Abstract: The direct α-arylation of carbonyl compounds using aryl halides represents a powerful method to synthesize critical building blocks for diverse useful compounds. Numerous synthetic methods exist to forge C(sp2)–C(sp3) bonds although mild and metal-free direct α-arylation of ketones remains a challenging transformation. Here we report a green-light-mediated α-arylation of ketones from readily available aryl halides via activation of a C(sp2)–X bond (X = I, Br, Cl) and an α-carbonyl C(sp3)–H bond in a single photocatalytic cycle. This approach is characterized by its mild reaction conditions, operational simplicity and wide functional group tolerance. Importantly, the impressive outcome of the multigram photocatalytic reaction underpins the strength of this method as a potentially practical and attractive approach for scale-up industrial purposes. The utility and scope of this reaction were further demonstrated by formal syntheses of several feedstock chemicals that are commercially expensive but critical for synthesizing numerous pharmaceutical agents.
* 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] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2098 - 2102
3
[ 621-23-8 ]
[ 855-97-0 ]
Reference：
[1] Journal of Chemical Research, 2014, vol. 38, # 1, p. 60 - 61
[2] Journal of Chemical Research, 2014, vol. 38, # 1, p. 60 - 61
4
[ 621-23-8 ]
[ 39066-42-7 ]
[ 1682-20-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1985, vol. 30, p. 211
5
[ 621-23-8 ]
[ 75-36-5 ]
[ 90-24-4 ]
Reference：
[1] Phytochemistry (Elsevier), 1989, vol. 28, # 11, p. 3193 - 3196
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 730 - 733
[3] European Journal of Medicinal Chemistry, 2010, vol. 45, # 6, p. 2629 - 2633
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 725 - 732
[5] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 725 - 732
[6] Medicinal Chemistry Research, 2012, vol. 21, # 9, p. 2292 - 2299
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 912 - 916
[8] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1315 - 1321
[9] Journal of Enzyme Inhibition and Medicinal Chemistry, 2015, vol. 30, # 1, p. 22 - 31
6
[ 621-23-8 ]
[ 90-24-4 ]
Reference：
[1] Journal of Chemical Research, 2014, vol. 38, # 1, p. 60 - 61
[2] Journal of Chemical Research, 2014, vol. 38, # 3, p. 134 - 136
[3] Journal of Chemical Research, 2014, vol. 38, # 11, p. 686 - 689
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 11, p. 2098 - 2102
7
[ 621-23-8 ]
[ 68-12-2 ]
[ 830-79-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
at -5 - 0℃; Inert atmosphere
Example 82,4,6-Trimethoxy-benzaldehyde2,4,6-Trimethoxy-benzene (40gm, 0.22x103 mmol) was added to dimethylformamide and stirred at a temperature in the range of -5 to 0°C under N2 atmosphere, followed by addition of phosphorus oxychloride (48 gm, 0.5x103 mmol) drop wise over a period of 30-45 minutes. The reaction mixture was stirred for one hour at 0°C, poured over crushed ice followed by saturated sodium carbonate solution. Precipitate obtained was filtered and washed with water to obtain the title compound.Yield: 46 gm (98percent); 1 HNMR (CDCI3): δ 10.35 (s, 1 H), 6.67 (s, 2H), 3.88 (s, 6H), 3.87 (s, 3H); MS: m/e 197 (M+1 ).
98%
at 20 - 30℃; for 1 h;
In a round bottom flask, POCl3 (7.3 ml, 80 mmol) was added to a mixture of 1,3,5-trimethoxybenzene (8.41 g, 50 mmol) in DMF (15 ml). The temperature of reaction mixture was kept below 30° C. by slowly adding POCl3. After addition of POCl3, the mixture was still stirred at room temperature for an addition 1 hour. The reaction mixture was added into a cold saturated NaHCO3 solution. The pH of the solution was adjusted to remain above 7. Precipitation of desired product occurred. The off-white product was filtered and rinsed with NaHCO3 aq., then with HCl aq. 0.5M and then with water. Off-white solid was collected and vacuum dried at room temperature to yield 14a (9.60 g, 48 mmol, 98percent).
91.6%
at 0 - 20℃; for 1 h;
Dimethylformamide (9.0 mL, 8.4 g, 0.116 mol) was addedto trimethoxy-phloroglucinol (15.0 g, 0.089 mol) andcooled at 0 °C. Phosphorousoxychloride (9.1 mL, 15.0 g)was added dropwise to this cooling mixture slowly underanhydrous conditions. The mixture was then allowed to stand for 1 h at room temperature. The reaction was monitoredby TLC using 40percent ethyl acetate in Hexane as mobilephase. After completion the reaction mixture was pouredinto crushed-ice and basified with 8M KOH. The solidprecipitate obtained was filtered and dried at 80 °C (VasuBabu et al. 2013). Pale pink color powder with 91.6percent ofyield obtained with melting point 119–121 °C (Scheme 1).
74.68%
Stage #1: for 0.5 h; Stage #2: at 30℃; for 3 h;
Using 1,3,5-trimethoxybenzene (I) as raw material, the reaction intermediate 2,4,6-trimethoxybenzaldehyde (IV) was prepared by Vilsmeier-Haauc acylation reaction.[0036]In a 250 ml three-neck flask equipped with a stirrer and placed in an ice bath,Add 8.76 g (0.12 mol) DMF,Then add 9.8g (0.064mol) P0C13 slowly to the three-necked flask.The Vi 1 smeier complex is formed after 0.5 h of reaction.Then 10.10g (0.06mol)1 , 3 , 5-trimethoxybenzene was gradually added to this complexation solution.Then, the ice bath was removed, the condenser was placed, the reaction flask was transferred to a 30°C water bath and the reaction was stirred for 3 h to form an intermediate. The intermediate reaction solution was poured into a beaker of 60 ml of ice water and stirred with a glass rod. After mixing, seal the membrane at the mouth of the beaker and place it in a refrigerator at 4 °C for cooling and crystallization. The following day's extraction gave 8.8 g of a beige-white powdery product with a yield of 74.68percent.
101 g
at 0℃; for 1 h;
100 g of the compound SM (phloroglucinol trimethylether) and 500 ml of DMF were mixed,Ice salt bath cooling to below 0 ,Dropping 201 g (2.2 eq) of phosphorus oxychloride, controlling the temperature below 0 ° C,Canada completed, the following 0 insulation reaction 1h,TLC followed the completion of the reaction; the reaction solution poured into ice water, potassium carbonate solution adjusted to weakly alkaline (pH 8-10), crystallization overnight, filtered to obtain a white solid, dried to 101g product (Compound I) Hydrogen nuclear magnetic resonance (HNMR) spectrum shown in Figure 1.
Reference：
[1] Journal of Chemical Research, Miniprint, 1991, # 9, p. 2401 - 2413
[2] Patent: WO2011/121505, 2011, A1, . Location in patent: Page/Page column 42
[3] European Journal of Organic Chemistry, 2015, vol. 2015, # 28, p. 6359 - 6369
[4] Patent: US2017/182051, 2017, A1, . Location in patent: Paragraph 0122
[5] Journal of Chemical Research, 2015, vol. 39, # 8, p. 458 - 461
[6] Tetrahedron, 2015, vol. 71, # 26-27, p. 4557 - 4564
[7] Medicinal Chemistry Research, 2018, vol. 27, # 6, p. 1690 - 1704
[8] Organic and Biomolecular Chemistry, 2015, vol. 13, # 2, p. 520 - 526
[9] Patent: CN107382730, 2017, A, . Location in patent: Paragraph 0034-0036
[10] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 403 - 411
[11] Patent: CN105601604, 2016, A, . Location in patent: Paragraph 0144; 0145; 0146; 0147; 0148
[12] Patent: CN107837247, 2018, A, . Location in patent: Paragraph 0058; 0066; 0067
8
[ 621-23-8 ]
[ 1535-67-7 ]
[ 830-79-5 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With tin(IV) chloride In dichloromethane at 20℃; for 2 h; Inert atmosphere Stage #2: With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water; dimethyl sulfoxide at 20℃; for 2 h;
General procedure: In a round-bottomed flask equipped with a stirring bar and rubber septum was placed a 1 M solution of SnCl4 in anhydrous CH2Cl2 (1 mL, 1 mmol). To this solution was added PhSCF2H (1; 240.2 mg, 1.5 mmol) in anhydrous CH2Cl2 (1.5 mL), followed by a solution of an aromatic compound (0.5 mmol) in anhydrous CH2Cl2 (1 mL). The reaction was allowed to proceed for 2 h before it was quenched with a solution of IBX (140 mg, 0.5 mmol) in DMSO/H2O (4 mL; 3:1 v:v). After 2 h of stirring at rt, the reaction mixture was quenched by addition of a saturated aqueous solution of sodium thiosulfate (10 mL), then basified with a saturated aqueous solution of sodium hydrogen carbonate (10 mL), followed by stirring and extraction with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and brine (10 mL), dried (anhydrous MgSO4), filtered and concentrated (aspirator). The residue was purified by PTLC, radial chromatography or column chromatography to furnish analytically pure product. 2,4,6-Trimethoxybenzaldehyde (4b) White solid (97.12 mg, 99 percent) from EtOAc/hexanes; mp 118–120 °C; Rf = 0.23 (hexanes/EtOAc, 5:1). IR (KBr): 2976, 2949, 2880, 1664 (C=O), 1600, 1475, 1333, 1161, 1127, 1025 cm–1. 1H NMR (300 MHz, CDCl3): δ = 10.36 (s, 1 H), 6.09 (s, 2 H), 3.89 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 187.6 (CO), 166.2 (C), 164.1 (2 × C), 108.9 (C), 90.3 (2 × CH), 56.0 (2 × CH3), 55.5 (CH3). HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H12O4Na: 219.0633; found: 219.0627.
Stage #1: With titanium tetrachloride In dichloromethane at 0℃; for 1 h; Inert atmosphere Stage #2: at 0℃; for 0.75 h; Inert atmosphere
General procedure: The appropriate benzene derivative (3.2–10.6 mmol) was dissolved in dry DCM (10–20 mL), purged with Ar, and cooled with an ice bath to 0 °C. Next, TiCl4 (2.2 eq.) was added dropwise. The reaction mixture was stirred for 1 h. Afterwards, dichloromethyl methyl ether (1.1 eq.) was added, and the mixture was left to react for a further 45 min. As a reaction quencher, a saturated solution of NH4Cl (25 mL) was added. The mixture was then left for 2 h. The organic layer was separated and washed with 0.1 N HCl solution (3 × 50 mL) and brine (3 × 50 mL). The organic layer was dried over MgSO4 and filtered, and the solvent was evaporated under vacuum to furnish the desired aldehydes (Figure 1). The purified products were homogeneous by HPLC and were characterized and purified by using various physical techniques.
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h;
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 °C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil.
With tetrabutylammomium bromide; dihydrogen peroxide; trifluoroacetic acid In water at 25℃; for 24 h; Inert atmosphere
General procedure: In a 10 mL two-necked flask equipped with a reflux condenser, substrate (0.25mmol) and tetrabutylammonium bromide (161.2 mg, 0.50 mmol) were placed. The flaskwas evacuated and backfilled with Ar. To the mixture, an ultrapure water (0.5 mL),trifluoroacetic acid (57.5 μL, 0.75 mmol), and 30percent H2O2 (77 μL, 0.75 mmol) wereadded. The mixture was stirred at 25 °C under Ar, followed by treatment with 1:1mixture of saturated Na2S2O3 aqueous solution and saturated NaHCO3 aqueous solution,and extraction with ether. The organic layer was dried over Na2SO4, filtered, andevaporated. 1,3,5-Trimethoxybenzene or hexamethylbenzene was added as an internalstandard, and 1H NMR analysis was performed to determine a NMR yield. Spectral dataof the products were identical with those of commercially available and authenticsamples.
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 17, p. 6849 - 6852
[2] ACS Catalysis, 2016, vol. 6, # 2, p. 1113 - 1121
[3] Chemistry - An Asian Journal, 2009, vol. 4, # 8, p. 1213 - 1216
[4] Tetrahedron Letters, 1996, vol. 37, # 47, p. 8609 - 8612
[5] Chemical Communications, 2009, # 42, p. 6460 - 6462
[6] Synlett, 2014, vol. 25, # 12, p. 1769 - 1775
[7] Chemistry Letters, 2017, vol. 46, # 12, p. 1708 - 1710
20
[ 621-23-8 ]
[ 1131-40-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-Bromosuccinimide In neat (no solvent) at 20℃; for 0.75 h; Milling; Green chemistry
General procedure: 1-Methoxy-3,5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetate and cooled at 0 °C. The product was isolated as filtrate upon paper filtration and waste succinimide as precipitate. The resulting filtrate were concentrated in vacuo to isolate 250 mg (yield: 85percent) of 2b as colourless powder. To test the efficiency in large scale, the reaction was also performed for the mono-bromination of 1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product was isolated in 87percent yield.[1] The milling apparatus was stopped and small portion of the sample was collected from the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
98%
With N-Bromosuccinimide In neat (no solvent) at 20℃; for 0.75 h; Milling; Green chemistry
General procedure: 1-Methoxy-3,5-dimethylbenzene (100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reactionwas monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetateand cooled at 0 °C. The product was isolated as filtrate upon paper filtrationand waste succinimide as precipitate. The resulting filtrate were concentrated in vacuoto isolate 250 mg (yield: 85percent) of 2bas colourless powder. To test the efficiency in largescale, the reaction was also performed for the mono-bromination of1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product wasisolated in 87percent yield.[1] Themilling apparatus was stopped and small portion of the sample was collectedfrom the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
94%
With C22H24N4Se2(2+)*2Br(1-); dihydrogen peroxide; sodium bromide In 1,4-dioxane; aq. phosphate buffer at 20℃; for 4.5 h;
General procedure: 1,4-Dioxane (5 mL) was added to a mixture of substrate (1.5 mmol) and NaBr (3.09 g, 30 mmol). Catalyst 4a, 2.5 mol percent (25 mg, 0.0375 mmol) was dissolved in 15 mL of a pH 4.2 phosphate solution (NaH2PO4 0.5 M) and added to the reaction mixture. Then, H2O2 (8.8 M) was added (the number of equivalents of H2O2 is described in Table 3) and the reaction stirred at room temperature for the amount of time reported in Table 3. The products were extracted with ethyl acetate (4×8 mL), the combined organic extracts were washed with 20 mL of NaHSO3 0.5 M, 20 mL of brine, dried over MgSO4, and concentrated under vacuum. When required, purification was performed by column chromatography on flash silica.
90%
With carbon tetrabromide; anthraquinone-2-carboxylic acid In ethanol at 20℃; for 20 h; Irradiation
A pyrex test tube containing solid of 1,3,5-trimethoxybenzene (1a, 0.3 mmol), carbon tetrabromide (0.075 mmol), AQN-2-CO2H (0.03 mmol) and dry EtOH (5 mL) was irradiated for 20 h at roomtemperature with stirring by a 21W fluorescent lamp under air. The reactionmixture was concentrated in vacuo, quenched with aq Na2S2O3 and extractedwith EtOAc. The organic layer was dried over MgSO4 and concentrated invacuo. Purification of the residue by flash chromatography on silica gel(hexane/ethyl acetate = 6:1) provided 2-bromo-1,3,5-trimethoxybenzene (2a)(66.8 mg, 90percent,) as a white solid.
60%
With bromine In dichloromethane at -78 - -40℃; for 1 h;
2',4',6'-Trimethoxy-biphenyl-3-carbonyl chloride (51)Step 1: KM03 Dissolve 1,3,5-trimethoxybenzene (10.0 g, 59.46 mmol) in anhydrous dichloromethane (10O mL), cool the reaction mixture to -78°C, add dropwise bromine (3.OmL, 59.44 mmol) stir the mixture for Ih between -700C and -400C. Warm up the solution to 0°C and add water. Separate layers and extract the aqu. layer with EtAOc (3 times). Wash combined organic layer with water and brine and dry it with Na2SO4. Remove solvent and purify the crude product by recrystallization from hot EtOAc and cyclohexane to obtain 2-Bromo-l,3,5-trimethoxy-benzene (48) as a white solid (8.84 g, 60percent). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3 H); 3.86 (s, 6 H); 6.15 (s, 2 H).
60%
With N-Bromosuccinimide In acetonitrile at 800℃; for 5 h;
To an oven-dried flask fitted with a septum was sequentially added 1,3,5-trimethoxybenzene (1.68 g, 10 mmol, 1.0 equiv.), N-Bromosuccinimide (1.78 g, 10 mmol, 1.0 equiv.) and 10 mL anhydrous acetonitrile. The resulting mixture was heated to 800° C. for 5 h under vigorous stirring. At this time, the mixture was cooled to room temperature and filtered. The solvent was removed under vacuum to get a crude product which was purified through silica column with 8 v percent of ethyl acetate in hexane to get a white solid (1.48 g, 60percent). 1H NMR (600 MHz, Chloroform-d) δ 6.18 (s, 2H), 3.89 (s, 6H), 3.83 (s, 3H) ppm.
60%
With bromine In dichloromethane at -78 - -40℃; for 1 h;
Step 1: KM03 Dissolve 1,3,5-trimethoxybenzene (10.0 g, 59.46 mmol) in anhydrous dichloromethane (100 mL), cool the reaction mixture to -78° C., add dropwise bromine (3.0 mL, 59.44 mmol) stir the mixture for 1 h between -70° C. and -40° C. Warm up the solution to 0° C. and add water. Separate layers and extract the aqu. layer with EtAOc (3 times). Wash combined organic layer with water and brine and dry it with Na2SO4. Remove solvent and purify the crude product by recrystallization from hot EtOAc and cyclohexane to obtain 2-Bromo-1,3,5-trimethoxy-benzene (48) as a white solid (8.84 g, 60percent). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3H); 3.86 (s, 6H); 6.15 (s, 2H).
59 %Chromat.
With carbon dioxide; oxygen; lithium bromide; copper(ll) bromide In water at 100℃; for 10 h; Autoclave; Green chemistry
General procedure: A mixture of substrate (1 mmol), CuBr2 (22.4 mg, 10 molpercent), LiBr (130.3 mg, 1.5 equiv.), and 0.05 mL of water was placed in a 50 mL stainless steel autoclave equipped with an inner glass tube in room temperature. CO2 (4 MPa) and O2 (1 MPa) were subsequently introduced into the autoclave and the system was heated under the predetermined reaction temperature for 15 min to reach the equilibration. Then the final pressure was adjusted to the desired pressure by introducing the appropriate amount of CO2. The mixture was stirred continuously for the desired reaction time. After cooling, products were diluted with acetone and analyzed by gas chromatograph (Shimadzu GC-2014) equipped with a capillary column (RTX-17 30 m × 25 μm and RTX-wax 30 m × 25 μm) using a flame ionization detector by comparing the retention times of authentic samples. The residue was purified by column chromatography on silica gel (200–300 mesh, eluting with petroleum ether/ethyl acetate from petroleum ether to 50:1) to afford the desired product. The isolated products were further identified with NMR spectra (Bruker 400 MHz) and GC–MS or GCD, which are consistent with those reported in the literature.
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 13, p. 4992 - 4995
[2] Tetrahedron Letters, 2010, vol. 51, # 2, p. 340 - 342
[3] Advanced Synthesis and Catalysis, 2010, vol. 352, # 17, p. 2937 - 2942
[4] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2154 - 2156
[5] Tetrahedron Letters, 2015, vol. 55, # 13, p. 2154 - 2156
[6] Chemical Communications, 2011, vol. 47, # 6, p. 1692 - 1694
[7] Advanced Synthesis and Catalysis, 2014, vol. 356, # 11-12, p. 2453 - 2458
[8] Tetrahedron, 2012, vol. 68, # 51, p. 10476 - 10481,6
[9] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[10] Journal of the Chemical Society, Chemical Communications, 1995, # 6, p. 611 - 612
[11] Tetrahedron Letters, 2015, vol. 56, # 43, p. 5886 - 5888
[12] Organic Letters, 2015, vol. 17, # 24, p. 6210 - 6213
[13] Advanced Synthesis and Catalysis, 2011, vol. 353, # 17, p. 3187 - 3195
[14] Advanced Synthesis and Catalysis, 2018, vol. 360, # 4, p. 626 - 630
[15] Chemistry - An Asian Journal, 2009, vol. 4, # 8, p. 1213 - 1216
[16] Patent: WO2007/39112, 2007, A1, . Location in patent: Page/Page column 39
[17] Medicinal Chemistry Research, 2012, vol. 21, # 10, p. 3177 - 3181
[18] Patent: US2016/207034, 2016, A1, . Location in patent: Paragraph 0413
[19] Patent: US2008/207741, 2008, A1, . Location in patent: Page/Page column 15-16
[20] Canadian Journal of Chemistry, 1989, vol. 67, p. 335 - 344
[21] Organic letters, 2001, vol. 3, # 3, p. 349 - 352
[22] Canadian Journal of Chemistry, 1983, vol. 61, p. 1045 - 1052
[23] Justus Liebigs Annalen der Chemie, 1893, vol. 276, p. 343[24] Justus Liebigs Annalen der Chemie, 1893, vol. 277, p. 308
[25] Chemische Berichte, 1960, vol. 93, p. 2761 - 2776
[26] Tetrahedron Letters, 2006, vol. 47, # 23, p. 3889 - 3892
[27] Tetrahedron, 2010, vol. 66, # 34, p. 6906 - 6911
[28] Dalton Transactions, 2013, vol. 42, # 33, p. 11804 - 11811
[29] Catalysis Today, 2012, vol. 194, # 1, p. 38 - 43
[30] ACS Catalysis, 2015, vol. 5, # 8, p. 4751 - 4755
[31] Dalton Transactions, 2016, vol. 45, # 37, p. 14603 - 14608
[32] ChemBioChem, 2016, vol. 17, # 21, p. 2028 - 2032
[33] ChemCatChem, 2018, vol. 10, # 18, p. 3960 - 3963
21
[ 621-23-8 ]
[ 1131-40-4 ]
[ 5876-90-4 ]
[ 105404-90-8 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1995, # 6, p. 611 - 612
22
[ 621-23-8 ]
[ 106-42-3 ]
[ 1131-40-4 ]
[ 5876-90-4 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 50, p. 18169 - 18178
23
[ 621-23-8 ]
[ 106-42-3 ]
[ 1131-40-4 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 50, p. 18169 - 18178
24
[ 621-23-8 ]
[ 106-38-7 ]
[ 1131-40-4 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 50, p. 18169 - 18178
25
[ 621-23-8 ]
[ 7726-95-6 ]
[ 1131-40-4 ]
[ 5876-90-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1893, vol. 276, p. 343[2] Justus Liebigs Annalen der Chemie, 1893, vol. 277, p. 308
26
[ 621-23-8 ]
[ 124-38-9 ]
[ 570-02-5 ]
Reference：
[1] Patent: US6057315, 2000, A,
27
[ 621-23-8 ]
[ 570-02-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1902, vol. 23, p. 95
[2] Monatshefte fuer Chemie, 1903, vol. 24, p. 866
28
[ 621-23-8 ]
[ 14227-17-9 ]
Yield
Reaction Conditions
Operation in experiment
41%
With oxygen; ammonium chloride; cesium fluoride In dimethyl sulfoxide at 20℃; for 48 h; UV-irradiation
In the reactor, 100 mg of 1,3,5-trimethoxybenzene and 20 mg of boron-nitrogen carbon photocatalyst were added.100 mg of ammonium chloride is an amine source, 3 ml of dimethyl sulfoxide and 1.2 equivalents of cesium fluoride (regulating the pH of the initial reaction solution to 8-10),The reaction was stirred with light at room temperature for 48 h in an oxygen atmosphere, and then extracted with ethyl acetate.The combined organic layers were dried, filtered and evaporatedThe column chromatography eluate used was a petroleum ether: ethyl acetate mixed solvent in a volume ratio of 10:1.The yield was 41percent.
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2545 - 2553
[2] Patent: CN108546233, 2018, A, . Location in patent: Paragraph 0014
[3] Chemistry Letters, 2003, vol. 32, # 6, p. 548 - 549
[4] Journal of Organic Chemistry, 1994, vol. 59, # 3, p. 682 - 687
[5] Tetrahedron Letters, 1993, vol. 34, # 15, p. 2441 - 2444
29
[ 621-23-8 ]
[ 14227-17-9 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 3, p. 563 - 567
30
[ 626-39-1 ]
[ 124-41-4 ]
[ 621-23-8 ]
[ 20469-65-2 ]
[ 74137-36-3 ]
Reference：
[1] Organic Preparations and Procedures International, 2003, vol. 35, # 2, p. 225 - 227
31
[ 626-39-1 ]
[ 124-41-4 ]
[ 621-23-8 ]
[ 20469-65-2 ]
[ 74137-36-3 ]
Reference：
[1] Organic Preparations and Procedures International, 2003, vol. 35, # 2, p. 225 - 227
32
[ 67-56-1 ]
[ 621-23-8 ]
[ 591-50-4 ]
[ 25245-27-6 ]
[ 151-10-0 ]
Reference：
[1] Journal of Physical Organic Chemistry, 2007, vol. 20, # 4, p. 241 - 244
Stage #1: With zinc(II) chloride In dichloromethane at 0 - 5℃; for 2 h; Reflux Stage #2: With hydrogenchloride In ethanol at 60 - 70℃; for 1 h;
In a separate dry reaction flask, 33.6 g of 1,3,5-trimethoxybenzene and 27.2 g of anhydrous zinc chloride were added.Dichloromethane 300mL, stirring and cooling to 0-5 degrees after dropping 36.5g 1-pyrrolidinoyl chloride, drops,The reaction was heated to reflux for 2 hours. After the reaction was complete, 15 mL of concentrated hydrochloric acid and 150 mL of pure water were added and washed.The resulting organic phase is washed with saturated sodium bicarbonate solution to a pH of 7-8, and the organic phase is dried over magnesium sulfate and then reduced to dryness.Add 100 mL of anhydrous ethanol to the concentrate.20percent hydrochloric acid ethanol100mLAfter stirring the reaction at 60-70°C for 1 hour, the ethanol is then reduced to dryness.After adding 400 mL of acetone to the residue and cooling and crystallizing, the white crystal was filtered to obtain 60.2 g of buflomedil hydrochloride.
Reference：
[1] Patent: CN107698539, 2018, A, . Location in patent: Paragraph 0006
35
[ 621-23-8 ]
[ 121-43-7 ]
[ 380430-67-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 6, p. 1016 - 1030
With nitric acid; acetic anhydride; for 2.5h;Cooling with ice;
1) In a 250 ml single-necked flask,To the acetic anhydride was added 1.3.5-trimethoxybenzene,Stir and dissolve under ice bath conditions 3 drops / minDropping 85% concentrated nitric acid to the solution color slowly darkened,TLC (ethyl acetate: petroleum ether = 5: 1)Monitoring response,About 0.5 hours the addition was complete,among them,The acetic anhydride was 80 ml,1.3.5-trimethoxybenzene 10.0 g (59 mmol),Concentrated nitric acid 65mmol; (2) stirring was continued for 2 hours,TLC (ethyl acetate: petroleum ether = 5: 1)After testing the raw material reaction completely,The reaction solution was stirred at room temperature of 20 ml / min into 500 ml of ice water,Precipitate a large amount of yellow solid; 3) was stirred at room temperature for 0.5 hour,filter,Washed twice,Drying 11.0 grams of crude,Ethyl acetate to recrystallize pure product 9.5g,Yield 95%.
With trichlorophosphate; at -5 - 0℃;Inert atmosphere;
Example 82,4,6-Trimethoxy-benzaldehyde2,4,6-Trimethoxy-benzene (40gm, 0.22x103 mmol) was added to dimethylformamide and stirred at a temperature in the range of -5 to 0C under N2 atmosphere, followed by addition of phosphorus oxychloride (48 gm, 0.5x103 mmol) drop wise over a period of 30-45 minutes. The reaction mixture was stirred for one hour at 0C, poured over crushed ice followed by saturated sodium carbonate solution. Precipitate obtained was filtered and washed with water to obtain the title compound.Yield: 46 gm (98%); 1 HNMR (CDCI3): delta 10.35 (s, 1 H), 6.67 (s, 2H), 3.88 (s, 6H), 3.87 (s, 3H); MS: m/e 197 (M+1 ).
98%
With trichlorophosphate; at 20 - 30℃; for 1h;
In a round bottom flask, POCl3 (7.3 ml, 80 mmol) was added to a mixture of 1,3,5-trimethoxybenzene (8.41 g, 50 mmol) in DMF (15 ml). The temperature of reaction mixture was kept below 30 C. by slowly adding POCl3. After addition of POCl3, the mixture was still stirred at room temperature for an addition 1 hour. The reaction mixture was added into a cold saturated NaHCO3 solution. The pH of the solution was adjusted to remain above 7. Precipitation of desired product occurred. The off-white product was filtered and rinsed with NaHCO3 aq., then with HCl aq. 0.5M and then with water. Off-white solid was collected and vacuum dried at room temperature to yield 14a (9.60 g, 48 mmol, 98%).
98%
With trichlorophosphate; at 20 - 30℃; for 1h;
In a round bottom flask, POCl3 (7.3 ml, 80 mmol) was added to a mixture of 1,3,5-trimethoxybenzene (8.41 g, 50 mmol) in DMF (15 ml). The temperature of reaction mixture was kept below 30 C. by slowly adding POCl3. After addition of POCl3, the mixture was still stirred at room temperature for an addition 1 hour. The reaction mixture was added into a cold saturated NaHCO3 solution. The pH of the solution was adjusted to remain above 7. Precipitation of desired product occurred. The off-white product was filtered and rinsed with NaHCO3 aq., then with HCl aq. 0.5M and then with water. Off-white solid was collected and vacuum dried at room temperature to yield 14a (9.60 g, 48 mmol, 98%).
91.6%
With trichlorophosphate; at 0 - 20℃; for 1h;
Dimethylformamide (9.0 mL, 8.4 g, 0.116 mol) was addedto trimethoxy-phloroglucinol (15.0 g, 0.089 mol) andcooled at 0 C. Phosphorousoxychloride (9.1 mL, 15.0 g)was added dropwise to this cooling mixture slowly underanhydrous conditions. The mixture was then allowed to stand for 1 h at room temperature. The reaction was monitoredby TLC using 40% ethyl acetate in Hexane as mobilephase. After completion the reaction mixture was pouredinto crushed-ice and basified with 8M KOH. The solidprecipitate obtained was filtered and dried at 80 C (VasuBabu et al. 2013). Pale pink color powder with 91.6% ofyield obtained with melting point 119-121 C (Scheme 1).
91%
With trichlorophosphate; at 0 - 20℃; for 1.25h;Inert atmosphere;
Anhydrous DMF (3.00 mL, 38.8 mmol) was added to 1,3,5-trimethoxybenzene 24 (5.01 g, 29.8 mmol) and cooled to 0 C in an ice-bath with stirring under nitrogen. Phosphorus oxychloride (3.30 mL, 35.4 mmol) was added dropwise and slowly over 15-20 min to the cooled mixture. The resulting mixture was allowed to stand at room temperature for 1 h. The pale yellow suspension was poured into crushed ice (100 g) and basified with 8 N KOH solution to give a white suspension. The crude product was filtered, washed with ice-cold water (2 × 50 mL), suction-dried and redissolved in CHCl3 (100 mL). The organic solution was washed with brine (2 × 100 mL), dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure. The crude residue was recrystallized from CHCl3/PE to afford benzaldehyde 25 (5.30 g, 91%) as a white powdery solid.
74.68%
Using 1,3,5-trimethoxybenzene (I) as raw material, the reaction intermediate 2,4,6-trimethoxybenzaldehyde (IV) was prepared by Vilsmeier-Haauc acylation reaction.[0036]In a 250 ml three-neck flask equipped with a stirrer and placed in an ice bath,Add 8.76 g (0.12 mol) DMF,Then add 9.8g (0.064mol) P0C13 slowly to the three-necked flask.The Vi 1 smeier complex is formed after 0.5 h of reaction.Then 10.10g (0.06mol)1 , 3 , 5-trimethoxybenzene was gradually added to this complexation solution.Then, the ice bath was removed, the condenser was placed, the reaction flask was transferred to a 30C water bath and the reaction was stirred for 3 h to form an intermediate. The intermediate reaction solution was poured into a beaker of 60 ml of ice water and stirred with a glass rod. After mixing, seal the membrane at the mouth of the beaker and place it in a refrigerator at 4 C for cooling and crystallization. The following day's extraction gave 8.8 g of a beige-white powdery product with a yield of 74.68%.
101 g
With trichlorophosphate; at 0℃; for 1h;
100 g of the compound SM (phloroglucinol trimethylether) and 500 ml of DMF were mixed,Ice salt bath cooling to below 0 ,Dropping 201 g (2.2 eq) of phosphorus oxychloride, controlling the temperature below 0 C,Canada completed, the following 0 insulation reaction 1h,TLC followed the completion of the reaction; the reaction solution poured into ice water, potassium carbonate solution adjusted to weakly alkaline (pH 8-10), crystallization overnight, filtered to obtain a white solid, dried to 101g product (Compound I) Hydrogen nuclear magnetic resonance (HNMR) spectrum shown in Figure 1.
With oxalyl dichloride; In dichloromethane; at 20℃; for 0.5h;Cooling with ice;
The compound raw material 1,3,5-trimethoxybenzene (Compound 5) (2 g, 11.89 mmol) And oxalyl chloride (1.3 mL, 15.46 mmol) Soluble in anhydrous dichloromethane (20mL) Slowly add anhydrous DMF (1.2 mL, 15.46 mmol) with a syringe under an ice bath. After the addition of the mixture was warmed to room temperature for 30 minutes. TLC monitoring After the reaction is over, Pour the reaction solution into saturated sodium bicarbonate solution. Dichloromethane extraction (100 mL x 3), Combine organic layers, Washed, Saturated salt water wash, Drying with anhydrous sodium sulfate, The crude 2,2,6-trimethoxybenzaldehyde 6 (2.3 g, 100%) was concentrated as a yellow solid. Crude product does not require purification. Direct investment in the next step.
With hydrogen; In cyclohexane; at 165℃; under 15001.5 - 26252.6 Torr; for 4h;Autoclave;
To a 1 L autoclave <strong>[830-79-5]2,4,6-trimethoxybenzaldehyde</strong> 200 g, Cyclohexane 300 mL, Modified Raney nickel 3g, Sealed with nitrogen, Hydrogen for 3 times, Nitrogen to 2MPa, Then heated to 165 C, Adjust the reactor pressure to 3.5MPa, The conditions were maintained for 4 hours, Sampling Gas Chromatography, The conversion of the raw materials was 100% 1,3,5-trimethoxybenzene selectivity 95%. The solution was withdrawn from the kettle, The catalyst was left in the autoclave for 2-3 times with cyclohexane, The cyclohexane wash solution was combined with the withdrawn solution, The combined solution is distilled for rectification 1,3,5-trimethoxybenzene fraction, 156 g, Yield 90.9%.
With N-Bromosuccinimide; chloro-trimethyl-silane; In acetonitrile; at 20℃; for 1h;
General procedure: To a solution of 4-bromoanisole (200.8 mg, 1.09 mmol, 1.0 equiv) in acetonitrile (2 mL) was added N-chlorosuccinimide(NCS) (158.3 mg, 1.19 mmol, 1.1 equiv) at rt to give a slightly cloudy mixture. Chlorotrimethylsilane (TMSCl) (14 muL, 0.11 mmol, 0.1 equiv) was then added drop-wise to the reaction mixture. Within a few minutes, the reaction mixture became clear pale yellow solution. The mixture continued to stir at rt for 1 h and was diluted with hexane. The biphasic mixture was concentrated on a rotary evaporator to a crude white solid-oil mixture. This mixture was taken up in hexane and filtered through a short plug of SiO2 and eluted with 5-10% EtOAc-hexane solution. The clear filtrate was concentrated to obtain a mixture of 4-bromo-2-chloro-1-methoxybenzene (2a-Cl) and 2,4-dichloro-1-methoxybenzene (2a-diCl) 237.0 mg (88% of 2a-Cl and 11% of 2a-diCl,based on NMR ratio 2a-Cl: 2a-diCl = 7.1: 1.0; as a pale yellow solid).
89%Spectr.; 2%Spectr.
With tetrabutylammomium bromide; dihydrogen peroxide; trifluoroacetic acid; In water; at 25℃; for 24h;Inert atmosphere;
General procedure: In a 10 mL two-necked flask equipped with a reflux condenser, substrate (0.25mmol) and tetrabutylammonium bromide (161.2 mg, 0.50 mmol) were placed. The flaskwas evacuated and backfilled with Ar. To the mixture, an ultrapure water (0.5 mL),trifluoroacetic acid (57.5 muL, 0.75 mmol), and 30% H2O2 (77 muL, 0.75 mmol) wereadded. The mixture was stirred at 25 C under Ar, followed by treatment with 1:1mixture of saturated Na2S2O3 aqueous solution and saturated NaHCO3 aqueous solution,and extraction with ether. The organic layer was dried over Na2SO4, filtered, andevaporated. 1,3,5-Trimethoxybenzene or hexamethylbenzene was added as an internalstandard, and 1H NMR analysis was performed to determine a NMR yield. Spectral dataof the products were identical with those of commercially available and authenticsamples.
The title compound was prepared using an adapted procedure for the same compound reported by Chaumeil et al.17 To a stirring solution of 1,3,5-trimethoxybenzene 7 (11.3 g, 67.2 mmol) in THF (200 mL) at 0 C, n-BuLi (45 mL, 1.60 M, 72.0 mmol) was added dropwise over 10 min. The resulting white suspension was stirred at this temperature for 2 h and then cooled to -78 C. B(OMe)3 (15.0 mL, 135 mmol) in THF (15 mL) was added dropwise over 1 h and the resulting mixture was stirred at -78 C for 1 h before being allowed to slowly warm in the cold bath to room temperature overnight. The resulting cloudy, white mixture was cooled to 0 C and water (100 mL) was added dropwise with stirring over 30 min. The mixture was poured into water (200 mL) and CH2Cl2 (300 mL) and stirred vigorously for 15 min. The phases were separated and the aqueous phase was extracted with CH2Cl2 (4×50 mL), and the combined organics were dried (Na2SO4), filtered and concentrated to provide a white powdery solid. The solid was dissolved in minimal boiling CHCl3 and a roughly equal portion of hot Et2O was added. The mixture was cooled to room temperature and placed in a -20 C freezer overnight to allow crystallization of the product. The resulting white crystals were isolated by suction, washed with cold Et2O (10 mL) and allowed to dry to provide 10.1 g (71%) of the desired boronic acid 9a. 1H NMR (400 MHz, CDCl3) delta 7.00 (s, 2H), 6.14 (s, 2H), 3.87 (s, 6H), 3.83 (s, 3H). NMR data for the synthesized compound corresponded to those reported for the title compound by Chaumeil et al.17
With water; trichlorophosphate; In acetic acid; at 25℃; for 3h;Product distribution / selectivity;
Example 3 1.68 g of 1,3,5-trimethoxybenzene, 2.32 g of methyl trans-3-methoxyacrylate, 0.18 g of water and 6 mL of glacial acetic acid were mixed, 164 mg of phosphorus oxychloride was added into the mixture at an inner temperature of 25C, the added mixture was stirred for 3 hours at the same temperature to cause a reaction. After completion of the reaction, 36 mL of water was added dropwise into the reaction liquid, and the precipitated crystals were filtrated. The crystals were washed with 20 vol% of aqueous methanol, then, dried to obtain 2.28 g of methyl trans-3-(2,4,6-trimethoxyphenyl)acrylate (white solid). Yield:91%. 1H-NMR (d/ppm, CDCl3, 400 MHz) 3.79 (3H, s), 3.85 (3H, s), 3.87 (6H, s), 6.12 (2H, s), 6.76 (1H, d, J=16 Hz), 8.08 (1H, d, J=16 Hz)
With oxygen; ammonium chloride; cesium fluoride; In dimethyl sulfoxide; at 20℃; for 48h;pH 8 - 10;UV-irradiation;
In the reactor, 100 mg of 1,3,5-trimethoxybenzene and 20 mg of boron-nitrogen carbon photocatalyst were added.100 mg of ammonium chloride is an amine source, 3 ml of dimethyl sulfoxide and 1.2 equivalents of cesium fluoride (regulating the pH of the initial reaction solution to 8-10),The reaction was stirred with light at room temperature for 48 h in an oxygen atmosphere, and then extracted with ethyl acetate.The combined organic layers were dried, filtered and evaporatedThe column chromatography eluate used was a petroleum ether: ethyl acetate mixed solvent in a volume ratio of 10:1.The yield was 41%.
With n-butyllithium; In tetrahydrofuran; hexane; water;
EXAMPLE H 2,4,6-Trimethoxybenzoic acid To a stirred solution of 1,3,5-trimethoxybenzene (10.0 g, 59.4 mmol) in 150 mL of dry THF at 0 C. in nitrogen atmosphere was added 27.3 mL (68.31 mmol) of 2.5 M n-BuLi in hexane dropwise via syringe. The resulting solution was stirred at room temperature overnight. The mixture was cooled to -20 C. and 30 g of dry ice was added. Stirring was continued for 1 hr before hydrolysis with 200 mL of water. The mixture was evaporated under reduced pressure to remove THF. The aqueous phase was extracted with ether, acidified with hydrochloric acid to pH 3 and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated. The solid residue was washed with ether and dried in vacuo to give 6.7 g of the title compound: mp 152-153 C. dec (lit.: 147 C. dec.; Beilsteins, 10, 1988). 1 H NMR (CDCl3): 6.16 (2 H, s), 3.91 (6 H, s), 3.86 (3 H, s).
With sodium persulfate; ethanol; at 60℃; for 18h;Sealed tube; Green chemistry;
General procedure: A solution of aromatic carboxylic acid (0.1 mmol), Na2S2O8 (1.0 equiv) in ethanol (1 mL) was stirred in a sealed tube under an atmosphere of air at 60 oC for 18 h. The reaction mixture was then evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (TLC) on silica gel with petroleum ether and ethyl acetate to achieve the pure product.
With trifluorormethanesulfonic acid; 1,1,1,3',3',3'-hexafluoro-propanol; at 60℃; for 24h;
General procedure: To a stirred solution of chloropurine 1 (0.50 mmol) in hexafluoroisopropanol (5 mL), aromaticnucleophile 2 (0.55 mmol, 1.1 equiv) and trifluoromethanesulfonic acid (TfOH, 44 L, 0.5 mmol, 1 equiv)were successively added. The resulting mixture was stirred at 60 C for 24 h. After completion of thereaction checked by TLC, the reaction mixture was poured into sat. NaHCO3 aqueous. The resultantsolution was extracted with ethyl acetate, dried with solid sodium sulfate, and then concentrated. Theresidue was puried by short-column chromatography on silica gel using hexane-ethyl acetate as theeluent to give the purine aromatic-linked compound 3 in the indicated yield in Table 2 or Scheme 3.
With bis-triphenylphosphine-palladium(II) chloride; water; sodium hydroxide; In tetrahydrofuran; at 70℃; for 24h;Inert atmosphere;
General procedure: A 25 mL round bottom flask was charged with 9a (ca. 320 mg, 1.51 mmol), either anhydrous NaOH or K2CO3 (ca. 3 mmol) and Pd(PPh3)2Cl2 (1 mol %). THF (10 mL) was then added and the mixture was stirred until the boronic acid and catalyst dissolved. The resulting mixture was degassed with an Argon sparge for 30 min. Neat BnBr (120 muL, 1 mmol) was added via syringe, followed by water (2 mL) for the aqueous reactions. The resulting mixtures were stirred for 24 h at 70 C, then cooled to room temperature and quenched by the addition of satd aq NH4Cl (10 mL). The resulting mixture was extracted with CH2Cl2 (2×20 mL) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The title product 10 was obtained in 10% isolated yield using aqueous K2CO3 as the base and 20% using aqueous NaOH as the base. In both cases the product was isolated as a white, powdery solid following silica gel chromatography (CH2Cl2/hexanes, 1:1) of the crude mixtures. 1H NMR (400 MHz, CDCl3) delta 7.24-7.07 (m, 5H), 6.15 (s, 2H), 3.93 (s, 2H), 3.80 (s, 3H), 3.77 (s, 6H). 13C NMR (100 MHz, CDCl3) delta 159.5, 159.1, 142.5, 128.6, 128.1, 125.4, 110.6, 90.9, 55.9, 55.5, 28.5. Mp 93-94 C (lit. Mp 93-95 C). NMR and mp data for the synthesized compound corresponded to those reported by Katritzky et al.24 for the title compound.
1,3,5-trimethoxy-2-[(4-methoxyphenyl)methyl]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With p-toluenesulfonic acid immobilized on silica; In toluene; at 0 - 20℃; for 2h;
General procedure: The corresponding benzyl acetate (0.16 mmol) was dissolved intoluene or 4:1 EtOH/toluene (see details in each reaction) (1 mL)and then aromatic compound (0.80e1.6 mmol) and PTS-Si(0.17 mmol) were sequentially added at 0 C. The stirring wascontinued (for time and temperature noted in each Table) and thenthe mixture was filtered through a short pad cotton wool. Removalof the solvent afforded the crude product, which was purified bypreparative thin-layer chromatography (PTLC). Following the general procedure and purification by PTLC, the product was obtained as colorless oil (0.038 g, 0.13 mmol, 81%). Rf 0.50 (10% EtOAc/hexanes, developed three times). FTIR (UATR): numax 2937, 2836, 1595, 1116 cm-1. 1H NMR (CDCl3, 300 MHz): delta 3.74 (s, 3H), 3.78 (s, 9H), 3.86 (s, 2H), 6.14 (s, 2H), 6.75 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H). 13C NMR (CDCl3, 75 MHz): delta 27.3, 55.1, 55.3, 55.7 (2C), 90.6 (2C), 110.7, 113.3 (2C), 129.2 (2C), 134.4, 157.3, 158.7 (2C), 159.5. LRMS (EI) m/z (rel intensity) 288 (M+, 36), 257 (15), 181 (27), 121 (100), 91 (23). ESITOF-HRMS calcd for C17H20NaO4 (M+Na+) 311.1253, found 311.1252.
With boron trifluoride diethyl etherate; at 20 - 100℃;
A mixture of 1,3,5-trimethoxybenzene (1) (0.8 g, 5 mmol) and 3,4-dimethoxycinnamic 5(1.56 g, 7.5 mmol) in BF3-Et2O (15 mL) was heated at 100 C for 4 h. After one night at room temperature, the red solid was filtered and dried to give red needles. A suspension of the needles in EtOH was heated at reflux for 2 h to give a clear orange solution. After the solution was decolourised with active charcoal and cooled to 0C, the precipitate was filtered and dried to give compound 6 (0.77 g); yield 45%, yellow crystals, 149-151 C (lit17. 154-156 C) 1H NMR (400 MHz, CDCl3) (delta, ppm): 14.29 (s, 1H, OH), 8.07 (d, J = 15.2 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.96 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.84 (s, 3H, OCH3). IR numax(KBr/cm-1): 3420 (OH), 1625 (C= O).
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; boron trifluoride diethyl etherate; iodosylbenzene; In dichloromethane; at 20℃; for 0.5h;
General procedure: To the stirred mixture of methoxybenzene (2.0 mmol) and benzylalcohol (1.0 mmol) in DCM (5 mL) were added PhIO (1.2 equiv), TEMPO (0.13 equiv) with BF3.OEt2 (2.0 equiv). The reaction mixture was stirred 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, NaHCO3 (3 equiv) was added to the reaction mixture and concentrated in vacuo. The crude product was directly poured into silica gel column chromatography (100-200 mesh) using ethyl acetate: hexane (03:97 to 10:90) as eluent to afford corresponding triarylmethane products. The all obtained products were characterized by 1H NMR, 13C NMR, Mass, HRMS and IR spectral data.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; boron trifluoride diethyl etherate; iodosylbenzene; In dichloromethane; at 20℃; for 0.5h;
General procedure: To the stirred mixture of methoxybenzene (2.0 mmol) and benzylalcohol (1.0 mmol) in DCM (5 mL) were added PhIO (1.2 equiv), TEMPO (0.13 equiv) with BF3.OEt2 (2.0 equiv). The reaction mixture was stirred 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, NaHCO3 (3 equiv) was added to the reaction mixture and concentrated in vacuo. The crude product was directly poured into silica gel column chromatography (100-200 mesh) using ethyl acetate: hexane (03:97 to 10:90) as eluent to afford corresponding triarylmethane products. The all obtained products were characterized by 1H NMR, 13C NMR, Mass, HRMS and IR spectral data.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; boron trifluoride diethyl etherate; iodosylbenzene; In dichloromethane; at 20℃; for 0.5h;
General procedure: To the stirred mixture of methoxybenzene (2.0 mmol) and benzylalcohol (1.0 mmol) in DCM (5 mL) were added PhIO (1.2 equiv), TEMPO (0.13 equiv) with BF3.OEt2 (2.0 equiv). The reaction mixture was stirred 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, NaHCO3 (3 equiv) was added to the reaction mixture and concentrated in vacuo. The crude product was directly poured into silica gel column chromatography (100-200 mesh) using ethyl acetate: hexane (03:97 to 10:90) as eluent to afford corresponding triarylmethane products. The all obtained products were characterized by 1H NMR, 13C NMR, Mass, HRMS and IR spectral data.
4-(bis(2,4,6-trimethoxyphenyl)methyl)-2,6-dimethoxyphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
General procedure: A solution of acetophenone 1 (1 mmol), SeO2 (2 mmol) and ytterbium chloride (0.3 mmol) inDMSO:H2O (9:1) (3 mL) was well stirred at 110 oC for 15 h. Then the 2-methylfuran/thiophene (2or 3) was added to the reaction mixture at room temperature and stir again for 10 min at 70 oC. Aftercompletion of the reaction, the reaction mixture brought to room temperature, and it was filteredthrough a short pad of Celite, excess SeO2 and other selenium-containing byproducts were removedby adsorption on Celite. Water was added to the filtrate and the mixture was extracted withdichloromethane. The combined organic layers were dried over anhydrous Na2SO4, concentrated invacuo and purified by chromatography on silica gel to afford required products (4 or 5). Therecovered catalyst was obtained from the aqueous layer after removing water.
1,3,5-trimethoxy-2-[(4-methoxyphenyl)sulfanyl]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: An oved dried two neck flask was charged with NCS (1.7 mmol), thiophenol 1a ( 2.3 mmol) and dichloromethane (2-3 mL). The above mixture was stirred for 30 min, then 1,3,5- trimethoxy benzene 3a (1.1 mmol) was added. Stirring was continued for another 30 min at room temperature and then the mixture was poured into 20 mL of saturated sodium bicarbonate solution. The product was extracted with dichloromethane (10 mL × 3) and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure, the left out residue was purified through column chromatography using silica gel (10 % EtOAc/hexane) to get 4a in 89% yield.
82%
With sodium tetrafluoroborate; potassium iodide; In acetonitrile; at 60℃; for 6h;Electrochemical reaction;
Electrolysis experiments were performed on Vertex Potentiostat/Galvanostat. Both the working electrode and the counter electrode were made of platinum (1.5cm×1.5cm). Ag/Ag+ electrode (0.1mol/L AgNO3 in CH3CN) was employed as the reference electrode. The 0.1mol/L of NaBF4/CH3CN solution (15mL) with 1,3,5-trimethoxybenzene (1a, 0.5mmol, 84mg), 4-chlorothiophenol (2a, 0.6mmol, 86mg) and KI (0.05mmol, 8.3mg) was added into a 25mL undivided beaker and the resulting mixture was stirred at 60C. After completion of the reaction (analysed by GC or TLC), the resulting mixture was concentrated under reduced pressure and purified by column chromatography on 200-300 mesh silica gel using petroleum ether: ethyl acetate (50:1) as eluent to afford (4-chlorophenyl) (2,4,6-trimethoxyphenyl)sulfane (3aa) as a white solid in 90% yield.
In a separate dry reaction flask, 33.6 g of 1,3,5-trimethoxybenzene and 27.2 g of anhydrous zinc chloride were added.Dichloromethane 300mL, stirring and cooling to 0-5 degrees after dropping 36.5g 1-pyrrolidinoyl chloride, drops,The reaction was heated to reflux for 2 hours. After the reaction was complete, 15 mL of concentrated hydrochloric acid and 150 mL of pure water were added and washed.The resulting organic phase is washed with saturated sodium bicarbonate solution to a pH of 7-8, and the organic phase is dried over magnesium sulfate and then reduced to dryness.Add 100 mL of anhydrous ethanol to the concentrate.20% hydrochloric acid ethanol100mLAfter stirring the reaction at 60-70C for 1 hour, the ethanol is then reduced to dryness.After adding 400 mL of acetone to the residue and cooling and crystallizing, the white crystal was filtered to obtain 60.2 g of buflomedil hydrochloride.
1,3,5-trimethoxy-2-[(4-methoxyphenyl)sulfanyl]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With acetic acid; ytterbium(III) triflate; In 1,2-dichloro-ethane; at 80℃; for 8h;
General procedure: First, a solution of rich arenes (0.3 mmol), arylsulfonyl hydrazides (0.6 mmol), Cu(OTf)2 (0.2 mmol), and HOAc (1 mL) in DCE (2 mL), was stirred at 80 C (or 110 C) for 8 h under air. Second, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were dried over anhydrous MgSO4 and filtered, followed by solvent removal under reduced pressure. The residue was purified by flash column chromatography on silica gel using PE/EtOAc as the eluent.
With acetic acid; ytterbium(III) triflate; In 1,2-dichloro-ethane; at 80℃; for 8h;
General procedure: First, a solution of rich arenes (0.3 mmol), arylsulfonyl hydrazides (0.6 mmol), Cu(OTf)2 (0.2 mmol), and HOAc (1 mL) in DCE (2 mL), was stirred at 80 C (or 110 C) for 8 h under air. Second, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were dried over anhydrous MgSO4 and filtered, followed by solvent removal under reduced pressure. The residue was purified by flash column chromatography on silica gel using PE/EtOAc as the eluent.
With ethanol; cobalt(II) tetrabutylporphyrin; potassium hydroxide; at 150℃; for 4h;Inert atmosphere;
1-Bromo-2,4,6-trimethoxybenzene (1g) (17.6 mg, 0.071 mmol), Co(tbp) (2.1 mg,0.0035 mmol) and KOH (157.5 mg, 2.8 mmol) were added in EtOH(1.0 mL). The mixture was degassed for three freeze-pump-thawcycles, purged with N2, and heated to 150C for 4 h. 99% yield of1,3,5-trimethoxybenzene was detected by GC-MS analysis usingdecalin as internal standard.
5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide; at 100℃; for 6h;Microwave irradiation; Sealed tube;
Adding 85 mg (about 0.5 mmol) to a 10 mL microwave reaction tube.<strong>[24415-66-5]7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine</strong> and 253 mg (about 1.5 mmol) of 1,3,5-trimethoxybenzene,14 mg (about 10 mol%) of the catalyst bistrifluoromethylsulfonimide and 1 mL of the solvent HFIP, and then the microwave reaction tube was sealed.Then, after stirring the reactants in the microwave reaction tube at 100 C for 6 hours,The solvent was evaporated under reduced pressure and purified by column chromatography using DCM / MeOH as eluent.Obtained about 122 mg of pure product e2 as a white solid, and yield81%;
1.05 g
With 1,1,1,3',3',3'-hexafluoro-propanol; bis(trifluoromethanesulfonyl)amide; at 100℃; for 6h;Sealed tube;
To an oven dried round flask was added 1H-1,2,4-triazol-5-amine (4.2 g, 50 mmol) along with ethyl 3-oxobutanoate (7.6mL, 60 mmol ) and AcOH (20 mL). The mixture was stirred at 120 for 6 h, after evaporation of the solvent, the residue was filtrated and washed with EtOAc. The crude product was used for the next step without any purification. Then the crude product was added to an oven dried round flask with POCl3 (25 mL). The mixture was stirred at 90 for 8 h, andthe solvent was removed under reduced pressure. Then the equivalent of water and EtOAc were added to the residue. The phases were separated and the aqueous phase was extracted with EtOAc (150 mL × 3). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to give <strong>[24415-66-5]7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine</strong> as a yellow solid. Then to a thick-walled pressure-resistant reaction bottle was added <strong>[24415-66-5]7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine</strong> (0.84 g, 5 mmol), 1,3,5-trimethoxybenzene (2.52 g, 15 mmol),1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (422 mg, 30 mol%) and hexafluoroisopropanol (HFIP) (3mL), then the tube was sealed. The mixture was stirred at 100 for 6 h, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using DCM/MeOH to afford the product 1 (1.05 g, yield: 70 %).
1-(2,4,6-trimethoxyphenyl)-1,3,3-triphenylpropa-1,2-diene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With toluene-4-sulfonic acid; In acetonitrile; at 20℃; for 0.5h;Green chemistry;
General procedure: To a mixture of the corresponding alkynol 1 (1 mmol) and the appropriate trimethoxyarene (1 mmol, 168 mg), 1,3-dimethoxybenzene (1 mmol, 138 mg) or allyltrimethylsilane (3 mmol, 0.5 mL) in MeCN (2 mL) was added p-toluenesulfonic acid monohydrate (PTSA) (5 mol %, 9 mg) for reactions with arenes or 2,4-dinitrobenzenesulfonic acid hydrate (DNBSA) (5 mol %, 15 mg) for reactions with allyltrimethylsilane. The resulted reaction mixture was stirred at room temperature until the reactants had been consumed, as determined by GC-MS and/or TLC. The crude mixture was neutralized by the addition of NaOH 0.5M (5 mL), and EtOAc (15 mL) was added. The separated aqueous phase was extracted with EtOAc (3×15 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: mixtures of hexane/AcOEt) to afford the corresponding allenes 2,4-7 in the yields reported in Tables 2-3 and Scheme 1.
4-(2,4,6-trimethoxyphenyl)-1,4-dihydroquinazolin-3-ium trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
In butan-1-ol; at 115 - 120℃; for 4h;
A mixture of 0.065 g (0.5 mmol) of <strong>[253-82-7]<strong>[253-82-7]qui</strong>nazoline</strong> (1), 0.085 g (0.5 mmol) of 1,3,5-trimethoxybenzene (2), 2.0 mL of butan-1-ol, and 0.5 mL of trifluoroacetic acid was heated at 115-120 C for 4 h. The solvent was distilled off under reduced pressure,and the solid residue was washed with 2-3 mL of ethanol and dried. Yield 0.090 g (43 %), mp 181-182 C. 1H NMR spectrum, delta, ppm: 3.29 s (6H, OCH3), 3.80 s (3H, OCH3), 6.30 s (2H, Harom), 6.42 s (1H, 4-H), 6.79 d (1H, Harom, 3JHH = 7.6 Hz), 7.05-7.11 m (2H, Harom), 7.23 t (1H, Harom, 3JHH = 7.6 Hz), 8.36 s (1H, 2-H), 10.50br.s (1H, NH). 13C NMR spectrum, deltaC, ppm: 45.24, 55.39, 56.00, 111.23, 115.92, 122.40, 126.47, 126.59, 128.27, 130.67, 148.19, 161.59. 19F NMR spectrum: deltaF -73.56 ppm (CF3). Mass spectrum, m/z (Irel, %): 296 (20), 298 (100) [M]+, 297 (88), 283 (21), 281 (19), 168 (20),139 (22), 131 (60). Found, %: C 55.38; H 4.47; N 6.85. C17H18N2O3 · C2O2F3. Calculated, %: C 55.47; H 4.38; N 6.81.
1,1-diphenyl-3-(2,4,6-trimethoxyphenyl)-1H-indene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With toluene-4-sulfonic acid; In acetonitrile; at 80℃; for 1h;
General procedure: A 25mL round-bottom flask equipped with a magnetic barand a water condenser was charged with <strong>[1522-13-0]propargylic alcohol</strong>1 (1.0mmol), arene 2 (1.1mmol), MeCN (2.0mL) andPTSA (10mol%) in air atmosphere. The flask was placedinto a constant temperature oil-bath at 80C and the progressof the reaction was monitored by TLC. After completionof the reaction, the solvent was removed under reducedpressure and the crude reaction mixture was purified by columnchromatography.
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