* 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] 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
2
[ 118-41-2 ]
[ 4521-61-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With thionyl chloride In chloroform for 4 h; Reflux
To a mixture of 3,4,5-trimethoxybenzoic acid (8.00 g, 37.7 mmol) in CHCl3 (30 mL) was added thionyl chloride (13.7 mL, 189 mmol) in a dropwise fashion. Once the addition was completed, the reaction mixture was heated to reflux for 4 h before being cooled back to room temperature. The solvent and excess thionyl chloride was removed under reduced pressure to yield the acyl chloride 20 in quantitative yield as a colourless oil, which was subsequently used without further purification: νmax/cm-1 (NaCl) 2970, 2944, 1750, 1590, 1457, 1415, 1130, 1128.
100%
With thionyl chloride In CH2C3 for 3 h; Reflux
A mixture of acid 29 (3.0 g, 14.1 mmol) and thionyl chloride (4.1 mL, 56.5 mmol) in dichloromethane (25 mL) was refluxed for 3 h. The pale yellow solution was concentrated in vacuo to give the crude acid chloride 7453 (3.26 g, quant.) as a yellow pale solid. 1H NMR (CDCl3, 400 MHz) δ (ppm) 3.93 (s, 6H, 2OCH3), 3.96 (s, 3H, OCH3), 7.27 (s, 2H, ArH).
100%
With thionyl chloride In dichloromethane for 3 h; Reflux
To a mixture of benzoic acid 3,4,5-trimethoxybenzoic acid (2.0 g, 9.43 mmol, 1.0 eq.) and SOCl2 (4.48 g, 37.70 mmol, 4.0 eq.) in anhydrous dichloromethane (10 mL), After refluxing for 3h, the reaction mixture was concentrated in vacuo to afford compound 2a (2.2 g, 100percent) as white solid.
90%
With thionyl chloride; sodium hydroxide In water; benzeneReflux
1) Synthesis of 3,4,5-trimethoxybenzoyl chloride. In 100 ml one necked flask equipped with reflux condenser and gas outlet tube placed in NaOH solution, 20 g (94 mmol) of 3,4,5-trimethoxybenzoic acid and 45 ml of abs. benzene are placed. Then 0.5 ml of DMFA and 10.8 ml (150 mmol) of thionyl chloride are added. After the end of gas evolution the mixture is refluxed for 2 h. The solution is cooled down to 20° C., poured into the glass with 50 ml of hexane. The precipitated white crystals of the product are filtered off. The filtrate is evaporated in vacuum up to 1/3 of the initial volume at 50° C. The second portion of the product is separated upon cooling down, it is filtered off and combined with the first one. The product is dried in vacuum at 50÷60° C. for 1 h. Yield of 3,4,5-trimethoxybenzoyl chloride-19.6 g (90percent), m. p. 77° C.
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3
[ 10026-13-8 ]
[ 118-41-2 ]
[ 4521-61-3 ]
Reference：
[1] Journal of the Chemical Society, 1906, vol. 89, p. 1655
4
[ 75-15-0 ]
[ 10026-13-8 ]
[ 118-41-2 ]
[ 4521-61-3 ]
Reference：
[1] Chemische Berichte, 1906, vol. 39, p. 4023
5
[ 10026-13-8 ]
[ 118-41-2 ]
[ 71-43-2 ]
[ 4521-61-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1905, vol. 340, p. 230
6
[ 118-41-2 ]
[ 24313-88-0 ]
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[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 40 - 42[4] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 1, p. 46 - 48
[5] Justus Liebigs Annalen der Chemie, 1905, vol. 340, p. 230
[6] Chemische Berichte, 1959, vol. 92, p. 862,866
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[8] Organic Preparations and Procedures International, 2013, vol. 45, # 4, p. 321 - 324
[9] PLoS ONE, 2015, vol. 10, # 6,
[10] Patent: WO2012/92880, 2012, A1,
7
[ 124012-42-6 ]
[ 3086-62-2 ]
[ 66335-38-4 ]
[ 118-41-2 ]
[ 69260-71-5 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 9, p. 2568 - 2571
3,4,5-trimethoxybenzoic acid (c-1)
To a stirred solution of methyl 3,4,5-trimethoxybenzoate(22.6 g, 0.1 mol) in 100mL of ethanol, a solution of 0.8mol/LNaOH (250mL) was added dropwise at room temperature.The reaction mixture was stirred at 50 °C for 2 h. Aftercooling to room temperature, the reaction mixture was carefullyacidified to pH 2~3 by adding concentrated hydrochloricacid under an ice-water bath. The precipitate was collected byfiltration, washed quickly with cold EtOH-H2O (3: 2), anddried at room temperature under high vacuum to give an3,4,5-trimethoxybenzoic acid c-1 (21.2 g, 100%).
100%
With sodium hydroxide In ethanol at 50℃; for 2h;
3,4,5-trimethoxybenzoic acid (c-1)
To a stirred solution of methyl 3,4,5-trimethoxybenzoate(22.6 g, 0.1 mol) in 100mL of ethanol, a solution of 0.8mol/LNaOH (250mL) was added dropwise at room temperature.The reaction mixture was stirred at 50 °C for 2 h. Aftercooling to room temperature, the reaction mixture was carefullyacidified to pH 2~3 by adding concentrated hydrochloricacid under an ice-water bath. The precipitate was collected byfiltration, washed quickly with cold EtOH-H2O (3: 2), anddried at room temperature under high vacuum to give an3,4,5-trimethoxybenzoic acid c-1 (21.2 g, 100%).
95%
Stage #1: 3,4,5-trimethoxybenzoic acid methyl ester With potassium hydroxide In ethanol; water monomer for 3h; Reflux;
Stage #2: With sulfuric acid In water monomer
95.6%
With potassium hydroxide In ethanol for 48h; Reflux;
2.2 4.2.2 Synthesis of 3,4,5-trimethoxybenzoic acid (4) 11
To a solution of 3 (3.59 g, 15.9 mmol) in ethanol (120 ml) was added KOH (10.5 g, 0.187 mol) and refluxed for 48 h. After concentration, the residue was extracted with chloroform and water. To the aqueous layer was added 1 M HCl aq and the precipitate was extracted with chloroform. After drying the organic layer over anhyd Na2SO4 and concentration, the yellow residue was purified by column chromatography (silica gel, chloroform) to obtain 4 (3.22 g, 15.2 mmol, 95.6%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 2H), 3.94 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.71, 152.93, 142.85, 124.03, 107.28, 60.97, 56.21. IR (KBr) cm-1: 2946.7, 2646.82, 1685.48, 1588.09, 1506.13, 1466.60, 1417.42, 1326.79, 1269.90, 1225.54, 1183.11, 1126.22, 1000.87, 939.16, 858.17, 761.74, 716.43, 548.65, 501.40, 459.94, 428.12. Mp 100-102 °C (lit. 100-101 °C) (lit. 99-101.5 °C). 11
95.6%
With potassium hydroxide In ethanol for 48h; Reflux;
2.2 Synthesis of 3,4,5-trimethoxybenzoic acid methyl ester (3)
4.2.2 Synthesis of 3,4,5-trimethoxybenzoic acid (4) 11 To a solution of 3 (3.59 g, 15.9 mmol) in ethanol (120 ml) was added KOH (10.5 g, 0.187 mol) and refluxed for 48 h. After concentration, the residue was extracted with chloroform and water. To the aqueous layer was added 1 M HCl aq and the precipitate was extracted with chloroform. After drying the organic layer over anhyd Na2SO4 and concentration, the yellow residue was purified by column chromatography (silica gel, chloroform) to obtain 4 (3.22 g, 15.2 mmol, 95.6%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 2H), 3.94 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 171.71, 152.93, 142.85, 124.03, 107.28, 60.97, 56.21. IR (KBr) cm-1: 2946.7, 2646.82, 1685.48, 1588.09, 1506.13, 1466.60, 1417.42, 1326.79, 1269.90, 1225.54, 1183.11, 1126.22, 1000.87, 939.16, 858.17, 761.74, 716.43, 548.65, 501.40, 459.94, 428.12. Mp 100-102 °C (lit. 100-101 °C) (lit. 99-101.5 °C). 11
91%
With lithium hydroxyde monohydrate In tetrahydrofuran; methanol at 20℃;
Hidrolysis reaction
General procedure: A solution of each methylation product and LiOH monohydrate 0.5 M in mixture THF:Methanol (3:1) were stirred at room temperature for 24 hours. The reaction mixture was then acidified using KHSO4 1M until pH-3, then added 15 mL of aquadest, and extracted with 3x15 ml ethyl acetate. The organic phase was washed with saturated NaCl and then added Mg2SO4 anhydrate to take out the water residue. The filtrate was then drying to obtain the product and give 3 products: 4-monomethoxygallic acid, 4,5-dimethoxygallicacid, 3,4,5-trimethoxygallic acid, respectively.
85%
With lithium hydroxyde monohydrate; water monomer In tetrahydrofuran; methanol at 20℃; for 24h;
General procedure of hydrolysis of methylated product
General procedure: A solution of methylated product and LiOH monohydrate 0.5 M in mixture THF:Methanol (3:1) were stirred at room temperature for 24 hours. The reaction mixture was then acidified using KHSO4 1M until pH=3, subsequently, 15 mL of aquadest was added, and extracted with 3x15 mL ethylacetate. This phase was washed with saturated NaCl and dried over anhydrous MgSO4. The filtrate was concentrated, resulting in a crude extract containing a mixture of 4-monomethoxy-gallic acid, 3,4-dimethoxygallic acid, 3,4,5-trimethoxygallic acid. Furthermore, the mixture is purified by silica gel chromatography column. Pure compounds were analyzed by Thin Layer Chromatography, Nuclear Magnetic Resonance Spectrometer, and High Resolution Mass Spectrometer
81%
With lithium hydroxide monohydrate In methanol for 2h; Reflux;
47.6%
With water monomer; sodium hydroxide In tetrahydrofuran Cooling with ice;
1 Example 1 Preparation of reaction intermediates
The obtained in step 1) of 12g 2,3,4-trimethyl ether gallate was dissolved in 100ml of tetrahydrofuran: water = 4: 1) solution was slowly added sodium hydroxide under ice bath, stirring. After the completion of the reaction of the raw material of the point plate, the mixture was neutralized with 4N hydrochloric acid, the pH was adjusted to be weakly acidic, the mixture was separated, the aqueous phase was extracted three times with 40 ml of ethyl acetate, the combined organic phases were washed, dry with anhydrous sodium sulfate. The organic phase was concentrated by rotary evaporator to give 10.1 g (yield: 47.6%) of 2,3,4-trimethyl ether gallic acid solid. 2,3,4-trimethyl ether gallic acid was used as a starting material for the next reaction. The reaction is as follows:
With potassium carbonate
With sodium hydroxide In various solvent(s) for 0.25h;
With potassium hydroxide In ethanol for 2.5h; Heating; Yield given;
With potassium hydroxide
With potassium hydroxide In ethanol for 4h; Heating;
With potassium hydroxide In ethanol Heating;
1.74 g
With lithium hydroxide In methanol; water monomer at 20℃; for 2h;
4.01 g
With potassium hydroxide In ethanol for 12h; Heating;
With sodium hydroxide at 20℃; for 8h;
52 g
With water monomer; sodium hydroxide for 2h; Reflux;
Preparation of 3,4,5-trimethoxybenzoic acid (8)
To a cold solution of sodium hydroxide (80 g, 2 mol) in water (500 mL) was added gallic acid monohydrate (50.005 g, 0.266 mol) in a stoppered flask while stirring in cold water bath till clear solution was obtained. Dimethyl sulfate (178 g, 134 mL, 1.411 mol) was then added intwo equal portions during 20 min. After that, the reaction mixture was refluxed for 2 h, then cooled and a solution of sodium hydroxide (20 g in30 mL water) was then added to hydrolyze any produced ester. Then, reflux was continued for additional 2 h. Finally, the reaction mixture wascooled and acidified with dilute HCl (6 M) to afford a white precipitate of the acid 8. After suction filtration, the product was sufficiently purefor many purposes. (Yield: 52 g, 92%), m.p. 165-167°C (reported [1] 167-169°C). Recrystallization from boiling water afforded needle crystals:IR; 1681 cm-1 (C=O).
With sodium hydroxide In water monomer Sealed tube; Reflux;
80%
In sodium hydroxide; chloroform Ambient temperature;
78%
With N,N,N-tributyl-1-butanaminium iodide; potassium carbonate for 12h; Reflux;
2 Example 2 General Procedure for Obtaining 3,4,5-Trimethoxyphenyl-Hydrazide Used to Obtain 3,4,5-Trimethoxyphenyl-Hydrazones 01-29
Example 2 General Procedure for Obtaining 3,4,5-Trimethoxyphenyl-Hydrazide Used to Obtain 3,4,5-Trimethoxyphenyl-Hydrazones 01-29 [0094] For the synthesis of 3,4,5-trimethoxyphenyl-hydrazide used in the preparation of acyl-hydrazones 01-29, we used the methodology already described (Chida, A. S.; Vani, P. V. S. N.; Chandrasekharam, M.; Srinivasan, R.; Singh, A. K. Synthesis of 2,3-dimethoxy-5-methyl-1,4-benzoquinone: a key fragment in coenzyme-Q series. Synthetic communications, 31, 657-660, 2001), carried out in two steps: [0095] Obtaining Ester: [0096] In a 1000 mL/1 mouth reaction flask, gallic acid (50 g, 0.294 mol) was placed with dimethyl sulfate (178.1 g, 1.413 mol), anhydrous potassium carbonate (175.5 g, 1.293 mol) and TBAI (tetrabutylammonium iodide) (1 g) in an organic solvent which may be ethanol, ethyl ether, ethyl acetate, acetone, petroleum ether (375 ml) and refluxed for 1 to 12 hours. The solid obtained was filtered and washed with the same organic solvent (3×50 mL). The ester was obtained in the form of a cream-colored amorphous solid, with a 78% yield; mp: 84° C. (lit. mp 82-83° C.). NMR 1H (CDCl3): 1.60 (s, 3H, CH3), 3.92 (s, 9H, OCH3), 7.33 (s, 2H, Ar). [0097] Obtaining Hydrazide: [0098] In a 1000 mL/1 mouth reaction flask, the ester obtained in the first step was placed (48 g, 0.212 mol), with a solution of 99% hydrazine hydrate (N2H4.H2O) (77.6 g, 1.54 mol) and an organic solvent which may be ethanol, ethyl acetate, dichloromethane, acetone, methanol (200 mL). The mixture was refluxed for 1 to 5 h and maintained overnight under magnetic stirring only at a temperature between 0 and 50° C. The solid obtained was filtered and recrystallized in methanol to obtain the 3,4,5-trimethoxyphenyl-hydrazide as white crystals with a yield of 85%; mp: 162-163° C. (lit. mp 168° C.). NMR 1H (CDCl3): 3.80 (s, 3H, OCH3), 3.90 (s, 6H, OCH3), 7.18 (s, 2H, Ar), 9.55 (NH).
76%
With potassium hydroxide for 3h; Heating;
74%
With sodium hydroxide In water monomer at 20℃; for 10.16h; Cooling;
3, 4, 5-Trimethoxybenzoic acid 2
Dimethyl sulphate (1.94 g, 17.6 mmol)was added slowly over a period of 10 min to acooled solution of compound 1 (1 g, 5.88 mmol)in 10% NaOH sol (20 mL ) maintained at 10-15oC.The reaction mixture was allowed to attain roomtemperature and stirred for 10 h. The completionof the reaction was checked by TLC followed byacidifcation by 6N HCl (25 mL) and then fltered toobtain compound 2. Brown solid; Yield: 74%; M.p.:80-82°C; 1H NMR (400 MHz, DMSO-d6): d 3.72 (s,3H), 3.85 (s, 6H), 7.23 (s, 1H), 12.90 (brs, 1H).
65%
With sodium hydroxide Heating;
65%
With sodium hydroxide at 20℃; Reflux;
65%
With sodium hydroxide at 20 - 90℃; for 3.33h;
62%
With potassium hydroxide for 3.5h;
62%
With potassium hydroxide In water monomer for 3h; Heating;
With sodium hydroxide anschliessendes Erwaermen mit wss. Natronlauge;
With methanol; potassium hydroxide
With sodium hydroxide
With sodium hydroxide; water monomer Verseifung des entstandenen Esters durch Kochen unter Zusatz von NaOH;
With sodium hydroxide
With sodium hydroxide
Stage #1: 3,4,5-trihydroxybenzoic acid; dimethyl sulfate With sodium hydroxide
Stage #2: With hydrogenchloride In water monomer
Stage #1: 3,4,5-trihydroxybenzoic acid; dimethyl sulfate With sodium hydroxide
Stage #2: With hydrogenchloride
Alkaline aq. solution;
8.7 g
With sodium hydroxide for 3.66h; Inert atmosphere; Reflux;
1 Example 1 preparation of 3,4,5-trimethoxybenzoic acid
8.5 g, 50 mmol of raw gallic acid and 100 mL of water were added to a 250 mL four-necked flask with a condenser reflux tubeAfter stirring under nitrogen, 4.8 g of 120 mmol of sodium hydroxide and 15.0 g of 120 mmol of dimethyl sulfate were added. After 10 minutes, 15.0 g of 120 mmol of dimethyl sulfate were added again and the temperature of the feed was below 35 ° C. , Dimethyl sulfate was added and stirred for 0.5 hours. Then add 4.8g, 120mmol sodium hydroxide, refluxed for 3 hours. After the reaction solution was cooled to room temperature, it was acidified with concentrated hydrochloric acid to pH = 2 and suction filtered to obtain a white solid.Recrystallized from water,Drying afforded 8.7 g of colorless needles, 3.4.5-trimethoxybenzoic acid (ie M-1-1 in the reaction scheme of Examples 2-6)
9.1 g
Stage #1: 3,4,5-trihydroxybenzoic acid With sodium hydroxide In water monomer at 25 - 40℃; for 0.333333h; Reflux; Inert atmosphere;
Stage #2: dimethyl sulfate With sodium hydroxide In water monomer at 40℃; for 3h; Reflux; Inert atmosphere;
3, 4, 5-trimethoxybenzoic acid (1)
When equipped with a reflux condenser, thermometer and constant pressure funnel of 250 mL reaction bottle, adding 10 g (0.053 mol) Gallic acid and 40 mL water, stirred under nitrogen protection and the temperature controlled at 25-40 in ice bath. After dropped NaOH solution (80 g (2 mol) NaOH + 300 mL water solution ), keep stirred for 20 min. Later, controlled the temperature below 40 , dropped 36 g (0.285 mol) dimethyl sulfate, then added the mixture of 5 g (0.125 mol) NaOH solution and 8 mL water, refluxed for 3 h. TLC tracking to no raw material points, natural cooling, and the reaction liquid pH value was adjusted to about 7 with concentrated HCl, then filtered, washed and dried respectively to give 3, 4, 5-trimethoxybenzoic acid (1), grey solid, 9.1 g. Yield: 81.5%, m.p.159-161 (literature value: 160-162 ).
With sodium hydroxide In water monomer at 0 - 100℃;
2 4.2 Methyl 3,4,5-trimethoxybenzoate (2)
Concentrated sulfuric acid (10 mL) was added dropwise at ambient temperature to a stirring solution of compound 1 (10.0 g, 47.2 mmol) in CH3OH (100 mL), then refluxed at 65 °C for 24 h and monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, ethyl acetate (100 mL) was then added, and the pH was adjusted to 7.0 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the remaining water phase was extracted with ethyl acetate (80 mL) two times. The combined organic layer was washed with saturated brines and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give compound 2 without further purification. Yield 100%, 10.8 g. White solid, mp 76-77 °C, literature 82-83 °C [39]. 1H NMR (400 MHz, Chloroform-d) δ 7.23 (s, 2H), 3.84 (s, 12H). 13C NMR (101 MHz, Chloroform-d) δ 166.7, 152.9, 142.2, 125.1, 106.8, 60.9, 56.2, 52.2. HRMS (ESI) calcd for C11H14O5 [M+Na]+ 249.0739, found 249.0734.
100%
at 65℃; for 24h; Acidic conditions;
Methyl 3,4,5-trimethoxybenzoate (2)
Measure 10 mL of concentrated hydrochloric acid and add dropwise to Compound 1 at room temperature.This is a solution of 3,4,5-trimethoxybenzoic acid (1.00 g, 47.2 mmol) in methanol (100 mL).After refluxing at 65 ° C for 24 h, TLC was detected and the reaction was completed. After cooling to room temperature,Concentrated, add 100 mL of ethyl acetate, and adjust the pH to 7 with a saturated aqueous solution of sodium bicarbonate.After liquid separation, the organic phase was separated and the remaining aqueous phase was extracted twice with ethyl acetate.The organic phase was combined, washed with saturated brine and dried over anhydrous sodium sulfate.Filtration and concentration gave Compound 2. 10.8g, the yield is 100%, melting point 76-77 °C.
97%
With sulfuric acid Reflux;
95%
With sulfuric acid for 8h; Reflux;
94%
With thionyl chloride at 0 - 20℃; for 0.166667h;
6
Take a dry 50mL pear-shaped flask, accurately weighed 3.4.5 - trimethoxybenzoic acid M-1-1 (1.06g, 5mmol)Was added to 15mL methanol as a reaction solvent to dissolve, cooled to 0 ° C,Thionyl chloride (2.08 g, 17.5 mmol) was slowly added dropwise,After the addition was completed, the reaction was stirred at the same temperature for 10 minutes, then slowly warmed to room temperature until the reaction was completed. The reaction was monitored by TLC. After the reaction was completed, the residue was purified by column chromatography (methylene chloride) to give M-5-1 as a white solid, which was weighed and calculated to give a white solid weighing 1.06 g in a yield of 94%
93%
With sulfuric acid for 24h; Reflux; Inert atmosphere;
Methyl 3,4,5-trimethoxybenzoate 16
To a solution of 3,4,5-trimethoxybenzoic acid (1.0 g) in methanol (20 mL) was added sulfuric acid (4 drops) and the solution was heated to reflux for 24 h. The mixture was then cooled, filtered through silica and concentrated in vacuo to afford the title compound 16 (1.0 g, 93%) as a white solid.
92%
With sulfuric acid for 5h; Heating;
92%
With sulfuric acid Reflux;
1.1.1. Synthesis of methyl 3,4,5-trimethoxybenzoate (Scheme 1)
To a solution of 3,4,5-trimethoxybenzoic acid (10.3 g, 48.4 mmol) in methanol (30 mL, 1 mol), concentrated H2SO4 (2.5 mL, 46.9 mmol) was added dropwise and stirred overnight at 65 °C under reflux. Progress of the reaction was monitored using TLC (AcOEt/Hex 1:4 as mobile phase) at regular intervals. After the completion of reaction, the solvent was evaporated. Crude product was dissolved in ethyl acetate and extracted twice with NaHCO3 (saturated solution). The combined organic phases were dried over MgSO4, and the solvent was evaporated to give the product with 92% yield. White, solid.
90%
With sulfuric acid for 4h; Reflux;
89%
With sulfuric acid
87%
With thionyl chloride for 3h; Reflux;
83%
With sulfuric acid
83%
With sulfuric acid for 6h; Reflux;
General procedure for the preparation of methyl esters(17a-j)
A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a-j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a-j).Methyl 3,4,5-trimethoxybenzoate (17a) White solid;Yield: 83 %; mp 85-87 °C; 1H NMR (CDCl3, 400 MHz):δ 7.31 (2H, s, H-2, H-6), 3.92 (6H, s, O-CH3), 3.84 (3H, s,O-CH3) 3.82 (3H, s, O-CH3); 13C NMR (CDCl3,100 MHz): δ 166.7 (C=O), 152.9 (C, C-3, C-5), 142.2 (C,C-4), 125.1 (C, C-1), 106.8 (CH, C-2, C-6), 60.9 (O-CH3), 58.2 (O-CH3), 52.2 (O-CH3); for C11H14O5 MS(ESI) (m/z) 227 [M + H]+.
80%
With sulfuric acid for 8h; Reflux;
With sulfuric acid
With hydrogenchloride
With hydrogenchloride
With boron trifluoride for 3h; Heating; Yield given;
With sulfuric acid
With sulfuric acid
With sulfuric acid for 6h; Reflux;
With sulfuric acid Reflux;
With thionyl chloride for 1h; Reflux;
With sulfuric acid at 20℃; for 8.5h; Reflux;
5.1.2 Methyl-3,4,5-trimethoxybenzoate (2)
3,4,5-trimethoxybenzoic acid (10g, 47mmol) was dissolved in 30mL methanol. When complete solution was obtained, 2.5mL concentrated sulphuric acid was incrementally added over 30min at room temperature. (0018) Then the reaction mixture was heated under reflux for 8h maintaining anhydrous conditions by use of a CaCl2 drying tube attached to the condenser. After cooled to room temperature, the resulting white needle crystal was filtered and used in the next step without further disposal, yield 93.5%; mp 75-76°C. 1H NMR (400MHz, DMSO-d6) δ: 7.14 (s, 2H, PhH), 3.90-3.85 (t, 9H, 3OCH3), 3.83 (s, 3H, COOCH3). 13C NMR (DMSO-d6) δ: 165.92, 153.11, 153.07, 143.52, 126.43, 106.42, 106.21, 60.87, 56.92, 56.23, 51.55. TOF MS (EI+): C11H14O5, calcd for 226.0357, found 226.0355.
With sulfuryl dichloride Reflux;
With sulfuric acid at 70℃;
With sulfuric acid Reflux;
With glycerol-based sulfonic acid functionalized carbon catalyst for 6h; Reflux; Green chemistry;
General Procedure for the Synthesis of Methyl Esters (2a-t)
General procedure: To a stirred solution of substituted aryl carboxylic acid 1 (0.15 mol) in methanol (0.75 mol) glycerol-based solid acid catalyst (28 wt% of aryl carboxylic acid) was added and heated to reflux for 6 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature. The catalyst was separated by filtration and was washed with methanol for recycle. Methanol was then distilled off under reduced pressure to get the pure methyl ester 2.
With sulfuric acid In water monomer at 70℃; for 0.45h; Microwave irradiation;
22.62 g
With sulfuric acid In water monomer for 12h; Reflux;
Stage #1: methanol; Eudesmic acid at 0℃; for 0.166667h;
Stage #2: With thionyl chloride for 6h; Reflux;
Step 1. General Procedure for Preparation of the Methyl Benzoates
General procedure: A mixture of benzoic acids (20.0 mmol), CH3OH (30.0 mL) were placed in a 100mL round-bottomed flask equipped with a magnetic stirrer. Stirring for 10 minutes in 0 °C. Then thionyl chloride (1.5 eq.) was addedto the flask. The mixture was stirred under reflux 6h. The progress wasmonitored by TLC. After the reaction, the reaction system wereconcentrated to remove CH3OH and most of thionylchloride. Aftercooling, the H2O (50 mL) and EtOAc (30 mL) were added into thecontents. The aqueous phase was extracted with EtOAc (30 mL×3), andthe organic phase was washed with saturated aqueous NaHCO3 solutionand brine. Then it was dried over anhydrous Na2SO4, filtered, and concentrated to give the ester as a faint yellow solid (liquid). The step yield was 80%~95%.
18.6 g
With sulfuric acid In neat (no solvent) for 5h; Reflux;
Methyl 3, 4, 5-trimethoxybenzoate (2)
25 g (0.118 mol) 3, 4, 5-trimethoxybenzoic acid (1) and 125 mL anhydrous methanol were added in 250 mL three mouth flask, then added 8 mL concentrated sulfuric acid slowly under stirring, after the drop, heat to reflux for 8 h, TLC tracking to no raw material points, natural cooling, a large number of solid precipitated, added 50 mL water, filtrated, washed and dried to give methyl 3, 4, 5-trimethoxybenzoate (2), white solid, 18.6 g. Yield: 69.7 %, m.p.75-76 (literature value: 82-84 ).
With sulfuric acid Reflux;
With sulfuric acid
at 20℃; for 20h; Acidic conditions;
With sulfuric acid at 0 - 80℃; for 6h;
General synthetic procedure for the synthesis of 5-phenyl-1,3,4-oxadiazole-2-thiol 4a-e
General procedure: To a solution of substituted benzoic acid (1 mmol) in methanol H2SO4 (2 mmol) was added drop-wise at 0 oC. The mixture was heated at 80 for 6 h. Upon completion, the reaction mixture was cooled to ambient temperature and the solvent was removed in vacuum. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and water, then the organic layer was dried to give the methyl ester of benzoic acid 2
With HNO3; glacial acetic acid at 0 - 20℃; for 12h;
4.11. Methyl (trans)-2-(3-hydroxy-4-methoxyphenyl)-4-oxo-1-(3,4,5-trimethoxyphenyl) azetidine-3-carboxylate (14)
400 mL of acetic acid and 160 mL of concentrated nitric acidwere added into 1 L three-mouth flask. After cooling in an ice bath,3, 4, 5-trimethoxybenzoic acid (11) (100 g, 0.47 mol) was added inbatches, and the reaction was raised to room temperature for 12 h.Pour the reaction solution into 1 L of water, filter, wash with waterto afford 12 as white solid (80 g, yield 80%).Mixture of 12 (30 g, 0.14 mol), isovanillin (21 g, 0.14 mol) andzinc powder (9.80 g, 0.15 mol) in methanol (30 mL) was stirred at0 C under N2 atmosphere for 30 min. Acetic acid was slowly added,the reaction was stirred at 0 C for 2 h, and then the reaction wascooled to room temperature for another 16 h. After the reactionwascomplete, the solution was filtered, and the solvent was removedby vacuum evaporation. Recrystallization from ethanol to obtainproduct 13 (15 g, yield 32%).Methyl propiolate (1.07 mL, 12 mmol) and Et3N (1.67 mL,12 mmol) dissolved in dry DMF (30 mL) under N2 atmosphere wasstirred for 15 min at 0 C. CuI (2.28 g, 12 mmol) was added to thesolution and stirred for 30 min at 0 C. Then compound 13 (4 g,12 mmol) was added to the mixture and gradually rise to roomtemperature, stirred for overnight. After the reaction completion,water (50 mL) was added into the solution, and the mixture wasextracted with EtOAc (20 mL 3). The organic layer was washedwith brine, dried over anhydrous Na2SO4, and filtered. The solventwas removed under reduced pressure and then purified by silicacolumn chromatography (CH2Cl2/MeOH 100:1, v/v) to generateracemic compound 14 as solid (2.50 g, yield 49%). 1H NMR(600 MHz, DMSO-d6) d 9.13 (s, 1H), 6.97 (dd, J 8.4, 1.8 Hz, 1H), 6.93(d, J 8.4 Hz, 1H), 6.90 (s, 1H), 6.57 (s, 2H), 5.32 (d, J 2.4 Hz, 1H),4.24 (d, J 2.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.66 (s, 6H), 3.58 (s,3H). 13C NMR (151 MHz, DMSO-d6) d 166.75, 159.03, 152.97, 148.01,146.70, 133.95, 132.61, 128.25, 118.17, 113.34, 112.03, 94.75, 61.69,59.92, 56.77, 55.60, 55.42, 52.41.
80%
With HNO3; glacial acetic acid at 0 - 20℃; for 12h;
4.11. Methyl (trans)-2-(3-hydroxy-4-methoxyphenyl)-4-oxo-1-(3,4,5-trimethoxyphenyl) azetidine-3-carboxylate (14)
400 mL of acetic acid and 160 mL of concentrated nitric acidwere added into 1 L three-mouth flask. After cooling in an ice bath,3, 4, 5-trimethoxybenzoic acid (11) (100 g, 0.47 mol) was added inbatches, and the reaction was raised to room temperature for 12 h.Pour the reaction solution into 1 L of water, filter, wash with waterto afford 12 as white solid (80 g, yield 80%).Mixture of 12 (30 g, 0.14 mol), isovanillin (21 g, 0.14 mol) andzinc powder (9.80 g, 0.15 mol) in methanol (30 mL) was stirred at0 C under N2 atmosphere for 30 min. Acetic acid was slowly added,the reaction was stirred at 0 C for 2 h, and then the reaction wascooled to room temperature for another 16 h. After the reactionwascomplete, the solution was filtered, and the solvent was removedby vacuum evaporation. Recrystallization from ethanol to obtainproduct 13 (15 g, yield 32%).Methyl propiolate (1.07 mL, 12 mmol) and Et3N (1.67 mL,12 mmol) dissolved in dry DMF (30 mL) under N2 atmosphere wasstirred for 15 min at 0 C. CuI (2.28 g, 12 mmol) was added to thesolution and stirred for 30 min at 0 C. Then compound 13 (4 g,12 mmol) was added to the mixture and gradually rise to roomtemperature, stirred for overnight. After the reaction completion,water (50 mL) was added into the solution, and the mixture wasextracted with EtOAc (20 mL 3). The organic layer was washedwith brine, dried over anhydrous Na2SO4, and filtered. The solventwas removed under reduced pressure and then purified by silicacolumn chromatography (CH2Cl2/MeOH 100:1, v/v) to generateracemic compound 14 as solid (2.50 g, yield 49%). 1H NMR(600 MHz, DMSO-d6) d 9.13 (s, 1H), 6.97 (dd, J 8.4, 1.8 Hz, 1H), 6.93(d, J 8.4 Hz, 1H), 6.90 (s, 1H), 6.57 (s, 2H), 5.32 (d, J 2.4 Hz, 1H),4.24 (d, J 2.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.66 (s, 6H), 3.58 (s,3H). 13C NMR (151 MHz, DMSO-d6) d 166.75, 159.03, 152.97, 148.01,146.70, 133.95, 132.61, 128.25, 118.17, 113.34, 112.03, 94.75, 61.69,59.92, 56.77, 55.60, 55.42, 52.41.
78%
With 2,2'-azobisisobutyronitrile; HNO3 In acetonitrile at 50℃; for 21h;
78%
With 1,3-disulfonic acid imidazolium nitrate In neat (no solvent) at 50℃; for 0.283333h; Inert atmosphere;
69%
With HNO3; glacial acetic acid at 10 - 20℃;
69%
With HNO3; glacial acetic acid at 0 - 25℃; for 6.5h;
1,2,3-Trimethoxy-5-nitrobenzene (6)
To a solution of HNO3 (20.0 mL) and AcOH (40.0 mL), 3,4,5-trimethoxy-benzoic acid 5 (10.0 g, 47.0 mmol) was added as portions below 0°C for 30 minutes. The mixture was stirred at 25°C for 6 h. The reaction mixture was then poured into ice-water (300 mL). The resulting precipitate was collected by filtration and washed with H2O, which was then recrystallized from EtOH to afford 6 (6.9 g, 69%) as colourless crystals, Mp 96-99 °C; 1H NMR (300 MHz, CDCl3) d 3.92 (s, 9H, OMe), 7.49 (s, 2H, ArH). 13C NMR (75 MHz, CDCl3) d 56.41, 61.06, 101.22, 143.65, 152.79.
69%
With 2,2'-azobisisobutyronitrile; HNO3 In acetonitrile at 23 - 50℃; for 16h; Inert atmosphere;
68.1%
With HNO3; glacial acetic acid at 0 - 40℃; for 4h;
7 Example 7 Organic Synthesis of · Compound 31bb
3,4,5-Trimethoxybenzoic acid (Compound 18) (20.00 g, 94.3 mmol, 1 equiv) was added to a mixed liquid of nitric acid (100 mL) and acetic acid (200 mL) at 0°C. Warm to 40°C and stir for 4h. The reaction solution was poured into ice water (500 mL), a white solid precipitated, and the solid was collected by filtration to obtain compound 19 (13.6 g, yield 68.1%, dark red solid); the structure of compound 19 was characterized as follows:
68.1%
With HNO3; glacial acetic acid at 40℃; for 4h;
5.8 1,2,3-trimethoxy-5-nitrobenzene (7)
6 (20.00 g, 94.3 mmol, 1 equiv) was added into the mixture of HNO3/AcOH (1:1, 400 mL) over 20 min, and stirred for 4 h at 40 . Water (500mL) was added to precipitate a solid product which was washed well with water. The solid was collected, washed with water until the washings were colorless and dried in air, giving product 7 (13.6 g, red solid, 68.1%). 1H NMR (400 MHz, CDCl3, δ ppm): 7.52 (s, 2H), 3.948 (s, 3H), 3.944 (s, 6H). 13C NMR (100 MHz, CDCl3, δ ppm): 152.60, 143.50,143.15, 101.07, 60.86, 56.21.
66.1%
With HNO3; glacial acetic acid at 10 - 20℃; for 0.5h;
B9.A
3,4.5-trimethoxYanilline ethoxy-5-nitrobenzene To a solution of nitric acid (20,0 mL) and acetic acid (40.0 mL) under 10 °C was added 3,4,5-trimethoxybenzoic acid (10.0 g, 47.0 mmol) in portions. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into ice-water. The resulting precipitate was collected by filtration and washed with water, which was then recrystailized from ethanol to afford the product 1 ,2,3-trimethoxy-5-nitrobenzene (6.64 g, yield 66.1 %). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (s, 2H), 3.87 (s, 6H), 3.77 (s, 3H).
66%
With HNO3; glacial acetic acid at 40℃; for 2.16667h;
1,2,3-Trimethoxy-5-nitrobenzene (10)
A flask immersed in a room temperature oil bath was charged with 9 (50 g, 0.235 mol) and acetic acid (150 mL) and heated to 40°C. Over a 10 min period, HNO3 (70%, 33 mL) was added dropwise with stirring. The deep orange solution was stirred for an additional 120 min. The reaction was quenched upon addition of 200 g of ice. A yellow precipitate formed, which was filtered and washed with H2O. The crude product was recrystallized from methanol to give pure 10. Yield: 66%.
With hydrogen bromide; acetic acid; at 40℃; for 36h;
- Syringic acid preparation method, in 10ml of the reaction tube by adding 3,4,5 - trimethoxybenzoic acid lmmol,After completion of the addition, 33 ml of a hydrogen bromide acetic acid solution (0.35 ml) was added thereto,To this, 0. 5 ml of glacial acetic acid was added, and a stir bar (agitated magnet) was added thereto, followed by capping the lid to prevent the solutionReaction time to emerge; and then at a temperature of 40 C environment,After 36 h of reaction, the reaction mixture was poured into a separatory funnel, 20 ml of water was added, and the mixture was treated with 30 ml of dichloromethaneThe extract was extracted twice, the organic phase was obtained, and the organic phase was combined, and the organic liquid phase was washed with saturated brineIn the normal temperature environment, cleaning three times, each time the use of saturated salt water volume of 20ml, cleaning is complete,Hydrogen bromide at a molar ratio of 4: 3, and then subjected to a filtration treatment, the filtrate was subjected to distillationAnd the solvent was distilled off under reduced pressure to obtain 172 mg of syringic acid.The reverse osmosis membrane was subjected to reverse osmosis filtration treatment.The pressure at the time of vacuum distillation was reduced from atmospheric pressure to a pressure of 10 mmHg.The distillation temperature during vacuum distillation was 60 C.The removal of the solvent under reduced pressure means that the organic solvent and the dichloromethane in the filtrate are removed by distillation under reduced pressure. The yield of syringic acid obtained by the above-mentioned preparation was calculated and found: the yield of syringic acid in the process was 86.8%
75%
With zirconium(IV) chloride; methoxybenzene; In dichloromethane; at 20℃; for 72h;Sealed tube;
106 mg (0.5 mmol) of 3,4,5-trimethoxybenzoic acid,233 mg zirconium chloride(ZrCl4) (l mmol), 435 [mu] L of anisole (2 mmol) and 3 mL of CH2C12 were added10 mL reaction tube, sealed, room temperature reaction 72 h. After the reaction was stopped, the reaction was extracted with ethyl acetate,Saturated with salt water, dried over anhydrous sodium sulfate, filtered, the filtrate was distilled under reduced pressure,And purified by silica gel column chromatography to obtain 75 mg of malic acid and 75% yield.
Multi-step reaction with 2 steps
1.1: oxalyl chloride / N,N-dimethylformamide / CH2Cl2
2.1: Na
2.2: 83 percent / methanol / 5 h / 20 °C
Multi-step reaction with 3 steps
1.1: oxalyl chloride / CH2Cl2; dimethylformamide / 2 h / Heating
2.1: pyridine / CH2Cl2 / 20 h
3.1: Na2HPO4 / acetonitrile / 20 °C
3.2: 95 percent / aq. NaHCO3 / 18 h
With sulfuric acid In methanol
4 2-[4-(2-Cycloheptimidazolyl)-1-piperazinyl]-6,7,8-trimethoxy-4-quinazolamine (Ia: R3 =2-cycloheptimidazolyl; R4, R5 and R6 =H; R7, R8 and R9 =OMe; and n=1)
EXAMPLE 4 2-[4-(2-Cycloheptimidazolyl)-1-piperazinyl]-6,7,8-trimethoxy-4-quinazolamine (Ia: R3 =2-cycloheptimidazolyl; R4, R5 and R6 =H; R7, R8 and R9 =OMe; and n=1) A solution of 50 g of 3,4,5-trimethoxybenzoic acid in 500 ml dry methanol containing 4.8 ml of conc. sulfuric acid was refluxed under anhydrous condition for 18 hr and concentrated to half the volume. The solution was poured into ice water and extracted with methylene chloride. The organic extract was washed with cold 0.5 N sodium hydroxide and water, dried over sodium sulfate, evaporated and crystallized from hexane to give 3,4,5-trimethoxybenzoic acid methyl ester, mp 65°-66° C.
Multi-step reaction with 2 steps
1: thionyl chloride / 2 h / Reflux
2: methanol / 2 h / 20 °C
1.a; 4.a; 6.a a) Synthesis of compound 3:
3,4,5-trimethoxybenzoic acid 1 (10.60 g, 0.05 mol) was dissolved in 50 ml EtOH 2, then EhS04(2.85 ml, 0.05 mol) was added, the reaction solution was refluxed overnight. The reaction was monitored by TLC until the starting material disappeared, the reaction was cooled down to room temperature and the precipitate was collected and washed by cold EtOH (95%). The solid compound 3 was recrystallized from EtOH to give pure product as white solid (10.92 g, 91%). NMR (400 MHz; CDCh) d 1.26 (3H, t, J = 8), 3.91 (3H, s), 3.92 (6H, s), 4.38 (2H, q , J = 8Hz), 7.31 (2H, s); 13 C NMR (200 MHz; CDCh) d 14.4, 56.2, 60.9, 61.1, 106.7, 125.5, 141.9, 152.9, 166.2. b)
81%
With sulfuric acid
77%
With sulfuric acid for 3h; Reflux;
75%
With sulfuric acid for 8h; Reflux;
With hydrogenchloride
With sulfuric acid for 20h; Heating;
With sulfuric acid
With sulfuric acid
With sulfuric acid Reflux;
With sulfuric acid
With sulfuric acid
With sulfuric acid for 12h; Reflux;
Preparation of 3,4,5-trimethoxybenzohydrazide (I)
To a 100 mL round-bottom flask, 3,4,5-trimethoxybenzoic acid (10.6g, 50 mmol), 1 mL of concentrated sulfuric acid and 30 mL of ethanol were added gradually. The resulting mixture was stirred at reflux for 12 h and was then concentrated on a rotary evaporator. The crude product obtained was poured into 50 ml of water and extracted with ethyl acetate (30 mL×3). The combined ethyl acetate extracts were washed with water (30 mL×2), dried with anhydrous magnesium sulfate, filtered off by suction and the solvent was evaporated to give crude ethyl 3,4,5-trimethoxybenzoate, which and hydrazine hydrate (7.5 g, 150 mmol, 60%) in 50 mL of ethanol was heated under reflux for 6 h. Excess ethanol was distilled out and the contents were allowed to cool. The solid product obtained was filtered, washed thoroughly with water, and dried to give II in total yield of 83%, which was used for the next reactions without further purification.
With sulfuric acid
With sulfuric acid
With sulfuric acid for 8h; Reflux;
4.1.3 General procedure for the preparation of substituted aromatic ethyl esters (12a-g)
General procedure: A mixture of substituted benzoic acids (11a-g) (0.001M, 2.12g) and ethanol (20mL) were heated under reflux until the benzoic acid was dissolved in ethanol then few drops of concentrated H2SO4 was added to the mixture and reflux for 8h. The resulting mixture was cooled to room temperature and a saturated solution of sodium bicarbonate was added to the mixture to neutralise the benzoic acid. The precipitated product was filtered and washed with water and dried. The dried product was recrystallized with ethanol.
With sulfuric acid at 85℃;
With sulfuric acid Reflux;
With sulfuric acid for 10h; Reflux;
General procedure for the synthesis of benzohydrazides7a-k [12,13]
General procedure: A mixture of benzoic acid (6.42 mmol), catalytic quantity of conc. H2SO4 in ethanol was heated to reflux for 10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates.
With sulfuric acid at 70℃; for 3h;
With sulfuric acid for 10h; Reflux;
Experimental procedure for synthesis of benzohydrazides7a-j [34-35]
General procedure: Benzoic acids a-j(8.12 mmol) was dissolved in ethanol (15 mL) and added catalytic qty of conc.H2SO4and heated to reflux for 10 h. Ethanol was evaporated and the obtained residue was diluted with ethylacetate (25 mL). The organic layer was washed with aqueous saturated NaHCO3(3 X 15 mL) followed by water (2 X 15 mL) and brine solution (20 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates.
With sulfuric acid for 12h; Reflux;
5.1.1. General procedure for the target compounds 5~6
General procedure: To a 100 mL round-bottom flask, 3,4,5-trimethoxybenzoic acid(10.6 g, 50 mmol), 1 mL of concentrated sulfuric acid and 30 mL ofethanol were added gradually. The resulting mixture was stirred atreflux for 12 h and was then concentrated on a rotary evaporator.The crude product obtained was poured into 50 mL of water andextracted with ethyl acetate. The combined ethyl acetate extractswere washed with water, dried with anhydrous magnesium sulfatefiltered off by suction and the solvent was evaporated to give crudeethyl 3,4,5-trimethoxybenzoate, which and hydrazine hydrate(7.5 g, 150 mmol, 60%) in 50 mL of ethanol was heated under refluxfor 6 h. Excess ethanol was distilled out and the contents wereallowed to cool. The solid product obtained was filtered, washedthoroughly with water, and dried to give 3,4,5-trimethoxybenzohydrazide in total yield of 83%, which was usedfor the next reactions without further purification. A solution of3,4,5-trimethoxybenzohydrazide (3.39 g, 15 mmol) and appropriateisothiocyanatobenzenes (15 mmol) in ethanol (40 mL) washeated at reflux for 1 h, then cooled at room temperature. Thesuspensionwas filtered, and the solidwaswashed with ethanol anddried to give the intermediate hydrazinecarbothioamide as whitesolid. Then 1 N NaOH (30 mL) was added to this solid and themixture was heated at reflux for 1 h. The resulting solution wascooled at room temperature and acidified to pH 5e6 with 1 M HCl.The precipitatewas filtered,washed withwater, and dried to obtainthe title compounds as white solid.
With sulfuric acid for 10h; Reflux;
With sulfuric acid Reflux;
General method for the preparation ofethylbenzoates (11-15) and ethyl-2-phenylacetates(16-20)
General procedure: Benzoicacids (1-5, 2g, 16.40mmol) and2-phenylaceticacid (6-10, 2g, 14.69 mmol) wasdissolved in ethanol (25 mL) and then catalyticquantity of concentrated sulphuric acid was addedand reuxed for 10-12h. Ethanol was concentrated upto 80% and diluted with ethylacetate (50 mL) followedby water (25 mL). The organic layer was washedwith saturated NaHCO3solution (4 X 20 mL), waterand brine solution. The separated organic layer wasdried on sodium sulphate, fltered and concentratedto obtain the corresponding ethylbenzoates (11-15)and ethyl-2-phenylacetates (16-20) in 75-80% yield.The isolated compounds were utilized in the next stepwithout any further purifcation.
With sulfuric acid Inert atmosphere;
With sulfuric acid Reflux;
With sulfuric acid Reflux;
4.1.1 General procedure for the synthesis of substituted ethylbenzoate 2a-e [57]
General procedure: A mixture of the appropriate substituted benzoic acid 1a-e (10mmol), absolute ethanol (20mL) and concentrated sulfuric acid (2mL) was heated under reflux for 12-18h. Excess solvent was removed under reduced pressure; The residue extracted with ether (2×50mL) and washed with saturated NaHCO3 (2×20mL). The ether layer was dried over anhydrous magnesium sulphate, and the ether was evaporated under vacuum to give the ethyl ester derivatives 2a-e.
With sulfuric acid Reflux;
4.1.1. General procedure for the synthesis of substitutedethylbenzoate 2a-e
General procedure: A mixture of the appropriate substituted benzoic acid 1a-e(10 mmol), absolute ethanol (20 mL), and concentrated sulfuric acid(2 mL) was heated under reflux for 12-18 h. Excess solvent was removedunder reduced pressure. The residue was extracted with ether(2 X 50 mL) and washed with saturated NaHCO3 (2 X 20 mL). The etherlayer was dried over anhydrous magnesium sulfate, and ether wasevaporated under vacuum to produce the ethyl ester derivatives 2a-e.
With sulfuric acid at 80℃; for 7h;
General synthetic procedure for intermediates 6a-6m
General procedure: Taking 6a as an example, a mixture of benzoic acid (2.5 g,20.0 mmol), 4 mL sulfuric acid, and 50 mL ethanol was heated under reflux for 7 h (hour, h). After finishing the reaction, it was poured into water and extracted by ethylacetate, dried with anhydrous Na2SO4, and then the solventof the organic phase was evaporated under vacuum to give colorless liquid 4a. Then excess 80% N2H4·H2O and 15 mLof ethanol were added into the flask containing 4a, which was heated under reflux about 5 h. After the reaction was completed, it should be cooled into room temperature overnight and the white solid 5a was given after being filtered, washed with ethanol and dried in open air. Finally, 5a (1.4 g,8.0 mmol) was then subjected to substitution reaction with KOH (0.9 g, 15.6 mmol) and CS2(1.2 g, 15.0 mmol) togenerate intermediate 6a. At the same time, 6b-6m was synthesized by the methods described in the literature (Shi et al.2015; Du et al. 2013).
With iodine; silver trifluoroacetate In chloroform for 3h;
93%
With iodine; silver trifluoroacetate In chloroform at 65℃; for 4.5h; Inert atmosphere;
3.1. Synthesis of 2-iodo-3,4,5-trimethoxybenzoic acid
A 250 ml one-necked round bottom flask equipped with a magnetic stirring bar, a pressure-equalizing dropping funnel padded with a thin layer of glass wool, combined with a reflux condenser, and a two-way tap was charged with 1.5 g (7.07 mmol) of 3,4,5-trimetoxybenzoic acid and 1.56 g (7.07 mmol) of freshly prepared, dry silver trifluoroacetate. The reaction set-up was then evacuated repeatedly under vacuum, carefully flamed and refilled with argon, using a double-manifold system (argon/vacuum) connected to the two-way tap. After that, 1.83 g (7.20 mmol) of iodine1 and 15 ml of chloroform were placed into the dropping funnel under an argon atmosphere. The flask was then heated to 65 C2 using an oil-bath. When the temperature was stabilized, the magnetic stirrer was switched on. After several minutes started the controlled (slow) addition of iodine into the flask;3 in our case, the complete dissolution and continuous supply of iodine (iodine crystals) into the reaction flask continued over 2.0 h by refluxing the solvent. Having completed the addition of iodine, the reaction mixture was refluxed for additional 2.5 h. Then, the reaction mixture was cooled to room temperature. The precipitate of silver iodide was removed by filtration4 and washed repeatedly with 5.0 ml chloroform. The obtained filtrate was concentrated to dryness under reduced pressure. After the solvent evaporation, the residue was dried additionally for 2.0 h at 70 C to remove the excess of iodine and trifluoroacetic acid. The obtained light yellow residue was crystallized from a mixture of equal amounts (v/v) of dichloromethane and cyclohexane to afford 2-iodo-3,4,5-trimethoxybenzoic acid as colorless thin needles.5 Recrystallization was effectuated in a mixture of dichloromethane- cyclohexane-toluene (at a 1:2:1 volume ratio) at 4.0 C for several days. The reaction product was analyzed by TLC; the presence of traces of 3,4,5-trimethoxybenzoic acid was not recorded (yield = 93.0%). Melting range: 151-152 C (lit. 135-142 C [20]; 142-145 C [21]; 147-148 C [22]). The recrystallization of 2-iodo- 3,4,5-trimethoxybenzoic acid from dichloromethane and cyclohexane yielded needle-shaped crystals analytically pure and suitable for a single crystal X-ray diffraction analysis.
With hydrazine hydrate monohydrate; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at 5 - 20℃;
Method 2: Compound 2 (1 g, 4.71 mmol)was dissolved in THF (10 mL) containing DIPEA(5.65 mmol) and cooled to 5°C. To the above solution,HATU (1.79 g, 4.71 mmol) was added in fve portionsand stirred at room temperature for 4 h. Water (20mL) was added to the reaction contents and wastaken in dichloromethane (50 mL), the organic layerwas separated, washed with water (2 X 15 mL) andthen with brine solution. The dichloromethane layerwas dried over Na2SO4, fltered and concentratedunder reduced pressure to isolate compound 3. Yield:95%.
85%
With hydrazine hydrate monohydrate Reflux;
2
Obtaining Hydrazide: [0098] In a 1000 mL/1 mouth reaction flask, the ester obtained in the first step was placed (48 g, 0.212 mol), with a solution of 99% hydrazine hydrate (N2H4.H2O) (77.6 g, 1.54 mol) and an organic solvent which may be ethanol, ethyl acetate, dichloromethane, acetone, methanol (200 mL). The mixture was refluxed for 1 to 5 h and maintained overnight under magnetic stirring only at a temperature between 0 and 50° C. The solid obtained was filtered and recrystallized in methanol to obtain the 3,4,5-trimethoxyphenyl-hydrazide as white crystals with a yield of 85%; mp: 162-163° C. (lit. mp 168° C.). NMR 1H (CDCl3): 3.80 (s, 3H, OCH3), 3.90 (s, 6H, OCH3), 7.18 (s, 2H, Ar), 9.55 (NH).
Multi-step reaction with 3 steps
1.1: oxalyl chloride / N,N-dimethylformamide / CH2Cl2
2.1: Na
2.2: 83 percent / methanol / 5 h / 20 °C
3.1: 75 percent / hydrazine hydrate / ethanol / 24 h / Heating
Multi-step reaction with 2 steps
1: H2SO4
2: NH2NH2*H2O
Multi-step reaction with 2 steps
1: 83 percent / H2SO4
2: 68 percent / 35percent aq. hydrazine / Ambient temperature
Multi-step reaction with 2 steps
1: conc. H2SO4 / 20 h / Heating
2: H2NNH2*H2O / 6 h / Heating
Multi-step reaction with 2 steps
1: thionyl chloride / 3 h / Reflux
2: hydrazine hydrate monohydrate / methanol / 6 h / Reflux
Multi-step reaction with 2 steps
1: sulfuric acid / 4 h / Reflux
2: hydrazine monohydrate / ethanol / 8 h / Reflux
Stage #1: Eudesmic acid at 210℃; for 2h;
Stage #2: With sulfuric acid In methanol Reflux;
Stage #3: With hydrazine hydrate monohydrate In ethanol Reflux;
220.7 mg
With CuO/Cr2O3; hydrazine hydrate monohydrate at 98 - 100℃;
3 Example 3
212 g of 3,4,5-trimethoxybenzoic acid, 320 g of hydrazine hydrate having a content of 99%, and 42 g of CuO/Cr 2 O 3 composite catalyst were placed in a stirring, thermometer,In the four-necked flask of the rectification column, the stirring is started, and the heating is heated to reflux. When the steam enters the rectification column, water vapor is collected at the column top temperature of 98 ° C to 100 ° C, and reacted at the reflux temperature for 4 to 6 hours. The reaction is terminated after the condensate is discharged from the top of the column.The hydrazine hydrate remaining in the flask was distilled off by vacuum distillation, and the hydrazine hydrate was completely distilled off, and then the solid substance in the flask was sufficiently dissolved by adding an appropriate amount of pure water, and then the solution was poured out, and the CuO/Cr2O3 composite catalyst was recovered by suction filtration, and the filtrate was filtrated. Transfer to a distillation flask, evaporate and concentrate under reduced pressure, and remove water to obtain crude 3,4,5-trimethoxybenzoyl hydrazide.After washing with absolute ethanol and drying, 220.7 g of a 3,4,5-trimethoxybenzohydrazide product was obtained.
With hydrazine monohydrate at 98 - 100℃; Molecular sieve;
3
212 g of 3,4,5-trimethoxybenzoic acid, 324 g of hydrazine hydrate having a content of 98%, and 42 g of ZSM-5 acid zeolite molecular sieve were placed with stirring,In the four-necked flask of the thermometer and the rectification column, the stirring is started, and the heating is heated to reflux, and when the steam enters the rectification column,Water vapor is collected at a column top temperature of 98 ° C to 100 ° C, and reacted at a reflux temperature for 4 to 6 hours. When the top of the rectification column is free of condensed water, the reaction is terminated, and the remaining hydrazine hydrate in the flask is distilled off by vacuum distillation, and the hydrazine hydrate is completely distilled off, and the solid substance in the flask is fully dissolved by adding an appropriate amount of pure water, and then The solution was poured out, and the ZSM-5 acid zeolite molecular sieve catalyst was recovered by vacuum filtration. The filter cake was washed with an appropriate amount of pure water, and the filtrate was transferred to a distillation flask and concentrated under reduced pressure.After removing water, a crude 3,4,5-trimethoxybenzoyl hydrazide is obtained, which is then washed with absolute ethanol.After drying, 220.2 g of a 3,4,5-trimethoxybenzoylhydrazine finished product was obtained.
220.6 g
With hydrazine hydrate monohydrate; dicyclohexyl-carbodiimide at 95 - 100℃;
3
212 g of 3,4,5-trimethoxybenzoic acid, 324 g of hydrazine hydrate having a content of 98% and 63 g of dicyclohexylcarbodiimide were placed in a four-necked flask equipped with a stirring, a thermometer and a rectification column. , stirring is started, heating is heated to reflux, and when steam enters the rectification column, water vapor is collected at a column top temperature of 95 ° C to 100 ° C, and reacted at a reflux temperature for 4 to 6 hours, when the top of the rectification column is not condensed.After the water is discharged, the reaction is terminated, and the remaining hydrazine hydrate and the dicyclohexylcarbodiimide catalyst are distilled off by distillation under reduced pressure, and the hydrazine hydrate and dicyclohexylcarbodiimide are completely distilled off, and then the flask is placed therein. The solid matter was dissolved in pure water, filtered, recrystallized and dried to give 220.6 g of 3,4,5-trimethoxybenzoylhydrazine.
220.5 g
With hydrazine monohydrate at 98 - 100℃; Molecular sieve; Reflux;
3 Example 3
212 g of 3,4,5-trimethoxybenzoic acid,Hydrazine hydrate 320g in a content of 99% and 42g of mordenite molecular sieve in a beltStirring,thermometer,In the four-necked flask of the rectification column,Turn on the agitation,Heating to reflux,When the steam enters the rectification column,Water vapor is produced at a column top temperature of 98 ° C to 100 ° C.React at reflux temperature for 4 to 6 hours,When the top of the distillation column has no condensed water flowing out, the reaction is terminated.The remaining hydrazine hydrate in the flask was distilled off by distillation under reduced pressure,After the hydrazine hydrate is completely distilled off, an appropriate amount of pure water is added to fully dissolve the solid matter in the flask.Then pour the solution out,The mordenite molecular sieve catalyst is recovered by vacuum suction filtration,The filtrate was transferred to a distillation flask and concentrated under reduced pressure.After removing water, a crude 3,4,5-trimethoxybenzoyl hydrazide is obtained.Wash with anhydrous ethanol,After drying, 220.5 g of a 3,4,5-trimethoxybenzoylhydrazine finished product was obtained.
To a mixture of 3, 4,5-trimethoxybenzoic acid (24.7 g, 116 mmol) and carbonyldiimidazole (20.8 g, 128 mmol) was added dry THF (300 mL) (Caution: gas evolution). The reaction mixture was stirred at room temperature for 4 h, then the Part A compound (20 g, 128 mmol) AND MGCL2 (12.2 g, 128 mmol) were added portionwise. The reaction mixture was stirred at 40°C for 2 days. The resulting precipitate was removed by filtration, and the filtrate was diluted with water and acidified with 1N HC1 until PH-4. The mixture was extracted with ether (200 mL) and washed with water (2 x 100 mL), aq. NAHC03 AND water, then dried over MGS04. Evaporation provided a crude product which was purified with flash chromatography on silica, eluting with a gradient OF 0percent to 50percent EtOAc/hexane to give the beta-keto ester (18 g, 58percent) as a white solid. MS (ES+) m/z (M+Na) += 291.22. 1H NMR (400 MHz, CDC13) : 8 3.76 (s, 3H), 3.92 (s, 6H), 3.93 (S, 3H), 3.98 (s, 2H), 7.22 (s, 2H). HPLC: Retention time = 2.26 min (Method C).
Stage #1: 1,2,3-Benzotriazole With thionyl chloride In dichloromethane at 25℃; for 0.5h;
Stage #2: Eudesmic acid In dichloromethane at 25℃; for 2h;
95%
Stage #1: 1,2,3-Benzotriazole With thionyl chloride In dichloromethane at 20℃;
Stage #2: Eudesmic acid In dichloromethane at 20℃;
93%
Stage #1: 1,2,3-Benzotriazole With thionyl chloride In dichloromethane at 25℃; for 0.5h;
Stage #2: Eudesmic acid In dichloromethane at 25℃; for 3h;
General procedure for the synthesisof N-acylbenzotriazoles 1a-1g
General procedure: To 4.76 g BtH (40 mmol) dissolved in 50 cm3 CH2Cl2,0.73 cm3 SOCl2(10 mmol) were added. The mixture wasstirred at 25 °C for 30 min, followed by the addition ofthe corresponding acid (10 mmol) and the reaction wasallowed to stir for an additional 3 h at 25 °C. The reactionwas diluted with 50 cm3 CH2Cl2and the organic layerwas washed with saturated Na2CO3(3 × 20 cm3), 20 cm3H2O,and 10 cm3 brine. The organic layer was dried overanhydrous sodium sulfate, 50 cm3 hexane was added tothe filtrate, and then the solid obtained was dried undervacuum to give compounds 1a-1g.
83%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h;
With methanesulfonic acid; phosphorus pentoxide; at 50℃; for 26h;Inert atmosphere;
General procedure: Eaton?s reagent was prepared from phosphorus pentoxide (P2O5) and methanesulfonic acid (CH3SO3H) (weight ratio P2O5:CH3SO3H 1:10). The mixture was heated at 40 C under nitrogen atmosphere until complete homogeneity. Carboxylic acid (1.15-1.5 equiv) and aromatic derivative (1.0 equiv) were then added to Eaton?s reagent. The mixture was heated at 40-80 C under inert atmosphere for 3-30 h. After cooling to room temperature, the reaction medium was diluted with dichloromethane and carefully poured into a separatory funnel containing sodium bicarbonate aqueous solution (50% NaHCO3). The aqueous solution was extracted with dichloromethane, and the combined organic layers were dried (MgSO4). Solvent was removed under reduced pressure to produce a brownish oil. The crude product was purified by column chromatography on silica gel to afford pure benzophenones (31, 33, 37, 38, 43, 45, 47, 53, and 56).
With methanesulfonic acid; phosphorus pentoxide; at 60℃; for 3h;Inert atmosphere;
General procedure: Eaton?s reagent was prepared from phosphorus pentoxide (P2O5) and methanesulfonic acid (CH3SO3H) (weight ratio P2O5/CH3SO3H 1:10). The mixture was heated at 40 C under nitrogen atmosphere until complete homogeneity. Benzoic acid (1.15-1.5 equiv) and aromatic derivative (1.0 equiv) were then added to Eaton?s reagent. The mixture was heated at 50 C under inert atmosphere for 3-14 h. After cooling to room temperature, the reaction medium was diluted with dichloromethane and carefully poured into a separatory funnel containing sodium bicarbonate aqueous solution (50% NaHCO3) (neutralization to pH 7). The aqueous solution was extracted with dichloromethane, and the combined organic layers were dried (MgSO4). Solvent was removed under reduced pressure to produce a brownish oil. The crude product was purified by Flash chromatography on RediSep packed columns to provide pure fluorobenzophenones 7a-f.
2.1.7. General procedure for the synthesis of target compounds 9 (Scheme 3)
General procedure: Equimolar quantities of compound 5 (1 mmol) and a substituted carboxylic acid were dissolved in phosphoryl chloride (5 mL) and heated under reflux at 80 °C for 3-6 h, the progress of reaction being monitored by TLC. The reaction mixture was then heated under reduced pressure to allow excess phosphoryl chloride to distill off, and the residue was purified by flash chromatography on silica gel using 15-25% acetone in petroleum ether as eluent to give the target compounds 9a-p (Table 3).
3,4,5-trimethoxy-N-(2-(2-methyl-1H-indol-1-yl)ethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6.0h;
General procedure: A solution of <strong>[883535-89-5]2-(2-methyl-1H-indol-1-yl)ethanamine</strong> (4a) (65 mg, 0.373 mmol) and 4-(piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ?5 mg) in dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6h. At the conclusion of the reaction (TLC), water (15 mL) was added to quench the reaction. The product was extracted with ethyl acetate (20mL×3). Organics were washed with dilute HCl (10 mL), saturated NaHCO3 solution (10 mL), water (10 mL) and brine solution (10 mL) and dried over Na2SO4 and concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40% ethyl acetate in hexane to furnish 7k (TG7-152) (100mg, 74% yield). 1H NMR (CDCl3): delta 7.52 (d, J=5.6Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.30 (d, J=8Hz, 1H), 7.07 (m, 2H), 6.80 (d, J=8.2Hz, 2H), 6.23 (s, 1H), 5.98 (t, J=5.4Hz, 1H), 4.33 (t, J=6Hz, 2H), 3.76 (q, J=6Hz, 2H), 3.25 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.6 (m, 6H). LCMS (ESI): >97% purity at lambda 254, MS; m/z, 362 [M+H]+. Anal. Calcd. for C23H27N3O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;
General procedure: Amide derivatives 6a and 6b were synthesized as starting from 2-(2-methyl-lH-indol-l- yl)ethan- 1 -amine (4a) and 3,4,5-trimethoxybenzoic acid (5a) and 3, 4-dimethoxy benzoic acid (5b). The other substituted derivatives on the phenyl ring (6c-z, 7a-z, & 8a-u), isomeric 3-inodole derivatives ((8x-z, & 9a-g),and imidazole derivatives ((8v-w) were synthesized analogous to 6a and 6b as illustrated.
With aluminum (III) chloride at 300℃; for 0.166667h; Microwave irradiation;
7
Microwaves Procedure: [0077] The dinitrile (3.0 mmol, 1.0 equiv.) is added, in a glass tube designed for this purpose, to a mixture of acid (3.0 mmol) and catalyst (0.06 mmol, 0.02 equiv.). The tube is then closed using a suitable stopper and then is left under microwave activation (appliance used: Monowave 300 from Anton Paar) and magnetic stirring at 300° C. for 10 min. After reaction, the crude reaction mixture is transferred into a 50 ml round-bottomed flask with 10 ml of ethanol. If necessary, the tube is placed in an ultrasonic bath at 60° C., in order to promote the dissolution of the reaction mixture in the ethanol. 3 g of silica are subsequently added to this mixture in order to produce a solid deposit after evaporation of the ethanol. Finally, the pure nitrile is obtained after chromatography on a silica column (gradient from M1 to M9, followed by M0). For its part, the cyclic imide is obtained after elution with ethyl acetate. The conversion to the desired nitrile is determined by 1H NMR of the crude product. The yields shown are the yields of the isolated products after purification. Note: [0078] M0 is an 80:20 dichloromethane/ethyl acetate mixture. [0079] M1 is a 90:10 petroleum ether/M0 mixture. [0080] M2 is an 80:20 petroleum ether/M0 mixture, and the like. [0081] M9 is a 10:90 petroleum ether/M0 mixture
52%
With aluminum (III) chloride at 300℃; for 0.166667h; Microwave irradiation;
2-(3,5-dimethylphenyl)-4,5,6-trimethoxyisoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With copper(l) iodide; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; sodium acetate; silver trifluoromethanesulfonate In 1,4-dioxane at 130℃; for 24h; Inert atmosphere; Green chemistry;
General experimental procedure for the synthesis of N-substituted phthalimide
General procedure: A mixture of [RuCl2(p-cymene)]2 (6.1 mg, 0.01 mmol, 5 mol%) and AgOTf (12.8 mg, 0.05 mmol, 25 mol%) in 0.1 mL dioxane in an oven-dried tube was stirred at room temperature for about 30 min. Then, substituted benzoic acid (0.2 mmol), isocyanates (0.5 mmol), NaOAc (32.8 mg, 0.4 mmol, 200 mol%), and CuI (9.5 mg, 0.05mmol, 25 mol%) were added. After the tube was evacuated and purged with argon three times, the remaining dioxane was added to the system by syringe. The mixture was stirred at 130 °C for 24 h. When the reaction completed, the resulting mixture was cooled to room temperature, filtered through a short silica gel pad, transferred to silica gel column directly and eluted with hexane and dichloroethane or dichloroethane to give the products.
With aluminum (III) chloride at 200℃; for 3h; Inert atmosphere;
Thermal-Catalyzed Reaction ofAcids 1 with (Phenylsulfonyl)acetonitrile; General Procedure 2 (GP2)
General procedure: In a 10 mL round-bottomed flask, (phenylsulfonyl)acetonitrile (544mg, 3.0 mmol, 1.0 equiv) was added to a mixture of acid 1(3.0mmol) and AlCl3(8 mg, 0.06 mmol, 0.02 equiv). The mixture was then stirred under argon at 200 °C for 3 h. After completion of the reaction, the crude mixture was diluted with CH2Cl2(5 mL + 5 mL),silica gel (3 g) was then added to make a solid deposit after evaporation of the solvent. A silica gel column chromatography (eluent:PE-EtOAc, 95:5) finally afforded the pure nitrile together with methyl phenyl sulfone.
With Oxone; trifluoroacetic acid In 1,4-dioxane for 10h; Reflux; Green chemistry;
Benzoic Acid (3a); Typical Procedure from Acetophenone or Phenylacetylene
General procedure: To a mixture of acetophenone (100 mg, 1 equiv) or phenylacetylene (1 equiv) in dioxane (5 mL), Oxone (2 equiv) and TFA (2 equiv) were added. The mixture was then heated to reflux for 10 h and then cooled to r.t. H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were treated with sat. NaHCO3 solution and the aqueous layer was poured onto crushed ice and treated with 2 M HCl; a colorless solid precipitated out. The precipitate was filtered off and dried in vacuo to give benzoic acid (3a) after column chromatography (silica gel; EtOAc-hexane, 1:9) as a white crystalline solid; yield: 0.096 g (95%) from 1a; mp 122-123 °C.
81%
With Iron(III) nitrate nonahydrate; iodine; oxygen; dimethyl sulfoxide at 130℃; for 12h; Sealed tube; Green chemistry;
Typical Procedure for the Synthesis of carboxylic acid (2a) from acetophenone (1a)
General procedure: To a 20-mL tube equipped with a magnetic stirring bar was added acetophenone 1a (120 mg, 1 mmol), 2 mL of DMSO, iodine (25 mg, 0.1 mmol) and Fe(NO3)3·9H2O (40 mg, 0.1 mmol). Then the tube was sealed after being charged with oxygen to replace the air in it. The tube was placed into a preheated oil bath (130°C), and the reaction solution was stirred for 12h. Then the reaction was quenched with water, and the pH of the aqueous phase was adjusted to 11 with 0.1 mol/L NaOH. After being washed with ethyl acetate (3 x 3 mL), the pH of the aqueous phase was adjusted to 2 with 0.1mol/L HCl and extracted with ether (3 x 6 mL). The combined ether phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography on silica gel using ethyl acetate/petroleum ether as eluent to afford 2a as a white solid (104 mg, 85% yield). 1H NMR(600 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.62-7.59 (m, 1H), 7.50-7.48 (m, 2H); 13C NMR (125MHz, DMSO-d6) δ 167.3, 132.7, 130.8, 129.2, 128.5.
81%
With Iron(III) nitrate nonahydrate; iodine; oxygen In dimethyl sulfoxide at 10℃; for 12h; Sealed tube;
35 Example 35: Preparation of 3,4,5-trimethoxybenzoic acid (formula (2-21))
1 mmol of 3,4,5-trimethoxyacetophenone (formula (1-21)), 0.1 mmol of I was added to a 25 mL glass tube equipped with a magnetic stir bar.2, 0.1 mmol of Fe (NO3)3·9H2O, 2mL of DMSO, replace the air in the glass tube with oxygen, seal the glass tube, then put the sealed glass tube into the oil bath preheated to 110 ° C, and turn on the magnetic stirrer, after 12h reaction, remove the sealing glass Tube, wait until it is cooled to room temperature, add water to the reaction solution to quench the reaction, then adjust the pH to about 11 with sodium hydroxide solution at a concentration of 0.1 mol / L, wash three times with ethyl acetate, the concentration of the aqueous phase is 0.1 mol /L hydrochloric acid solution to adjust the pH to about 2, and then extracted three times with diethyl ether, the three ether extracts were combined, the ether was evaporated under reduced pressure, and then separated by column chromatography to ethyl acetate / petroleum ether volume ratio 1 The mixture of 25 was used as an eluent, and the eluent containing the target compound was collected, and the solvent was evaporated to give the product 3,4,5-trimethoxybenzoic acid in an isolated yield of 81%.
With water; potassium hydroxide at 20℃; Electrolysis;
General procedure: To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 percent yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
General procedure: CDI (8.63 mmol) was added to a round-bottomed flask containing compound 8 (5.08 mmol) and anhydrous DMF, and the mixture was stirred vigorously for 30 min at room temperature. Subsequently, the flask was placed in an ice bath, and methyl phenyl acetates 7 (5.33 mmol) and NaH (17.76 mmol) were added. The reaction was stirred for 4 h, the mixture was poured into a saturated solution of NH4Cl(aq) until pH = 7 was reached, and it was extracted with AcOEt. The combined organic phases were washed with a saturated solution of NaCl(aq) and dried over anhydrous MgSO4. After filtration, the organic solvent was removed under reduced pressure. The crude residue was purified by column chromatography using petroleum ether/ethyl acetate (2:1) as the eluent to yield purified compounds 9a-9e.
With sodium hydroxide In N,N-dimethyl-formamide at 10 - 35℃; for 3h;
5 Example 5: Method for synthesizing 3,4,5-methoxybenzoate, and the specific method steps are:
(1) In three bottle was charged 3,4,5-trimethoxy benzoic acid 100g, DMF600ml, sodium hydroxide, 25g, polyethylene glycol 10g, stirring, cooling to 10 , methyl chloride gas passed through 30g.Through Albert, heating to about 35 , insulation reaction 3h;(2) After completion of the reaction was concentrated by distillation and the concentrate was added to 1500ml test water and stirred to cool to room temperature and allowed to stand, the precipitate after filtration, crude;(3) The crude product into 300ml of methanol, stirred warmed to 60 ~ 65 , cooled to room temperature and refluxed for 1 hour.Concentrated distillation, filtration, after drying in pure 91.5g, a yield of about 85.9%,
With potassium carbonate In N,N-dimethyl-formamide at 20 - 120℃; Inert atmosphere;
10.1; 10.2; 10.3; 10.4; 10.5 Example 10
1) 1313.2 mL (17 mol) of solvent N, N-dimethylformamide was sequentially added to the reaction vessel heated under an inert gas at a temperature of 20 to 25 ° C,Gallic acid 17 g (0.1 mol)Catalyst Potassium carbonate 48.3 g (0.35 mol)And 121.5 g (1.35 mol) of dimethyl carbonate were added and stirred for 0.5 to 1 hour to allow the contents to be thoroughly mixed.2) the reaction bottle material heated to 110 ~ 120 , insulation reaction 8 to 10 hours;3) after the completion of the reaction, the initial in -0.1MPa, 75 under the conditions of vacuum distillation to recover excess dimethyl carbonate, and then increase the temperature to 90 ~ 100 distillation of N, N-dimethyl formamide,Until the bottle into a paste. The recovered dimethyl carbonate was distilled under reduced pressure,N, N-dimethylformamide is reserved for the feed cycle in step 1)4) Add 576 mL (32 mol) of water, 1.08 g (0.09 mol) of activated carbon to the reaction flask, heat to 80 to 90 ° C, and stir for 0.5 to 1 hour to stop heating.5) the material is hot filter, the filtrate into a clean reaction bottle, open the mixing, the reaction bottle temperature down to 15 below, cooling crystallization, filtration, cake drying after 3,4,5-trimethoxy Benzoic acid finished product, the yield was 95.6%, purity99.7%.
With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 0.5h;
4 Synthesis of Compound C
In the above chemical reaction formula, compound A was trimethoxybenzoic acid in an amount of 0.9 mmol; compound B was used in an amount of 1.1 mmol in the presence of catalytic CDI (N, N′-dicyclohexylcarbodiimide) which was dissolved in 1.8 ml of DMF, then stirred at room temperature for 30 minutes to synthesize XB-A-26 (C). XB-A-26 was added in an amount of 1.4 mmol, and the reaction mixture was heated under reflux at 75° C. for 36 hours, monitored by TLC. The mixture was poured into 20 mL of water and extracted with EtOAc (3×10 mL). The combined layers were dried by Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel (hexane:EtOAc=3:1) to get the oxadiazole product as a white solid, which can collect 0.25 g of the final product C.
General procedure: The TN salts/molecular salts was preparedby grinding an equimolar mixture containing 200mg (1 mmol) of TN and 1mmol of correspondingcarboxylic acids/PTSA wetted with few drops of waterwas manually grounded in an agate mortar for 100minutes until a dried powder was obtained.
Stage #1: (E)-2-Hexen-1-ol; Eudesmic acid With diisopropyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: With dmap In tetrahydrofuran at 20℃; for 24h;
Esterification reaction
General procedure: A solution of gallic acid or 3,4,5-trimethoxygallic acid (1 mmol), alcohols (2 mmol)and 1.5 mmol diisopropyl carbadiimide (DIC) as catalisator in tetrahydofurane (10 mL) were stirred in 0 °C for 30 min. then added solution of 0,1 mmol N,N-Dimethylaminopiridine (DMAP) in 1 ml THF. This mixture was stirred at room temperature for 24 hours. The reaction mixture was then added aquadest and extracted with chloroform. The organic phase was then added Mg2SO4 anhydrate to take out the water residue. The filtrate was then drying to obtain the crude product. The product was purified using chromatography colomn with appropriate mobile phase.
2-(3,4,5-trimethoxyphenyl)benzo[d]oxazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With polyphosphoric acid; at 80 - 95℃;
<strong>[137-09-7]2,4-Diaminophenol dihydrochloride</strong> (0.01 M) and 3, 4,5-trimethoxybezoic acid (0.01 M) was condensed with polyphosphoric acid (24 g) at 80-95C for 4-5 h. After completition of the reaction, mixture was poured into ice cold water, neutralized with 10N NaOH and extracted with toluene. Toluene was evaporated under vacuum. The product thus obtained was collected and washed with cold water and recrystallized from ethanol.
2-[5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazol-3-yl]benzo[d]thiazol-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With hydroxylamine hydrochloride; Acetate de N,N-dimethylamino-4 pyridinium; at 100℃; for 6h;
In a 5-mL round-bottom flask, compound 3 (10 g, 56.7 mmol), hydroxylamine hydrochloride (7.8 g, 113.5 mmol) and 3,4,5-trimethoxybenzoic acid 4 (12 g, 56.7 mmol) were mixed with 4-(dimethylamino)pyridinium acetate (51.6 g, 283.5 mmol). The reaction mixture was heated to 100°C for 6 h. The mixture was cooled down to room temperature, ethanol (1 mL) was added, and stirring continued for 30 min more. Water (5 mL) was added to the reaction mixture. The solid product was filtered off, washed twice with water (2×5 mL) and purified by column chromatography with hexanes/ethyl acetate (3 : 7) to afford pure compound 5. Yield 75percent, mp 271?273°C. 1H NMR spectrum, delta, ppm: 3.88 s (3H), 3.92 s(6H), 7.28 d (1H, J = 7.56 Hz), 7.40 s (1H), 7.46 s (2H),7.82 d (1H, J = 7.56 Hz), 9.67 s (1H). MS (ESI): 386 [M]+.
3,4,5-trimethoxy-N-(4-methoxy-3-nitrophenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
General procedure: To a solution of substituted benzoic acid (1mmol) in DMF was added TEA(1mmol), HOBt(1.2mmol),TEA(1.1mmol),EDCI(1.2mmol) and stirred for 10min.Then added substituted phenol (1mmol) or substituted aniline (1mmol). After stirring for 1 days at room temperature, the reaction mixture was added water and then obtain the compound as a white or yellow powder. Yield: 90%.
4-methoxy-3-nitrophenyl 3,4,5-trimethoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
General procedure: To a solution of substituted benzoic acid (1mmol) in DMF was added TEA(1mmol), HOBt(1.2mmol),TEA(1.1mmol),EDCI(1.2mmol) and stirred for 10min.Then added substituted phenol (1mmol) or substituted aniline (1mmol). After stirring for 1 days at room temperature, the reaction mixture was added water and then obtain the compound as a white or yellow powder. Yield: 90%.
3,4,5-trimethoxyphenyl 4-methoxy-3-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: To a solution of substituted benzoic acid (1mmol) in DMF was added TEA(1mmol), HOBt(1.2mmol),TEA(1.1mmol),EDCI(1.2mmol) and stirred for 10min.Then added substituted phenol (1mmol) or substituted aniline (1mmol). After stirring for 1 days at room temperature, the reaction mixture was added water and then obtain the compound as a white or yellow powder. Yield: 90%.
N,N′-(decane-1,10-diyl)bis(3,4,5-trimethoxybenzamide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
In a round bottom flask, 0.400 g of 3,4,5-trimethoxybenzoic acid, 0.130 g of decanediamine, 0.361 g of EDCI, 0.018 g of DMAP, and 10 mL of anhydrous dichloromethane were successively added, and the mixture was stirred at room temperature for 12 hours. The white solid was precipitated, suction filtered, washed successively with dichloromethane (2×2.5 mL) and water (3×5 mL), and dried to give a white solid, 0.302 g, yield 63% (see Figure 43 for the synthetic route). Figure 44).
63%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: Compounds 9e-35e were obtained by using one-pot reaction. A mixture of aromatic acid (6.30 mmol), EDCI (7.50 mmol), DMAP (0.60 mmol), and anhydrous dichloromethane (20 mL) was stirred to dissolve, then decane-diamine (3 mmol) was added and stirred at room temperature for 12 h. The mixture solution was filtered under reduced pressure. After that, the residue was washed with little amount of CH2Cl2and water successively, and dried to give the solid. Then, the residue was purified on preparative TLC eluted with chloroform/methanol = 40:1-7:1 to yield compounds 26e, 28e, 30e, and 31e.
Stage #1: 3,4-dimethoxybenzoic acid chloride; Eudesmic acid With triethylamine In dichloromethane at 0 - 20℃; for 2h;
Stage #2: With trimethylsilyl trifluoromethanesulfonate; triethylamine In dichloromethane at 95℃; for 2h;
2.2
2,3,4-trimethoxy-6-hydroxyacetophenone, which is compound 13a (904 mg, 4.0 mmol), was added to 16 mL of dichloromethane solution. Triethylamine (1.47 mL, 12 mmol) and 3,4-dimethoxybenzoyl chloride (1.04 g, 5.2 mmol). The reaction system was raised from 0 ° C to room temperature for 2 hours. After the reaction was completed, the system was quenched with water and extracted with ethyl acetate three times. It was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain the product 2-acetyl-3,4,5-trimethoxy-3,4-dimethoxy-benzoic acid methyl ester (1.3 g, 3.4 mmol), white solid, yield: 85%.2-Acetyl-3,4,5-trimethoxy-3,4-dimethoxy-benzoic acid methyl ester (1.17 g, 3.0 mmol) was added to 18 mL of dichloroethane solution, and triethylamine (1.2 mL, 9.0 mmol) and trimethylsilyl trifluoromethanesulfonate (3.3 mL, 18 mmol), and stirred at 95 ° C for 2 hours. After the reaction was completed, the reaction mixture was quenched with methanol, and extracted with ethyl acetate three times. It was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2: 1) to obtain the product 2- (3,4-dimethoxyphenyl) -5,6,7-trimethoxy-4H-benzopyran-4-one (905 mg, 2.4 mmol), brown solid, yield: 81%.
3-fluoro-4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenylisonitrile[ No CAS ]
[ 118-41-2 ]
1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)amino)-3,3-dimethyl-1-oxobutan-2-yl 3,4,5-trimethoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.6%
In tetrahydrofuran; water at 40℃; for 24h;
4.1.4. General procedure for synthesis of 6,7-dimethoxy-4-(2-fluorophenoxy)quinoline derivatives bearing a-acyloxycarboxamidemoiety 10a-y
General procedure: To a solution of aldehyde/ketone (0.4 mmol) in THF/H2O (0.5 mL,v/v 3:1) was added carboxylic acid (0.4 mmol) and 9 (0.2 mmol)at room temperature. The reaction mixture was subsequentlyheated at 40 C for 24 h. Upon completion of the reaction (TLCmonitoring), the mixture was cooled to room temperature andsolvent was evaporated. The residue was purified by chromatographyon silica gel using ethyl acetate/hexaneas eluent to give 10ay.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;
1 Example 1.
In a two-necked round flask, 10 mmol of the compound of Scheme 1 (see Table 1) was added at room temperature, and 50 ml of dimethylformamide was added. 12 mmol of potassium carbonate (K2CO3) was added as a catalyst, and then 12 mmol of bromomethane was slowly added dropwise. After the dropwise addition, the mixture was reacted for 4 hours at room temperature. 500 ml of purified water was added to the reaction mixture and extracted with 100 ml of n-hexane. After drying the hexane layer under reduced pressure, a mixture of n-hexane and ethyl acetate was subjected to silica gel column chromatography as a developing solvent to obtain a pseudo-reaction product.
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃; for 12h;
4.1.2. General procedure for the synthesis of 4a-4u
General procedure: Trifluoroacetic acid anhydride (TFAA, 2 mmol) was added to a solution of 1-methoxynaphthalene 2 (1.5 mmol) and various commercial available aromatic carboxylic acid (1 mmol) in Trifluoroacetic acid (TFA, 1 mL) and stirred at room temperature for 12 h. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by chromatography to give the desired products 4a-4u. Spectral data of all title compounds (4a-4u) were provided in Supplementary Material.
d. (4-methylbenzo[d]thiazol-2-amine): (3,4,5-trimethoxybenzoic acid) [(L) . (Htmba)] (4)
4-methylbenzo[d]thiazol-2-amine (32.8 mg, 0.2 mmol) was dis- solved in 5 mL of ethanol. To this solution was added 3,4,5- trimethoxybenzoic acid (42.4 mg, 0.2 mmol) in 8 mL methanol. The solution was left standing at room temperature for several weeks, colorless prisms were afforded after slow evaporation of the solvent. The crystals were dried in air to give [(L) . (Htmba)] ( 4 ), yield 54.8 mg, 72.79%. m. p. 153-155 °C. Anal. Calcd for C 18 H 20 N 2 O 5 S (376.42): C, 57.38; H, 5.31; N, 7.44; S, 8.50. Found: C, 57.28; H, 5.23; N, 7.31; S, 8.42. Infrared spectrum (KBr disk, cm -1 ): 3694s( ν(OH)), 3470s( νas (NH)), 3364s( νs (NH)), 3288 w, 3126 m, 3068 m, 2962 m, 2874 m, 2496 w, 1906 w, 1672( νas (C = O)), 1553 m, 1510 w, 1466 m, 1420 m, 1374 m, 1324 m, 1272s( νs (C-O)), 1226 m, 1180 m, 1135 m, 1090 m, 1046 m, 1004 m, 960 m, 916 m, 870 m, 838 m, 794 m, 752 m, 710 m, 668 m, 626 m, 608 m.
5,6,7-trimethoxy-1,2,3,4-tetrakis(4-methylphenyl)naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,2,3,4-tetraphenylcyclopentadiene; copper diacetate In o-xylene at 160℃; for 24h; Inert atmosphere;
Decarboxylative Coupling of 1 with 2; General Procedure
General procedure: A mixture of benzoic acid 1 (0.38 mmol), alkyne 2 (0.5 mmol),[Rh(cod)Cl2]2 (2.5 mg, 0.005 mmol), C5H2Ph4 (7.4 mg, 0.02 mmol),Cu(OAc)2 (181.6 mg, 1.0 mmol) and 1-methylnaphthalene (ca. 50 mg)as an internal standard in o-xylene (2.5 mL) was stirred at 160 °C under Ar (1 atm) for 3-24 h. After the reaction was complete, the mixturewas diluted with dichloromethane (100 mL). The organic layerwas washed with water (2 × 100 mL) and brine (100 mL), and thendried over Na2SO4. After evaporation of the solvents under vacuum,products 3 (and 3′) were isolated by column chromatography on silicagel using hexane-ethyl acetate as eluent. Further purification by GPC(gel permeation chromatography) was performed, if needed.
5,6,7-trimethoxy-1,2,3,4-tetrakis(4-methoxyphenyl)naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,2,3,4-tetraphenylcyclopentadiene; copper diacetate In o-xylene at 160℃; for 24h; Inert atmosphere;
Decarboxylative Coupling of 1 with 2; General Procedure
General procedure: A mixture of benzoic acid 1 (0.38 mmol), alkyne 2 (0.5 mmol),[Rh(cod)Cl2]2 (2.5 mg, 0.005 mmol), C5H2Ph4 (7.4 mg, 0.02 mmol),Cu(OAc)2 (181.6 mg, 1.0 mmol) and 1-methylnaphthalene (ca. 50 mg)as an internal standard in o-xylene (2.5 mL) was stirred at 160 °C under Ar (1 atm) for 3-24 h. After the reaction was complete, the mixturewas diluted with dichloromethane (100 mL). The organic layerwas washed with water (2 × 100 mL) and brine (100 mL), and thendried over Na2SO4. After evaporation of the solvents under vacuum,products 3 (and 3′) were isolated by column chromatography on silicagel using hexane-ethyl acetate as eluent. Further purification by GPC(gel permeation chromatography) was performed, if needed.
5,6,7-trimethoxy-1,2,3,4-tetrakis(4-fluorophenyl)naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,2,3,4-tetraphenylcyclopentadiene; copper diacetate In o-xylene at 160℃; for 24h; Inert atmosphere;
Decarboxylative Coupling of 1 with 2; General Procedure
General procedure: A mixture of benzoic acid 1 (0.38 mmol), alkyne 2 (0.5 mmol),[Rh(cod)Cl2]2 (2.5 mg, 0.005 mmol), C5H2Ph4 (7.4 mg, 0.02 mmol),Cu(OAc)2 (181.6 mg, 1.0 mmol) and 1-methylnaphthalene (ca. 50 mg)as an internal standard in o-xylene (2.5 mL) was stirred at 160 °C under Ar (1 atm) for 3-24 h. After the reaction was complete, the mixturewas diluted with dichloromethane (100 mL). The organic layerwas washed with water (2 × 100 mL) and brine (100 mL), and thendried over Na2SO4. After evaporation of the solvents under vacuum,products 3 (and 3′) were isolated by column chromatography on silicagel using hexane-ethyl acetate as eluent. Further purification by GPC(gel permeation chromatography) was performed, if needed.
5,6,7-trimethoxy-1,2,3,4-tetrakis[4-(trifluoromethyl)-phenyl]naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,2,3,4-tetraphenylcyclopentadiene; copper diacetate In o-xylene at 160℃; for 24h; Inert atmosphere;
Decarboxylative Coupling of 1 with 2; General Procedure
General procedure: A mixture of benzoic acid 1 (0.38 mmol), alkyne 2 (0.5 mmol),[Rh(cod)Cl2]2 (2.5 mg, 0.005 mmol), C5H2Ph4 (7.4 mg, 0.02 mmol),Cu(OAc)2 (181.6 mg, 1.0 mmol) and 1-methylnaphthalene (ca. 50 mg)as an internal standard in o-xylene (2.5 mL) was stirred at 160 °C under Ar (1 atm) for 3-24 h. After the reaction was complete, the mixturewas diluted with dichloromethane (100 mL). The organic layerwas washed with water (2 × 100 mL) and brine (100 mL), and thendried over Na2SO4. After evaporation of the solvents under vacuum,products 3 (and 3′) were isolated by column chromatography on silicagel using hexane-ethyl acetate as eluent. Further purification by GPC(gel permeation chromatography) was performed, if needed.
5,6,7-trimethoxy-1,2,3,4-tetraphenylnaphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,2,3,4-tetraphenylcyclopentadiene; copper diacetate In o-xylene at 160℃; for 24h; Inert atmosphere;
Decarboxylative Coupling of 1 with 2; General Procedure
General procedure: A mixture of benzoic acid 1 (0.38 mmol), alkyne 2 (0.5 mmol),[Rh(cod)Cl2]2 (2.5 mg, 0.005 mmol), C5H2Ph4 (7.4 mg, 0.02 mmol),Cu(OAc)2 (181.6 mg, 1.0 mmol) and 1-methylnaphthalene (ca. 50 mg)as an internal standard in o-xylene (2.5 mL) was stirred at 160 °C under Ar (1 atm) for 3-24 h. After the reaction was complete, the mixturewas diluted with dichloromethane (100 mL). The organic layerwas washed with water (2 × 100 mL) and brine (100 mL), and thendried over Na2SO4. After evaporation of the solvents under vacuum,products 3 (and 3′) were isolated by column chromatography on silicagel using hexane-ethyl acetate as eluent. Further purification by GPC(gel permeation chromatography) was performed, if needed.
(2R,3S)-1,2,3,4-tetrahydronaphthalene-2,3-diyl bis-(3,4,5-trimethoxybenzoate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
2.1.3. General procedure for the preparation of 4-9.
General procedure: A100 ml flask was charged with the diol (500 mg, 3.04 mmol,1.0 equiv.), the acid (6.08 mmol, 2.0 equiv.), 4-(dimethylamino)-pyridine (594 mg, 4.86 mmol, 1.6 equiv.), 3-[3-(dimethylamino)-propyl]-1-ethylcarbodiimide hydrochloride (EDACHCl; 1.282 g,6.69 mmol, 2.2 equiv.) and dichloromethane (40 ml). Thesuspension was stirred at room temperature for 48 h. Afterthis time, TLC on silica gel (eluent: hexane/ethyl acetate = 7:3)indicated the complete consumption of the starting materials.The mixture was washed with water (2 50 ml), brine (1 50 ml), aqueous citric acid at pH = 2 (2 50 ml) and a saturatedNaHCO3 aqueous solution (1 50 ml). The organiclayer was dried over Na2SO4 and concentrated under reducedpressure. The crude was purified by column chromatographyon silica gel (eluent: hexane/ethyl acetate = 90:1080:2070:30, unless otherwise stated) to afford the product.
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