300 MHz, CDCl3): δ 7.56 (s, 1H, Ar-H), 6.76 (s, 1H, Ar-H), 6.19 (s, 2H, CH2), 2.50 (s, 3H, CH3). TLC: 33% ethyl acetate in hexane, Rf=0.5.
76%
With nitric acid at 40℃; for 1h;
76%
With nitric acid In nitromethane at 20℃; for 2h;
1.1
At room temperature,Concentrated nitric acid (20.7ml) was slowly added dropwise to a solution of 3,4-methylenedioxyacetophenone (8.1g, 49.3mmol) in nitromethane (80ml), and the reaction was stirred for 2h.Slowly add a saturated sodium bicarbonate solution to the reaction solution,After adjusting the pH to neutral, extract three times with dichloromethane, combine the organic phases,It was washed three times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a yellow oily liquid, which was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1)After concentration, 7.8 g of 6-nitro-3,4-methylenedioxyacetophenone was obtained as a pale yellow solid with a yield of 76%;
76%
With nitric acid In nitromethane for 2h;
1 Step 1: Preparation of 6-amino-3,4-methylenedioxyacetophenone:
3,4-methylenedioxyacetophenone was dissolved in nitromethane (80mL), and concentrated nitric acid (20.7niL) was added dropwise to it. The mixture reacted for 2 hr and saturated sodium bicarbonate solution was added dropwise to it to get the pH to about 7. The mixture was extracted with dichloromefhane for 3 times. The organic layer was combined washed with brine, dried by anhydrous MgSCri and concentrated. The yellow oil resultant was purified by column chromatography(ethyl acetate; petroleum ethei=l : 8) and resulted in 7.8 g light yellow solid (76%). nip 110-112 e C
74%
With nitric acid In nitromethane at 23℃; for 3h;
68%
With nitric acid at 10 - 15℃; for 1h;
66%
With nitric acid In nitromethane at 20℃; for 6.33333h;
58%
With nitric acid; acetic acid In water at 0 - 40℃; for 4.5h; Inert atmosphere;
4',5'-Methylenedioxy-2'-nitroacetophenone (4b)
Following a slightly modified procedure described by McGall et al50, a solution of 3', 4'- (methylenedioxy)acetophenone 4a (16.416 g, 0.1 mol) in glacial CH3COOH (64 mL) was added drop-wise to a 2 litre three-necked round-bottomed flask containing cone. HN03 (136 mL, 70% strength) at o°C over 1 h. The reaction mixture was maintained at o°C during addition and for a further 1 h with stirring under an argon atmosphere. The mixture was then warmed to 40 °C and stirred for additional 2.5 h. Finally, the mixture was cooled to r.t. and poured slowly into crushed ice (1 litre) in a beaker. A yellow precipitate appeared which was stirred for 15 min and then filtered. The yellow solid was washed with water (3 x 200 mL) and dried in vacuum. The crude yellow solid was then purified by recrystallization (THF/n-hexane) and then by flash chromatography on Si02 [eluent: CH2Cl2/n-hexane (1:1) to ioo%CH2Cl2] to obtain 4',5'-methylenedioxy- 2'-nitroacetophenone32’50’51 4b as yellow crystals (12.141 g, 58%): R/= 0.52 (CH2Cl2); m.p. 122.8-124.O °C(51 m.p. 112 °C); NMR (400.13 MHz, CDCl3) £2.45 (s, 3H), 6.16 (s, 2H), 6.71 (s, lH), 7.48 (s, lH); 13C NMR (100.61 MHz, CDCl3) £30.2 (CH3), 103.8 (CH2), 104.8 (CH), 106.2 (CH), 135.1 (C), 140.1 (C), 148.9 (C), 152.8 (C), 199.3 (C); IR (CH2Cl2) Vmax 2980, 1708, 1525, 1506, I484, 1424, 1362, 1338, 1271, 1152, 1038, 932, 875, 819 cm 1; MS (ESI+) m/z (rel intensity) 232 [(M+Na)+, 10%], 210 (2), 209 (7), 194 (100), 171 (45), 130 (32), 111 (9)·
36%
With trifluoroacetic acid; sodium nitrite for 20h;
1 Step 1; Synthesis of 1-(4,5-(methylenedioxy)-2-nitrophenyl)ethanone
<> 3,4-(Methylenedioxy)acetophenone (5.04 g, 30.7 mmol) was put into a 200 mL two-necked eggplant flask to be dissolved in trifluoroacetic acid (50 mL), sodium nitrite (6.30 g, 91.4 mmol) was gradually added thereto, and the solution was stirred for 20 hours. Pure water (100 mL) was added thereto for extraction using dichloromethane (100 mL*3), and the organic layer was washed with saturated saline solution (100 mL*3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The resultant was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), thereby obtaining 2.35 g (11.2 mmol, 36%) of a yellow solid (intermediate compound 21; 1-(4,5-(methylenedioxy)-2-nitrophenyl)ethanone). The identification result of the obtained intermediate compound 21 is described below. 1H NMR (CDCl3/TMS, 400 MHz): δ 2.49 (3H, s), 6.18 (2H, s), 6.75 (1H, s), 7.55 (1H, s).
With chloroform; nitric acid
With nitric acid; acetic acid at 0 - 20℃; for 2.5h;
With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;
General procedure: Method B: to a solution of compound 4a (1.65 g, 9.94 mmol) inanhydrous CH2Cl2 (100 mL) stirred at 0 C under argon was addedDess-Martin reagent (5.06 g,11.93 mmol). The mixture was allowedto warm to room temperature after 10 min and stirred for 16 h. Thereaction was quenched with a saturated sodium bicarbonate solution and salts were filtered off. The filtrate was extracted withCH2Cl2. The combined organic layers were dried over MgSO4,filtered and evaporated under reduced pressure. Purification bysilica column chromatography using CH2Cl2 as eluent gave thedesired ketone 5a (1.42 g, 87%) as a pale yellow solid.
81%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline; In 1,4-dioxane; at 80℃;Schlenk technique;
General procedure: In an oven dried Schlenk tube, were added alcohol 1 (69.0-199.5 mg, 0.5 mmol), CuI (10 mol%)and 1,10-Phenanthroline (20 mol%) and K3PO4 (2 mmol) followed by the addition of dioxane (2mL) at room temperature under open air atmosphere. The stirred reaction mixture was heated inan oil bath at 80 C for 7-48 h. Progress of the reaction was monitored by TLC till the reaction iscompleted. Then, the reaction mixture was cooled to room temperature, quenched with aqueousNH4Cl solution and then extracted with CH2Cl2 (3 10 mL). The organic layer was washed withsaturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the solvent under reducedpressure and purification of the crude material by silica gel column chromatography (petroleumether/ethyl acetate) furnished the aldehyde/ketone 2 (61-97%).
Synthesis of chalcones (3a-g):
General procedure: A mixture of 2,4,5-trimethoxybenzaldehyde (1, 5 mmol), substituted acetophenone (2a-g, 5 mmol) and sodium hydroxide (5 mmol) in 95 % ethyl alcohol (25 mL) was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was poured in to ice cold water and kept in the refrigerator for overnight. The solid formed was filtered and washed with cold hydrochloric acid (5 %). Crude products obtained were crystallized from methyl alcohol to obtain pure chalcones (3a-g).
29.8 g
With sodium hydroxide In ethanol Ambient temperature;
With potassium hydroxide In methanol at 20℃; for 24h;
With potassium hydroxide In methanol at 20℃; for 24h;
2.2. General Procedure for the Preparation of Chalcones
General procedure: Sodium hydroxide solution (50 % w/v, 5.3 ml, 66.7mmol) was added to a stirred solution of the acetophenone(6.67 mmol) and aldehyde (6.67 mmol) in methanol (30 ml). The resulting mixture was stirred at room temperature and sequentially monitored by TLC until the reaction was complete. The reaction was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic extracts were washed with brine (50 ml), dried with anhydrous magnesium sulfate and the solvent removed invacuo. The crude product was recrystalised from ethanol
2.2. General Procedure for the Preparation of Chalcones
General procedure: Sodium hydroxide solution (50 % w/v, 5.3 ml, 66.7mmol) was added to a stirred solution of the acetophenone(6.67 mmol) and aldehyde (6.67 mmol) in methanol (30 ml). The resulting mixture was stirred at room temperature and sequentially monitored by TLC until the reaction was complete. The reaction was quenched with water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic extracts were washed with brine (50 ml), dried with anhydrous magnesium sulfate and the solvent removed invacuo. The crude product was recrystalised from ethanol
Stage #1: 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one With sodium hydride In toluene for 0.5h; Reflux;
Stage #2: carbonic acid dimethyl ester In toluene for 3h; Reflux;
1
Compound No. 1 (17.00 (^, 0.10311101) was dissolved in toluene (1501111) and sodium hydride (8.284 g, 0.207 mil, 2 eq) was added in portions in an ice bath under reflux. After 30 min, the compound dimethyl carbonate (27.834 g, 0.309 mol, 3. Oeq) was slowly added dropwise. After completion of the reaction, the reaction was complete and the reaction solution was poured into saturated ammonium chloride solution. Ester (150ml * 3), the organic phase was separated and saturated brine was washed 2-3 times.The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give 29.0 g of crude product.
With sodium hydride In toluene for 16h; Inert atmosphere; Reflux;
Stage #1: 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one With sodium hydride In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere;
Stage #2: carbonic acid dimethyl ester In 1,4-dioxane Reflux; Inert atmosphere;
With sodium hydride In tetrahydrofuran at 80℃; for 3h;
Synthesis of Compounds 2a-2g
General procedure: To a suspension of 1a (1.5 g, 0.01 mol) in THF (15 mL), NaH (0.8 g, 0.02 mol) and dimethyl carbonate (1.8 g, 0.02 mol) were added and the resulting mixture was stirred at 80 °C for 3h. The reaction mixture was concentrated. The residue was distributed between ethyl acetate (20 mL) and water (20 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate (30 mL × 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to afford crude compound 2a. The same method produces for compounds 2b-2g.
With sodium hydride In tetrahydrofuran at 80℃; for 3h;
Synthesis of Compounds 2a-2g
General procedure: To a suspension of 1a (1.5 g, 0.01 mol) in THF (15 mL), NaH (0.8 g, 0.02 mol) and dimethyl carbonate (1.8 g, 0.02 mol) were added and the resulting mixture was stirred at 80 °C for 3h. The reaction mixture was concentrated. The residue was distributed between ethyl acetate (20 mL) and water (20 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate (30 mL × 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to afford crude compound 2a. The same method produces for compounds 2b-2g.
Step 1. Preparation of 1-(1,3-benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione Ethyl difluoroacetate (1.72 g, 11 mmol) was dissolved in ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3',4'-(methylenedioxy)acetophenone (1.64 g, 10 mmol). After stirring 16 hours, 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2*25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification or characterization.
With C28H35ClCoN5(1+)*Cl(1-); potassium tert-butylate; hydrogen; In tetrahydrofuran; at 20℃; under 22502.3 Torr; for 16h;Autoclave;
General procedure: In an argon filled glove box, the cobalt catalyst (LNHC/CoCl2 or Co-2a) and the base wereweighted into a 4mL vial equipped with a magnetic stir bar, followed by addition of the solvent.After shaking of the vial for 30 seconds, the carbonyl substrate was then added. The vial wasplaced into a Parr Instruments autoclave, which was then sealed, removed from the glove boxand purged with hydrogen gas. The autoclave was heated to certain temperature. After reactionfor 16 hours, the autoclave was cooled down to 0 oC before releasing the hydrogen gas. Forquantitative GC analysis, biphenyl (1.0 mmol) as internal standard was added. The organiclayer was then filtrated and diluted for GC analysis. The stereo-selectivity of the hydrogenatedproducts of cyclohexanones were determined by NMR with mesitylene as the internal standard.The desired hydrogenation product was further isolated by flash column chromatography.
90%
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
To a stirred solution of 3,4-methylenedioxy acetophenone (4.5 g, 27 mmol, Alfa aesar) in dry MeOH (50 mL), NaBH4 (1.08 g, 42 mmol, Loba chemie) was added slowly at 0 C. The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was concentrated under vacuum and diluted with DCM. The DCM layer was washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and resulting crude alcohol was used as such in the next step. Yield: 90% (4.0 g, colorless liquid). 1H NMR (400 MHz, CDCl3): delta 6.89 (s, 1H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J = 8.0 Hz, 1H), 1.46 (d, J = 8.0 Hz, 3H). LCMS: (Method B) 149.0 (Hydroxy elimination mass), Rt. 2.51 min, 98.6% (Max). HPLC: (Method A) Rt. 2.499 min, 99.5% (Max).
9%Spectr.
With bis(2-hydroxyethyl)ammonium formate; palladium dichloride; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
General procedure: (Table 2, entry 4): To a solution of acetophenone (1) (120 mg, 1.00 mmol) in [BHEA][HCO2] (5.00 mL, 39.7 mmol) was added PdCl2 (17,7 mg, 10.0 mol%) at rt and the mixture was stirred at the same temperature for 6 h under argon atmosphere. The mixture was poured into brine (10 mL) and extracted with EtOAc (10 × 10 mL). The organic layer was washed with brine (100 mL) and dried with MgSO4. After removal of the solvent, the residue was subjected to column chromatography (Merck kieselgel 60, phi = 2.0 cm, l = 11.5 cm; EtOAc-hexane, 1:5) to give 1-phenylethanol (2) as colorless oil; yield: 110 mg (90%).
9%Spectr.
With bis(2-hydroxyethyl)ammonium formate; palladium dichloride; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
General procedure: To a solution of 4'-(trifluoromethyl)acetophenone (3e) (188 mg, 1.00 mmol) in DMF (5.00 mL) was added [BHEA][HCO2] (5.00 mL, 39.7 mmol) and PdCl2 (35.5 mg, 20.0 mol %) at rt and the reaction mixture was stirred at the same temperature for 2 h under argon atmosphere. The mixture was poured into brine (10 mL) and extracted with Et2O (10 10 mL). The organic layer was washed with brine (150 mL) and dried with MgSO4. After removal of the solvent, the residue was subjected to column chromatography (Merck Kieselgel 60, Phi=2.0 cm, l=7.5 cm; EtOAc-hexane, 1:5) to give 1-(4-trifluoromethylphenyl)ethanol (4e) as colorless oil; yield: 174 mg (91%).
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
To a stirred solution of 3,4-methylenedioxy acetophenone (10.0 g, 60.91 mmol, Alfa aesar) in dry MeOH (200 mL), NaBH4 (2.7 g, 71 .3 mmol, Loba chemie) was added slowly at 0C. The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was concentrated under vacuum and diluted with DCM. The DCM layer was washed with water, brine and, dried over anhydrous Na2S04. The solvent was removed under reduced pressure and resulting crude alcohol was used as such in the next step. Yield: 99% (10.0 g, colorless liquid). LCMS: (Method D) 149.0 (M-H20+H), RT. 2.513 min, 98.6% (Max), 97.7% (254 nm). H NMR (400 MHz, CDCI3): delta 6.89 (s, 1 H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J = 8.0 Hz, 1 H), 1 .46 (d, J = 8.0 Hz, 3H).
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;
To a stirred solution of 3, 4-methylenedioxy acetophenone (4.5 g, 27 mmol, Alfa aesar) in dry MeOH (50 mL), NaBH4 (1.08 g, 42 mmol, Loba chemie) was added slowly at 0 C. The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was concentrated under vacuum and diluted with DCM. The DCM layer was washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and resulting crude alcohol was used as such in the next step. Yield: 90% (4.0 g, colorless liquid). 1H NMR (400 MHz, CDCI3): delta 6.89 (s, 1H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J = 8.0 Hz, 1H), 1.46 (d, J = 8.0 Hz, 3H). LCMS: (Method B) 149.0 (Hydroxy elimination mass), Rt. 2.51 min, 98.6% (Max). HPLC: (Method A) Rt. 2.499 min, 99.5% (Max).
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;
To a stirred solution of 3, 4-methylenedioxy acetophenone (4.5 g, 27 mmol, Alfa aesar)in dry MeOH (50 mL), NaBH4 (1.08 g, 42 mmol, Loba chemie) was added slowly at 0C. The reaction mixture was stirred at room temperature for I h. Then the reactionmixture was concentrated under vacuum and diluted with DCM. The DCM layer waswashed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and resulting crude alcohol was used as such in the next step.Yield: 90% (4.0 g, colorless liquid). 1H NMR (400 MHz, CDCI3): 66.89 (s, IH), 6.89- 6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J= 8.0 Hz, IH), 1.46 (d, J= 8.0 Hz, 3H). LCMS:(Method B) 149.0 (Hydroxy elimination mass), Rt. 2.51 mm, 98.6% (Max). HPLC:(Method A) Rt. 2.499 mm, 99.5% (Max).
Example 64; 5-(1-Benzo[1,3]dioxol-5-yl-ethoxy)-quinazoline-2,4-diamine; [00206] Step 1; To a solution of 1-benzo[1,3]dioxol-5-yl-ethanone (2.5 gm; 15.2 mmol) in methanol (50 mL) is added sodium borohydride (634 mg; 16.7 mmol) in portions allowing for gas evolution. The reaction is stirred at room temperature for 3 hours before additional sodium borohydride is added to give a complete reaction by TLC (20% EA/Hex). The reaction is quenched with saturated ammonium chloride' and extracted with ethyl acetate. The organics are separated, washed with water, dried over magnesium sulfate, and the solvent is removed to give 2.18 grams of 1- benzo[ 1,3]dioxol-5-yl-ethanol.
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
To a stirred solution of 3, 4-methylenedioxy acetophenone (50.0 g, 0.31 mol, Alfa aesar) in dry methanol (1000 ml_), NaBH4 (13.83 g, 0.37 mol, Loba chemie) was added slowly at 0 C and the reaction mixture was stirred at RT for 1 h. Completion of the reaction was monitored by TLC, then the reaction mixture was concentrated under vacuum. The resulting material was dissolved in EtOAc, the organic layer was washed with water (100 ml_), brine solution (100 ml.) and dried over anhydrous Na2S04. The organic layer was evaporated under vacuum and the resulting crude material was forwarded to the next step without any further purification. Yield: 98% (50.0 g, colorless liquid). 1H NMR (400 MHz, CDCI3): delta 6.89 (s, 1 H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J = 8.0 Hz, 1 H), 1.46 (d, J = 8.0 Hz, 3H). LCMS: (Method B) 149.0 (M-H20+H); Rt. 2.5 min, 98.6% (Max). HPLC: (Method A) RT 2.4 min, 99.5% (Max).
50 g
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;
To a stirred solution of 3, 4-methylenedioxy acetophenone (50.0 g, 0.31 mol, Alfa aesar) in dry methanol (1000 mL), NaBH4 (13.83 g, 0.37 mol, Loba chemie) was added slowly at 0 C and the reaction mixture was stirred at RT for 1 h. Completion of the reaction was monitored by TLC and the mixture was concentrated under vacuum. The resulting material was dissolved in EtOAc, the organic layer was washed with water, brine and dried over anhydrous Na2S04. The organic layer was evaporated under vacuum and the resulting crude material was forwarded to the next step without any further purification. Yield: 98% (50.0 g, colorless liquid). 1H NMR (400 MHz, CDCI3): delta 6.89 (s, 1 H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J = 8.0 Hz, 1 H), 1.46 (d, J = 8.0 Hz, 3H). LCMS: (Method B) 149.0 (M-H20+H); Rt. 2.5 min, 98.6% (Max). HPLC: (Method A) RT 2.4 min, 99.5% (Max).
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With lithium hydroxide monohydrate In methanol at 25℃; for 0.5h;
Stage #2: isovanillin In methanol at 25℃;
General Procedure for Synthesis of the Compounds as Shown in the Scheme S15
General procedure: To a solution of LiOH• H2O (21.12 mmol) in MeOH (20 mL) was added substituted acetophenone (1.32 mmol). The reaction mixture was stirred at 25°C for 0.5 h. Then substituted benzaldehyde (1.32 mmol) was added. The reaction mixture was stirred at 25°C for 3 to 5 days until the consumption of the staring materials. The reaction solvent was removed in vacuo. Hydrochloric acid (10%) was added until the pH = 2~3. The solid was obtained by filtration and purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 1:1) to affordpure product.
70%
With lithium hydroxide In methanol at 20℃; for 148h;
1-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-propan-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydride; In dimethyl sulfoxide; at 15 - 23℃; for 16h;Inert atmosphere;
A dry, 500-mL, three-necked flask is fitted with a Teflon-coated magnetic stirring bar, a rubber septum, a thermometer, and a reflux condenser to which is attached a T-tube connected to a source of pure nitrogen. The remaining joint of the T-tube is connected to a bubbling device so that the rate of nitrogen flow can be observed throughout of the reaction. The apparatus is arranged so that the flask may be cooled intermittently with a water bath. After the reaction vessel has been flushed with nitrogen a static nitrogen atmosphere is maintained in the reaction vessel for the remainder of the reaction. The flask is charged with ca. 60% dispersion of sodium hydride (5 g, 0.125 mole) in mineral oil (Note 1). The mineral oil is washed from the hydride with petroleum benzine 40/60 (3 x 40 ml.) (Note 2). The supernatant petroleum benzine layer is removed using a Luer-lock hypodermic syringe with a stainless-steel needle inserted through the rubber septum. The residual sodium hydride is mixed with 80 ml_ of dimethyl sulfoxide (Note 3), and the rubber septum is replaced with a pressure-equalizing dropping funnel. A solution of 16.4 g (0.1 mole) of 1-(1 ,3-benzodioxol-5- yl)ethanone (Note 4) and 26.9 g (0.125 mole) of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (Note 5) in 60 mL of dimethyl sulfoxide is placed in the dropping funnel. The funnel is stoppered, stirring is begun and the contents of the flask are cooled in a water bath to 15 0C. The solution of 1- (1 ,3-benzodioxol-5-yl)ethanone and <strong>[618-89-3]methyl 3-bromobenzoate</strong> is added slowly so that hydrogen evolution is maintained at the controllable rate and the temperature did not rise above 20 0C over a period of 60 minutes (Note 6). After the addition is completed, the bath is removed, and the reaction mixture is stirred at room temperature (23 0C) for 15 hours. The resulting red-brown homogeneous reaction mixture is poured slowly into 500 mL of an ice and water containing 5 mL of 85% orthophosphoric acid (Note 7) with stirring. After 1 hour stirring the product is removed by filtration (Note 8), washed by suction filtration with water (2 x 100 mL), and vacuum dried to constant weight at 40 0C for 6 hours to give 34.4 g of the crude (Note 9) product. Recrystallization from 200 mL of 99.9% ethanol and 200 mL ethyl acetate (Note 10) and drying in vacuum to constant weight at 40 C for 6 hours gives 28.5 g (82% yield) of pure (Note 11) 1-(1 ,3-benzodioxol-5-yl)-3-(3-bromophenyl)propane-1 ,3-dione, m.p. 136-137 0C. The filtrate is concentrated under reduced pressure to a volume ca. 30 mL, the crystalline solid that separates is collected on a filter, washed by suction filtration with ethanol (2 x 10 mL) and vacuum dried to constant weight at 40 0C for 6 hours, yielding an additional crop (3.15 g) of the crude product. The crude product is recrystallized twice from 20 mL of 99.9% ethanol and 20 mL ethyl acetate and vacuum dried to constant weight at 40 CC for 6 hours to afford additional 1.8 g (5% yield) of pure 1-(1 ,3-benzodioxol-5-yl)-3-(3- bromophenyl)propane-1 ,3-dione (Note 12). The total yield of the product is 30.3 g (87%).2. Notes1. Sodium hydride, 57-63% oil dispersion, order number 13431 available from Alfa Aesar GmbH & Co KG, Karlsruhe was used. 2. Petroleum benzine GR for analysis boiling range 40-60 0C, order number 101775 from Merck KGaA, Darmstadt was used.3. The dimethyl sulfoxide GR for analysis, order number 102952 from Merck KGaA, Darmstadt was used without further purification. 4. 1-(1 ,3-Benzodioxol-5-yl)ethanone, 98%, order number A13597 available from Alfa Aesar GmbH & Co KG, Karlsruhe was used.5. Methyl 3-bromobenzoate, 98%+, order number A16174 available from Alfa Aesar GmbH & Co KG, Karlsruhe was used.6. A foaming is observed during the addition of the solution. The usage of mechanical stirrer and an antifoaming agent like polyethylene glycol dimethyl ether may be necessary at the upscaling.7. The orthophosphoric acid, 85% w/w aq. solution, GR for analysis, order number 100573 from Merck KGaA, Darmstadt was used.8. The pH-value of the reaction mixture is pH = 7. By acidification with additionally 15 ml_ ortophosphoric acid to pH = 2, 1.3 g of 3-bromobenzoic acid may be obtained.9. Purity of the product determined by HPLC is 96.3%.10. The ethanol 99.9% absolute GR for analysis, order number 100983, and ethyl acetate GR for analysis, order number 109623 available from Merck KGaA, Darmstadt was used. 1 1. Purity of the product determined by HPLC is 99.3%. Analytical HPLC is performed by using a Waters HPLC system with a Waters 996 Photodiode Array Detector. All separations involved a mobile phase of 0.1% v/v trifluoroacetic acid (TFA) in water (solvent A) and 0.1% v/v TFA in acetonitrile (solvent B) by using a reversed phase (RP) column Eurospher RP 18, 100 A, 5 μm, 250 x 4.6 mm at flow rates of 1 mL/min. The compound is dissolved in acetonitrile GR for HPLC at a concentration 1 mg/mL. Peaks with retention times (RT) 20.9 and 10.3 min are enol and keto forms respectively ...
With dihydrogen peroxide; acetic acid; In toluene; at 45℃; for 10h;
In a glass container equipped with a stirrer and a thermometer, 1.64 g (10.0 mmol) of 60% hydrogen peroxide, 1.134 g (20.0 mmol) of tin-containing 0.186 g (about 1 mmol) of the catalyst, 4 g of toluene and 0.600 g (10.0 mmol) of acetic acid were added and stirred at 45 C. for 10 hours. Thereafter, the reaction solution was cooled to room temperature, and insoluble matter was removed by filtration. Subsequently, the obtained filtrate was analyzed (GC: internal standard method, HPLC; absolute calibration curve method), whereby the conversion of 3,4-methylenedioxyacetophenone was 58.8%, the conversion ratio of acetic acid (3,4- Oxyphenyl) ester was 87.8% (based on the amount of 5-acetyl-1,3-benzodioxole used), and the reaction yield was 51.6%.
With potassium hydroxide In methanol at 20℃; for 24h;
Preparation of chalcones
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 μm 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.
95%
With potassium hydroxide In methanol; water at 20℃; for 24h;
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 hydroxide In ethanol at 20℃; Sonication;
General procedure for the preparation and purification of chalcones 3(a-l):
General procedure: A solution of equimolar amounts of 4-(4-Morpholinyl)benzaldehyde1a (1 mmol) and acetophenone 2a-s (1 mmol), using Potassium hydroxidein ethanol (10 mL) as a solvent in an Erlenmeyer, was placed ina water bath and sonicated at room temperature for an appropriate time(10-20 min) until the reaction was completed (the reaction was monitored by TLC). The reaction mixture was then treated with a cold bath and filtered to leave a solid product, which was washed with a hexane to yield pure products 3 (a-l). The synthesized compounds with theirphysical data are listed below.
53%
With potassium hydroxide In methanol at 20℃;
General procedure for the synthesis of curcumin mimics 3a-3g by alkaline method
General procedure: 1,4-Terephthaldehyde (300mg, 1.12mmol) in 7% methanolic KOH (10mL) was stirred at room temperature. To this acetophenone derivative (2.4mmol) was added and reaction mixture was further stirred for 7-8h. On completion methanol was evaporated and water was added to it, acidified with 5% HCl (10mL) and extracted with ethyl acetate (3*20 mL). Organic layer was washed with water, dried over anhydrous sodium sulphate and dried in-vacuo. The residue was purified through column chromatography using ethyl acetate-hexane as eluents to get pure compound
53%
With potassium hydroxide In methanol at 20℃;
5.2.2. General procedure for the synthesis of CD1 to CD6 and CD8):
General procedure: To a solution of 7% KOH in methanol (10 mL), 1, 4- terephthaldehyde (300 mg, 1.12 mmol) was added and stirred at room temperature. To this acetophenone derivative (2.4 mmol) was added and the reaction mixture was stirred for 7-8 h. After completion of reaction, methanol was distilled off, residue was diluted with water (10 mL), acidified with 5% HCl (10 mL) and extracted with ethyl acetate (3x10mL). After this the ethyl acetate layer was washed with water and dried over anhydrous sodium sulphate and finally dried in-vacuo. Then the crude residue was further purified through column chromatography using solvents ethyl acetate-hexane to isolate the pure compound.
General procedure: A 50 mL flask was charged with substituted acetophenone (5 mmol) and a solution of sodium hydroxide (10 mmol) in a 4:1 (v/v) mixture of ethanol/H2O (25 mL), and the resulting mixture was stirred at room temperature for 5 min. A substituted benzaldehyde (5 mmol) was then added to the reaction, and the resulting mixture was stirred at room temperature. The reaction was then monitored byTLC using ethyl acetate/petroleum ether (1:4 or 1:2 v/v) as the solvent system. Upon completion of the reaction, the crude product was filtered off and recrystallized from a mixture of dichloromethane and ethanol or purified by column chromatography over silica gel eluting with a mixture of petroleum ether and ethyl acetate to give the pure product.
1-(1,3-benzodioxol-5-yl)-5-(2-bromophenyl)pentane-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: A three-necked flask (100 mL) fitted with a dropping funnel and reflux condenser was charged with 1.1-2 equivalents of the base(see details at individual compounds). The apparatus was evacuated and backfilled with argon three-times. Subsequently, the basewas suspended in anhydrous THF (20 mL). In the case of using a toluene solution of t-AmOK as the base the empty apparatus was3 evacuated and backfilled with argon and the solution of the base was thereafter added via syringe. After homogenization of themixture by intensive stirring (in the cases of using solid t-BuONa or t-BuOK, resp.), the solution of the ketone 6 (8.5 mmol) in anhydrous THF (8 mL) was added dropwise during 10 min. The mixture was then stirred for 30 min. at room temperature. Afterwards, the solution of the ester 5 (8.5 mmol) in anhydrous THF (8 mL) was added dropwise during 15 min. The reaction mixture was then stirred over 1-2 nights (see details at individual compounds) at room temperature under argon atmosphere. Subsequently, saturated aqueous NH4Cl (15-40 mL, depending on the amount of the base) was added into the reaction mixture, the organic layer was separated and the aqueous layer was extracted with EtOAc (3 35 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (2 35 mL) and brine (1 35 mL) and dried over anhydrous sodium sulfate. The volatile components were evaporated under reduced pressure. The residue was subjected to purification either through Cu2+ complex (the procedure published in [13] was adopted, for details vide infra) or chromatography or recrystallization (see details at individual compounds).
1-(1,3-benzodioxol-5-yl)-5-(2-chlorophenyl)pentane-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With potassium 2-methylbutan-2-olate In tetrahydrofuran; toluene at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 3-chlorophenylpropionic acid methyl ester In tetrahydrofuran; toluene at 20℃; Inert atmosphere;
General procedure for the synthesis of β-diketones 4a-h
General procedure: A three-necked flask (100 mL) fitted with a dropping funnel and reflux condenser was charged with 1.1-2 equivalents of the base(see details at individual compounds). The apparatus was evacuated and backfilled with argon three-times. Subsequently, the basewas suspended in anhydrous THF (20 mL). In the case of using a toluene solution of t-AmOK as the base the empty apparatus was3 evacuated and backfilled with argon and the solution of the base was thereafter added via syringe. After homogenization of themixture by intensive stirring (in the cases of using solid t-BuONa or t-BuOK, resp.), the solution of the ketone 6 (8.5 mmol) in anhydrous THF (8 mL) was added dropwise during 10 min. The mixture was then stirred for 30 min. at room temperature. Afterwards, the solution of the ester 5 (8.5 mmol) in anhydrous THF (8 mL) was added dropwise during 15 min. The reaction mixture was then stirred over 1-2 nights (see details at individual compounds) at room temperature under argon atmosphere. Subsequently, saturated aqueous NH4Cl (15-40 mL, depending on the amount of the base) was added into the reaction mixture, the organic layer was separated and the aqueous layer was extracted with EtOAc (3 35 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (2 35 mL) and brine (1 35 mL) and dried over anhydrous sodium sulfate. The volatile components were evaporated under reduced pressure. The residue was subjected to purification either through Cu2+ complex (the procedure published in [13] was adopted, for details vide infra) or chromatography or recrystallization (see details at individual compounds).
(2Z)-3-amino-1-(1,3-benzodioxol-5-yl)-5-(2-chlorophenyl)pent-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With potassium 2-methylbutan-2-olate In tetrahydrofuran; toluene at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 3-chlorophenylpropionic acid methyl ester In tetrahydrofuran; toluene at 20℃; Inert atmosphere;
Stage #3: With ammonium acetate In methanol for 5h; Reflux;
In tetrahydrofuran; at 70.0℃; for 8h;Inert atmosphere;
In a two-necked flask, sodium hydroxide (28 mmol) was added to 20 ml of anhydrous THF.And 2.42 mL (20 mmol) of diethyl carbonate were heated under an argon atmosphere at 70 C.1.642 g of Compound 1 was dissolved in 10 ml of dry tetrahydrofuran and added to the reaction system, followed by reflux for 8 h. After cooling, 25 mL of 10% acetic acid was added and the mixture was stirred for 15 minutes.The mixture was extracted three times with ethyl acetate.It was then dried and filtered and purified by column chromatography (PE/EA 25:1). Made of colorless oily particles,By the nuclear magnetic resonance detection, it is confirmed that the structure of the compound 2 in Figure 1, namely triethyl orthoformate, the yield of the compound 2 in this step is 1.78 g, the yield is 72%
72%
In a two-necked flask, sodium hydroxide (28 mmol) and 2.42 mL (20 mmol) of diethyl carbonate were added to 20 ml of anhydrous THF, and heated under an argon atmosphere at 70 C. 1.642 g of Compound 1 was dissolved in 10 ml of dry tetrahydrofuran and added to the reaction system, followed by reflux for 8 h.After cooling, 25 mL of 10% acetic acid was added and the mixture was stirred for 15 minutes. The mixture was extracted three times with ethyl acetate. It was then dried and filtered and purified by column chromatography (PE/EA 25:1) to obtaining colorless oily particles, which are detected by nuclear magnetic resonance, and are indeed the structure of compound 2 in Fig. 1, That is, triethyl orthoformate,The yield of the compound 2 in this step is 1.78 g, and the yield is 72%;
With sodium hydride; In 1,4-dioxane; toluene; mineral oil; at 80.0℃;
General procedure: As a typical procedure, the preparation of aryl ethyl acetate derivative 9 is described in detail. 2.36g (98.33mmol) of NaH 60% dispersion in mineral oil was placed in a 100mL round-bottomed flask and washed with toluene to remove oil. Then, 7.12mL (59.75mmol, d=0.975g/mL) of diethyl carbonate and 20mL of anhydrous dioxane were added. The mixture was heated to 80C with stirring and then 4.46mL (29.37mmol, d=1.120g/mL) of 1-acetyl naphthalene was added dropwise. The mixture was stirred at 80C for 15h and monitored by TLC analysis (eluent ethyl acetate/petroleum ether, 1:5). The reaction mixture was allowed to cool to room temperature, and 25mL of water was added. The water layer was separated and extracted twice with ethyl acetate. The organic layers were combined and washed with water and brine, dried over Na2SO4, filtered, and evaporated to dryness, giving 5.73g of a yellow oil. The crude product was used for the next reaction step without further purification.
With sodium hydride; In toluene; mineral oil; for 1h;Inert atmosphere; Reflux;
General procedure: Compounds 2 were prepared according to the previous literature(Scheme 4) [16]. A mixture of compound 7 (66 mmol), toluene(20 mL) and NaH (3.7 g, 60% in mineral oil, 92 mmol)was added to adried 250 mL RBF under N2 atmosphere. The mixturewas heated toreflux and a solution of compound 6 (33 mmol) in toluene (20 mL) was added into the mixture dropwise. After 1 h, the mixture wascooled to room temperature. Glacial acetic acid (10 mL) was addeddropwise and a heavy pasty solid separated. Ice-cold water(150 mL) was slowly added until the solid was dissolvedcompletely. Then, the reaction system was diluted with 200 mL ofEtOAc. The organic layer was separated,washed withwater (20 mL)and brine (20 mL) and dried over Na2SO4. And the combined extractswere concentrated under reduced pressure and purified bycolumn chromatography to afford the pure product b-keto esters 2.
(E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(6-methoxynaphthalen-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In ethanol; at 20℃; for 0.133333h;Sonication;
The starting materials 3, 4-(methylenedioxy) acetophenone, 6-methoxy-2-naphthaldehyde, potassium hydroxide and ethanolare purchased from Sigma-Aldrich chemical company with a statedpurity and are used as such without further purification. The titlecompound is synthesized according to Scheme 1. <strong>[3453-33-6]6-methoxynaphthalene-2-carbaldehyde</strong> (1 mmol), 1-(benzo[d][1,3]dioxol-6-yl)ethanone (1 mmol), 95% Ethanol (3 mL) and NaOHpellets (1 mmol) were added in a Pyrex flask (50 mL). The mixturewas irradiated in the water bath of an ultrasonic cleaner at roomtemperature for the period of 8 min (Sonication was continueduntil aldehydes spot was disappeared indicated by Thin LayerChromatography)
(E)-N-(4-(3-(benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-1-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.6%
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With lithium hydroxide monohydrate In methanol at 25℃; for 0.5h;
Stage #2: para-acetamidobenzaldehyde In methanol at 25℃;
General Procedure for Synthesis of the Compounds as Shown in the Scheme S15
General procedure: To a solution of LiOH• H2O (21.12 mmol) in MeOH (20 mL) was added substituted acetophenone (1.32 mmol). The reaction mixture was stirred at 25°C for 0.5 h. Then substituted benzaldehyde (1.32 mmol) was added. The reaction mixture was stirred at 25°C for 3 to 5 days until the consumption of the staring materials. The reaction solvent was removed in vacuo. Hydrochloric acid (10%) was added until the pH = 2~3. The solid was obtained by filtration and purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 1:1) to affordpure product.
3-(benzo[d][1,3]dioxol-5-yl)-1-(3-bromophenyl)-3-hydroxyprop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With lithium hexamethyldisilazane In tetrahydrofuran at -80 - 20℃; for 3h;
Stage #2: 3-bromobenzoyl chloride at -80 - 20℃; for 18h;
3.4.2. 3-(Benzo[d][1,3]dioxol-5-yl)-1-(3-bromophenyl)-3-hydroxyprop-2-en-1-one-GeneralProcedure 1 (GP1)
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (1.5 g, 9.1 mmol), in anhydrous THF(20 mL) was added 1 m LiHMDS in THF (27.3 mL) and the resulting solution was stirred for 1 h at80 C. The solution was warmed to room temperature and stirred for 2 h. Thereafter, it was cooled to80 C and 3-bromobenzoyl chloride (1.2 mL, 2.0 g, 9.1 mmol) was added dropwise. The solution wasallowed to warm to room temperature and stirred for additional 18 h. Afterwards, a saturated solutionof NH4Cl (50 mL) was added, the pH was adjusted to 7.0 and the mixture was extracted with EtOAc(3 50 mL). The combined organic layers were washed with brine (100 mL), dried and concentratedunder reduced pressure. The residue was purified by column chromatography (Et2O/petroleum ether,1:4) affording the title compound [57]. Yield 2.82 g, 89%Appearance yellow solidMolecular formula C16H11BrO4Molar mass 347.164TLC Rf = 0.46 (Et2O/petroleum ether, 1:4)1H-NMR(200 MHz, CDCl3): (ppm) = 7.88 (q, J = 1.7 Hz, 1H), 7.75-7.60 (m, 1H), 7.53-7.34 (m, 2H),7.31-7.23 (m, 1H), 7.23-7.08 (m, 1H), 6.75-6.61 (m, 1H), 6.54 (s, 1H), 5.87 (s, 2H).13C-NMR(50 MHz, CDCl3): (ppm) = 151.34, 147.91, 136.89, 136.87, 134.57, 129.91, 129.50, 125.19, 122.91,122.42, 107.89, 106.85, 101.61, 92.48.HRMS m/z: [M H] calcd for C16H10BrO4: 344.97679; found: 344.97664. Correct isotopic pattern.
3-(benzo[d][1,3]dioxol-5-yl)-1-(3-fluorophenyl)-3-hydroxyprop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With lithium hexamethyldisilazane In tetrahydrofuran at -80 - 20℃; for 3h;
Stage #2: 3-fluorobenzoyl chloride at -80 - 20℃; for 18h;
3.4.2. 3-(Benzo[d][1,3]dioxol-5-yl)-1-(3-bromophenyl)-3-hydroxyprop-2-en-1-one-GeneralProcedure 1 (GP1)
General procedure: To a solution of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (1.5 g, 9.1 mmol), in anhydrous THF(20 mL) was added 1 m LiHMDS in THF (27.3 mL) and the resulting solution was stirred for 1 h at80 C. The solution was warmed to room temperature and stirred for 2 h. Thereafter, it was cooled to80 C and 3-bromobenzoyl chloride (1.2 mL, 2.0 g, 9.1 mmol) was added dropwise. The solution wasallowed to warm to room temperature and stirred for additional 18 h. Afterwards, a saturated solutionof NH4Cl (50 mL) was added, the pH was adjusted to 7.0 and the mixture was extracted with EtOAc(3 50 mL). The combined organic layers were washed with brine (100 mL), dried and concentratedunder reduced pressure. The residue was purified by column chromatography (Et2O/petroleum ether,1:4) affording the title compound [57].
3 Embodiment 3
In a 1 L three-opening in the bottle, to join the nitrobenzene 500 ml, aluminum chloride/silicon dioxide (166.3 g, loading 10 wt %), stirring slowly into the acetic acid under the condition (33.0 g, 0 . 55 µM), the completion of the dropping, then gradually dripped into the pepper link (61.0 g, 0.5 µM, dissolved in 100 ml of nitrobenzene); after dropping, slow heating to 80 °C stirring reaction, until the pepper ring reaction finishes, cooling, filtering to obtain aluminum chloride/silicon dioxide catalyst; the reaction liquid layered extraction, the combined organic layer, evaporating the solvent under reduced pressure, drying to obtain products 78.8 g, yield 96%.
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere;
Stage #2: ethyl acetate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;
4.1.1 4.1.1. The synthesis of N-hydroxy-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide (8)
General procedure: A solution of 27 p-methylacetophenone (0.67g, 5mmol) in dry 28 THF (20mL) was added dropwise to 29 NaH (0.24g, 10mmol) in dry THF (50mL) under nitrogen atomosphere and the mixture was stirred for 1h at 0°C. Then a solution of 30 ethyl trifluoroacetate (0.9mL, 7.5mmol) in dry THF (10mL) was added dropwise. The mixture was warmed to room temperature for 12h. The reaction was quenched with saturation NaHCO3 and extracted with ethyl acetate (50mL×3). The combined organic extracts were washed with brine (50mL), dried with Na2SO4 and evaporated. Finally, the resulting residue was purified by column chromatography on silica gel as indicated to give 6a as canary yellow solid.
1-(benzo[d][1,3]dioxol-5-yl)-3-(3-methylthiophen-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium hydroxide; In methanol; at 20℃;
General procedure: To a solution mixture of 3-methylthiophene-2-carbaldehyde, 1 (5 mmol) and acetophenones, 2(a-h) (5 mmol) in methyl alcohol, potassium hydroxide solution (40%, 2 mL) was added. Then the solution mixture was stirred at room temperature for 2-3 h. The progress of the reaction was monitored by TLC. After the completion, the reaction mixture was cooled to room temperature and poured into ice cold water. The solids separated were filtered, washed successively with cold hydrochloric acid (5%) and cold water. The crude solids were recrystallized from methyl alcohol to obtain the compounds 3(a-h).
With potassium hydroxide; In methanol; at 20℃;
General procedure: To a solution mixture of 3-methylthiophene-2-carbaldehyde, 1 (10mmole) and acetophenones, 2(a-h) (10 mmole) in methyl alcohol,potassium hydroxide solution (40%, 2 mL) was added. Then the solutionmixture was stirred at room temperature for 2-3 h. The progress ofthe reaction was monitored by TLC. After the completion, the mixturewas cooled to room temperature and poured into ice cold water. Thesolids separated were filtered, washed successively with cold hydrochloricacid (5%) and cold water. The crude solids were recrystallizedfrom methyl alcohol to obtain compounds 3(a-h) [26].
2,4-bis(benzo[d][1,3]dioxol-5-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 66%
2: 10%
With iron(III) chloride; palladium diacetate; copper(II) acetate monohydrate; DavePhos In dimethyl sulfoxide; N,N-dimethyl-formamide at 120℃; for 40h; Inert atmosphere;
With iron(III) oxide; potassium-t-butoxide In toluene for 15h; Inert atmosphere; Sealed tube;
91%
With potassium-t-butoxide; oxygen In toluene at 130℃; for 24h; Green chemistry;
81%
With [(p-cymene)Ru(BiBzImH2)Cl][Cl]; Cs2CO3 In tert-Amyl alcohol at 125℃; for 12h;
4.4. Procedure for acceptorless dehydrogenative coupling of ketoneswith o-aminobenzyl alcohols to quinolines catalyzed by [(p-cymene)Ru(BiBzImH2)Cl][Cl]
General procedure: In a round-bottomed flask with a condenser tube were added oaminobenzylalcohols 1 (1 mmol) and ketones 2 (1.2 mmol, 1.2equiv), cat. 1 (6 mg, 0.01 mmol, 1 mol %), Cs2CO3 (163 mg,0.5 mmol, 0.5 equiv) and tert-amyl alcohol (1 mL). The reactionmixture was heated at 125 C in an oil bath for 12 h and thencooled to ambient temperature, concentrated in vacuo and purifiedby flash column chromatography with hexane/ethyl acetate (10:1,v/v) to afford corresponding products.
79%
With samarium diiodide; potassium-t-butoxide In tetrahydrofuran; toluene at 140℃; for 1h; Microwave irradiation; Inert atmosphere;
With zinc(II) chloride; In tetrahydrofuran; at 50℃; for 32h;
(1) 1.00 g of compound d-1 and 1.00 g of <strong>[34813-49-5]t-butylsulfonamide</strong> were dissolved in 50 mL of tetrahydrofuran.Adding 0.34 g of ZnCl2 to form an acidic condition,Heating to 50 C for 32 h to obtain 1.59 g of compound d-2;
(E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-(pyrrolidin-1-yl)phenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With sodium hydroxide; In methanol; water; at 20℃;
General procedure: Chalcones analogs were synthesized by Claisen-Schmidt condensation reaction using appropriate equimolar amounts of substituted acetophenones and benzaldehydes in MeOH. NaOH was dissolved in the least amount of water and added dropwise (3mmol) (Scheme 1). Reactions were stirred overnight. All reactions were monitored by TLC using appropriate solvent or mixture of solvents. When the reaction was complete, the obtained precipitate was filtered, washed with cold methanol and dried under vacuum. The crude products were crystallized from different solvent systems based on their solubility or purified by column chromatography to give pure crystalline compounds.
With diatomite-solid acid catalyst In 1,2-dichloro-ethane at 80℃; for 6h;
2.1; 2.2 Example 2
(1) Take commercial diatomite (30g, 303 mmol) and bake at 120 ° C for 7 h to remove water from the diatomite,Add dried diatomite to the reactor,Chlorosulfonic acid (15g, 128 mmol) was slowly added under mechanical stirring at room temperature,After 60 min of reaction, it can be directly used as a catalyst for Friedel-crafts acylation reaction, and not used for further processing.(2) Use 3.9 g of the above diatomite-solid acid catalyst, 200 mL of dichloroethane,Pepper ring (30 g, 246 mmol) and acetyl bromide (60.5 g, 492 mmol) were reacted at 80 ° C.TLC detection showed that the raw material reaction was complete after 6h.Filter while hot to remove the solid acid catalyst, extract the organic layer with dichloroethane,The combined organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate.Concentrate under reduced pressure to obtain a solid, which is recrystallized from ethanol / water = 20: 1.30 g of 3,4-methylenedioxyacetophenone was obtained as a white solid with a melting point of 89 ° C. and a yield of 76%.
(3,4-dimethoxyphenyl)acetic acid 4-benzo[1,3]dioxol-5-yl-6,7-dimethoxynaphthalen-2-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h;
Stage #2: 1-(benzo[d][1,3]dioxol-6-yl)ethanone In acetonitrile at 25 - 80℃; for 20h;
Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure
General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag.
4-benzo[1,3]dioxol-5-yl-6,7-dimethoxynaphthalen-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h;
Stage #2: 1-(benzo[d][1,3]dioxol-6-yl)ethanone In acetonitrile at 25 - 80℃;
Synthesis of 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1; General Procedure
General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homoveratricacid (1a, 98 mg, 0.5 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2h, 2k, 2o, 2v or2w (0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to 1:1) affordedcompounds 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1.
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With formic acid In toluene at 30 - 40℃; for 0.5h;
Stage #2: With dihydrogen peroxide In toluene for 12h;
Stage #3: With water at 35 - 40℃; for 4h; Alkaline conditions;
1-5 Example 3:
Put 200ml of toluene in the four-port reaction bottle,Formic acid 144g, 3,4-methylenedioxyacetophenone 72g,Stir and heat to 30-40°C for 30 minutes;72g of 50% hydrogen peroxide was slowly added dropwise for 12 hours.After the dropwise addition, keep stirring for 1 hour and let stand for 30 minutes,The lower acid water was separated, and the toluene layer was washed with 100ml water,The lower layer of water was separated, and the toluene layer was desolvated under reduced pressure to remove toluene, and the residual liquid was set aside. Add 280ml of water and 120g of 30% liquid alkali to the four-port reaction bottle.Add the residue in Example 3 and stir at 35-40°C for 4 hours.At the end of the reaction, add 10% hydrochloric acid to adjust PH=6~6.5, and stir the reaction for 1 hour.Let stand for 30 minutes, separate the lower water layer and collect the oil layer,The oil layer is rectified by high vacuum decompression, collecting normal fractions,50g of 3,4-methylenedioxyphenol was obtained with a yield of 82.5%.Content (HPLC) 99.6%.
164 g
Stage #1: 1-(benzo[d][1,3]dioxol-6-yl)ethanone With peracetic acid In toluene at 30℃; for 2h;
Stage #2: With water; sodium hydroxide
9.9B Preparation of dihydrosafrole
278 g of 5-Acetyl-l,3-benzodioxole and 550g of toluene charged into a 3 litre reaction flask at 30 °C under stirring. Add 730g of 22% peracetic acid in 2 hours under stirring. The reaction mass was subjected to aqueous work up followed by alkaline hydrolysis using 25% aq. NaOH (800 g) and acidification to obtain 32g of unreacted 5-Acetyl- 1,3-benzodioxole and 164g of 5 -Hydroxy- 1,3-benzodioxole (Sesamol) with a yield of 72.2% (wt./wt. on 1,3- benzodioxole) and purity of > 99% by GC analysis
(E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium hydroxide In methanol; water at 40 - 46℃; Inert atmosphere;
Generalprocedure for the synthesis of chalcones 5a-f.
General procedure: To a mixture of 4-O-propargylvanillin (1b) (1.000 mmol)and the substituded acetophenones (1.000 mmol) in methanol (15 mL), was added dropwise and slowly anaqueous solution of KOH (50%, 1 mL/mmol of the substituded acetophenone). The reaction mixture wasstirred at 40-46 °C for 18-43 h, a under nitrogen atmosphere and monitored byTLC. The precipitate formed was filtered, dried and then recrystallized as appropriate.Some of the products were cooled with ice, neutralized with AcOH/H2O(1/1) or HCl (10 %), and purified by silica gel column chromatography using n-hexane-EtOAc as a solvent mixture.
1-(benzo[1,3]dioxol-5-yl)-3-quinolin-2-yl-propen-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.86%
With sodium carbonate In methanol; water at 65℃; for 2h;
20. Phenyl-3- (7-trifluoromethyl-quinolin-2-yl)-propenone (A16).
General procedure: To a solution of 3 (50mg, 1eq) in 5mL of methanol-water (v/v = 1:1) in a round-bottom flask, acetophenone (29L, 1.1eq) and Na2CO3 (6mg, 0.25eq) was added. The solvent was refluxed for 2h at 65. Solid formed during the reaction. After filtration, the cake was washed with 50% methanol (2mL x 5) to obtain 58 mg of a pale yellow precipitate (yield: 79.81%).
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