* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 100 - 110℃; for 1.25 h;
General procedure: To aromatic aldehyde (500 mg, 1.0 equiv) and malonic acid (981 mg, 2.0 equiv) was added DABCO (105 mg, 2 equiv) in dimethyl formamide (5 mL) and the reaction mixture was stirred at 100-110 °C for 60-90 min. After completion of the reaction (TLC monitoring), reaction mixture was poured in water and then extracted with ethyl acetate. Crude product was recrystallized from chloroform/hexane system to provide cinnamic acids in good yield.
88%
Stage #1: at 105 - 110℃; Stage #2: With sodium hydroxide In water at 25 - 30℃; Stage #3: With sulfuric acid In water at 15 - 20℃;
To a solution of 1000 g (6.024 mol) of 3, 4-dimethoxybenzaldehyde in 3L pyridine, 1378.3 g (13.25 mol) of malonic acid and 100 mL of piperidine were added. The resulting mixture was stirred at 105 °C to 1 10 °C for 6 - 8 h. After completion of the reaction, the reaction mixture was cooled to 25 °C to 30 °C and slowly quenched the reaction mixture into 10 L of 5 percent sodium hydroxide solution at 25 °C to 30 °C (pH: 9- 10). The reaction mixture was washed with ethyl acetate (2 x 5 L) and the organic layer separated was washed with 2 L of 5 percent sodium hydroxide solution. The aqueous layers were combined and cooled to 15 °C to 20 °C. The aqueous layer was acidified slowly with 2.5 L of 50 percent sulphuric acid below 20 °C (pH: 1-2). After an additional 30 - 45 min stirring at 15 °C to 20 °C, the solid obtained was collected by filtration, washed with 10 L of water followed by 4 L of n-hexane. The partially dried compound was unloaded into trays and dried at 55 °C to 60 °C for 8-10 h to give 1 1 10 g of the title compound.Yield: 1 1 10 g (88 percent); 1H NMR (DMSO-d6, 300 MHz): δ 7.51 (d, 1 H), 7.30 (s, 1 H), 7.19 (d, 1 H), 6.96 (d, 1 H), 6.44 (d, 1 H), 3.79 (s, 6H); MS (ES-): 207 (M-1 ).
88.9%
at 75℃; for 5 h;
100 g of a three-necked reaction flask was charged with 25 g (240 mmol)Malonic acid, 33.2 g (200 mmol)3,4-dimethoxybenzaldehyde,40 ml (496 mmol) of pyridine,2 ml (20.4 mmol) of hexahydropyridine,Heated to 75 ° C and then reflux 5h,Reaction is completed,Cooling 10min,150 ml of 3 mol / ml of ice hydrochloric acid solution was added,Place the night,Filter,The precipitate was washed with 1000 ml of water,Get white crude.The crude product was recrystallized from absolute ethanol,A mixture of 37.0 g of pure white 3,4-dimethoxyphenylacrylic acid,Yield 88.9percent.
86.5%
at 85℃; for 4 h;
1. In a 100 ml three-necked flask, 6.24 g (60 mmol) of malonic acid, 8.3g (50 mmol) of 3,4-dimethoxybenzaldehyde, 10 ml (124 mmol) of pyridine and 0.5 ml (5.1 mmol) of piperidine were heated 85°C for 4h. After completion of the reaction, the solution was cooled for 10 min, 60 ml of 3 mol / ml ice hydrochloric acid solution was added, and the mixture was left to stand overnight. The precipitate was washed with 400 ml of water to give a white crude product. The crude product was recrystallized from absolute ethanol to give 9 g of white pure 3,4-dimethoxyphenylacrylic acid in a yield of 86.5percent.
71.4%
for 4 h; Reflux
Example 7 Preparation of 3,4-Dimethoxycinnamic acid In a 1L round bottomed flask fitted with a magnetic stirrer and a reflux condenser, a mixture of 166 g (1 mol) of veratraldehyde and 208 g (2 mol) of malonic acid in 500 mL of pyridine and 5 mL of piperidine was refluxed for 4 h. The excess pyridine was evaporated using a rotavap and 3 L of water was added to the syrupy residue which caused the formation of a solid. The mixture was acidified with 250 mL of concentrated HCl with stirring. Filtration and washing with three 100-mL portions of water and drying in air afforded 150 g (71.4percent) of the cinnamic acid, m.p. 183-185 °C. (lit. m.p. 180-182 °C.) as shown in J. G. Stuart et al, /. Het. Chem., 24. 1589 (1987); 1H-NMR (DMSO-d6) δ 3.78 (s, 3), 3.80 (s, 3), 6.44 (d, 1), 6.96 (d, 1) 7.19 (dd, 1), 7.31 (d,l), 7.52 (d, 1).
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Yield
Reaction Conditions
Operation in experiment
98%
With bromine In methanol; water at 20℃; for 4 h;
(1) To a solution of 500g of 3,4-dimethoxybenzaldehyde in 2.5L of methanol was added dropwise 529g of bromine at room temperature (under cooled condition, if necessary) over 1 hour, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added dropwise 2.5L of water, and the crystals were precipitated. To a suspension of the crystal was added 20percent aqueous sodium hydroxide solution at room temperature to adjust it to pH about 9 to 10, and then cooled. The precipitated crystals were collected by filtration and washed with water, and then dried at 50°C for 12 hours to give 718.78g of 6-bromo-3,4-dimethoxybenzaldehyde (yield: 98percent).
95%
With bromine In methanol at 20℃; for 3 h;
Bromine (1.82 mL, 5.67 g, 31.5 mmol) was added dropwise to a stirred solution of veratraldehyde (4.98 g, 30.0 mmol) in MeOH (25 mL) in 7 minutes to bring the solution to gentle reflux. After 3 hours the reaction mixture color changed to pale orange and some solid precipitated. The reaction mixture was diluted with MeOH for the precipitate dissolution and it was poured into water (120 mL). To the yellow suspension was added 20percent NaOH solution until pH = 10. The precipitate was filtered, washed with water and dissolved in CH2Cl2 (120 mL). The organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo to give pure by 1H NMR bromobenzaldehyde SI-1b (6.99 g, 28.5 mmol, 95percent) as white solid. Recrystallization from EtOAc/hexane (1/2)gives 6.32 g (25.8 mmol, 86percent) of crystalline product in two crops if needed.
89%
With bromine In methanol at 15 - 40℃; for 24 h;
3,4-Dimethoxybenzaldehyde (100 g, 0.602 mol) represented by the following Formula 1 was dissolved in 600 mL of methanol, Control solution temperature is 15 ~ 20 deg C, Bromine (106 g, 0.663 mol) was added dropwise thereto, After the addition was complete, the solution was warmed to 35-40 ° C, Reaction for 24 hours. Continue to add 10percent aqueous sodium thiosulfate solution (200 ml, 0.126 mol)Steamed out 200 ml of methanol, The solution is then cooled to 10-15 ° C, Stirred for 2 hours, Suction filtration, Dried to give the following formula 2 130 grams of light yellow solid 3,4-bismethoxy-2-bromobenzaldehyde, Yield 89percent.
86%
With bromine In methanol at 20℃; for 6 h;
[0067] Total Synthesis of Patentifiorin A (3) (Scheme 1 ) . To a solution of veratral (4a) (63.2 mmo.) in methanol (MeOH, 250 mL), a solution of bromine (Br2, 69.5 mmol) was added slowly. The reaction was allowed to stir at room temperature for 6 hr to afford 2- bromo-veratral (13.4 g, 86 percent). 2-Bromo-veratra. (50.3 mmol) was then dissolved in 300 mL benzene, to which, 1 , 3-propanedifhiol (50.4 mmol) and p-toluenesulfonic acid (p- TsOH, 2.5 mmol) were added. The reaction mixture was allowed to be stirred at reflux for 10 hr then ambient temperature for 48 hr to yield 5 (15.6 g, 93 percent). To a stirred solution of compound 5 (46.6 mmoi) in tetrahydrofuran (THF, 1 50 mL) at -78 °C was added n-butyllithium (n-BuLi) (1 .6 M solution in hexanes, 69.9 mmol) in 1 hr, followed by addition of a solution of piperonal (4b) (55.9 mmol) in THF (30 mL). The reaction was allowed for a further 2 hr and then 3 hr at room temperature to yield 6 (9.5 g, 50 percent). Compound 6 (20.7 mmol) in CH2CI2 (200 mL) was added a suspension of activated manganese dioxide (MnO2, 345 mmol) at room temperature. The reaction was allowed for 16 hr, and was then filtered through a plug of celite to afford the oxidative product 7 (8.2 g, 98 percent). n-Butyliithium (1 .6M solution in hexanes, 100 mmoi) was added dropwise over 5 min to a cooled (-78 °C) solution of diisopropylamine (100 mmoi) in THF (43 mL) under Argon to make fresh lithium diisopropylamide (LDA) solution. The solution was warmed to ambient temperature over 30 min and 25.7 mL added, dropwise via syringe over 3 min to a cooled (-78 °C) THF solution (80 mL) of the dithiane 7 (14.29 mmoi). After 40 min, 2,5-dihydrofuranone (17.1 mmol) as a solution in THF (10 mL) was added over 1 min. The reaction is warmed to ambient temperature for 1 hr to afford 8 (3.95 g, 57 percent). A solution of compound 8 (0.85 mmol), mercury oxide (HgO, 0.71 mmoi) and mercury chloride (HgC , 1 .43 mmol) in 84 percent acetonitriie (AcCN) aqueous (25 mL) was heated to reflux for 3 hr to afford 9 (134 mg, 52 percent). The ketone 9 (0.34 mmol) and p~ TsOH (0.19 mmol) were heated to reflux in benzene (150 mL) for 18 hr to yield the desired compound diphyllin (10, 108 mg, 83 percent). To the solution of D-quinovose (0.61 mmol) in pyridine (5 mL) was added 4-dimethylaminopyridine (DMAP, 0.06 mmol) and acetic anhydride (AC2O, 1 .5 mL) at room temperature, and the mixture was stirred overnight and quenched with MeOH (1 mL) to afford 1 ,2,3,4-tetraacetyl-D-quinovose. Without further separation, the tetraacetate was dissolved in glacial acetic acid (AcOH, 1 mL), and 1 .5 mL hydrobromic acid (HBr) (33percent in AcOH) was added to the solution slowly at room temperature. The reaction was allowed for 15 min to afford 11 (215 mg, 97 percent). To a solution of TBAB (tetrabutylammonium bromide, 0.95 mmoi) and diphyllin (10, 0.95 mmol) in 15 mL of dichloromethane (CH2C ) was added aqueous 0.1 M sodium hydroxide (NaOH, 20 mL). After stirring for 10 min at 40 °C, compound 11 (0.81 mmol) was then added, and the two-phase reaction was stirred for 6 hr at 40 °C to afford the solid 12. Without further separation, the solid 12 (538 mg) was dissolved in MeOH (10 mL), and potassium carbonate (K2CO3, 1 .0 mmol) was then added. The reaction was allowed for 1 hr to afford patentiflorin A (3) (122 mg).
85.85%
at 20℃; for 3.5 h;
I. Synthesis of 2-Bromo-4,5-dimethoxybenzaldehyde of formula VI; Three necked round bottom flask (500 mL) equipped with dropping funnel, magnetic stirrer, and stopper was charged with veratraldehyde or 4,5-dimethoxybenzaldehyde (formula V, 15 g, 0.090 mole) and acetic acid (210 mL). To this solution was added bromine (9.67 mL) in acetic acid (60 mL) dropwise with constant stirring over half an hour and stirring was further continued for 3 h at room temperature. During this time all the starting materials was consumed as confirmed by TLC (3:7, EtOAc:Hexane). Water (250 mL) was added to the reaction mixture and cooled to 0° C. The precipitated solid was filtered off, washed with cold water and dried under vacuum to get a white solid 2-bromo-4,5-dimethoxybenzaldehyde (formula VI).The yield and NMR details of compound of compound of formula VI were as follows:Yield: 19 g (85.85percent)1HNMR (CDCl3, 300 MHz): δ=10.19 (s, 1H), 7.43 (s, 1H), 7.07 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H).
81.3%
With bromine In methanol at 25 - 40℃; for 3 h;
Example 1 Preparation of 2-Bromo-4,5-dimethoxybenzaldehyde In a 5 liter (L) 3-neck round bottomed flask fitted with a mechanical stirrer, a dropping funnel and a thermometer, there was added 500 grams (g) (3001 millimoles (mmol)) of veratraldehyde in 1500 milliliter (mL) of methanol. Due to the endothermic solution process the temperature of the solution dropped below 25°C and therefore the solution was warmed with a heating mantle until the temperature again reached 25 °C. At this point 573.5 g (3589 mmol, 185 mL) of bromine was added dropwise at such a rate that the temperature remained under 40°C to avoid the formation of the 2,3-dibromo derivative. The addition required about one hour and gave a reddish yellow solution. After about two hours a precipitate began to separate and after three hours, 7 L of water was added and the precipitate was filtered and washed with an additional 7 L of water. Recrystallization from 7 L of ethanol gave 600 g (81.3percent) of the bromo aldehyde, melting point (m. p.) 145-146°C (lit. m.p. 149-151°C, as shown in S. Chandrasekhar et al. Tetrahedron 62, 12908 (2006)); IR (NaCl): 1683, 1594, 1504 cm"1; 1H-NMR (CDC13) δ 3.88 (s, 3), 3.93 (s, 3), 7.02 (s, 1), 7.37 (s, 1), 10.14 (s, 1). 13C-NMR (CDC13, 75 MHz): δ 56.05, 56.44, 110.28, 115.34, 120.26, 126.41, 148.76, 154.37, 190.55.
76.1%
With bromine In acetic acidInert atmosphere
Prepared according to the literature [3], starting with veratraldehyde (49.85 g, 0.3 mol) in glacial acetic acid (400 mL), adding bromine (18.5 mL, 0.3 mol) in 100 mL glacial acetic acid, yielding 55.95 g (76.1percent) of 3c, colourless needles, mp 149-150°C (80percent MeOH). Chemical formula: C9H9BrO3. Molecular weight: 245.07. Elemental analysis: Calculated: C, 44.11; H, 3.70; found: C, 44.25; H, 3.79. 1H-NMR (400 MHz; CDCl3): 3.91 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 7.04 (s, 1H, C3-H), 7.40 (s, 1H, C6-H), 10.17 (s, 1H, CHO). 13C-{1H}-NMR (100 MHz; CDCl3): 56.1, 56.5, 110.4, 115.4, 120.4, 126.5, 148.9, 154.5, 190.8.
56%
With bromine; sodium hydrogencarbonate; sodium thiosulfate In acetic acid
First Stage Synthesis of 6-bromo-3,4-dimethoxybenzaldehyde A solution of bromine (0.96 g) in acetic acid (10 ml) was dropped into a solution of 3,4-dimethoxybenzaldehyde (1.0 g) in acetic acid (4 ml) and the mixture was stirred for three hours. Sodium thiosulfate was added to the reaction mixture, then sodium bicarbonate was added thereto and the mixture was filtered. The crude crystals collected by the filtration were recrystallized from chloroform-ether to give the title compound (0.83 g, 56percent). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
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[1] Patent: CN106748862, 2017, A,
47
[ 120-14-9 ]
[ 123-54-6 ]
[ 160096-59-3 ]
Yield
Reaction Conditions
Operation in experiment
34%
Stage #1: With boric anhydride In ethyl acetate at 45℃; for 0.5 h; Stage #2: With boric acid tributyl ester In ethyl acetate at 45℃; for 0.5 h; Stage #3: With N-butylamine In ethyl acetate at 45℃; for 16 h;
2,4-Pentanedione (3 g, 30.0 mmol) and boric anhydride (1 .46g, 21 .Ommol) weredissolved in ethyl acetate (EA) (30 ml) and heated at 45 °C for 30 minutes. 3,4-Dimethoxybenzaldehyde (9.96 g, 59.9mmol) and tributylborate (13.79 g, 59.9 mmol)were added and the mixture stirred at 45 °C for 30 minutes. Butylamine (4.44 ml, 44.9mmol) in EA (30 ml) was added dropwise over 15 minutes and the solution stirred at 45°C for 16 hours. Aqueous HCI (prepared by adding 4.5 ml conc. HCI to 25.5 ml water)was added and the biphasic mixture stirred and heated at 60 °C for 1 hour. The layerswere separated and the aqueous layer extracted with EA (50 ml). The combinedorganic layers were washed with water, saturated NaCI, dried with Na2504, filtered and the solvents removed under reduced pressure to give crude product as a red oil (10.42g). The crude product was purified by FC on silica gel eluting with EA:hexane (50:50) togive (1 E,6E)-1 ,7-bis(3,4-dimethoxyphenyl)hepta-1 ,6-diene-3,5-dione as an orangesolid (4.0 g, 34percent). HPLC-UV showed >97percent purity. 1H NMR (60 MHz, ODd3), 16.05(1H, bs), 7.59 (2H, d), 6.76-7.26 (6H, m), 6.45 (2H, d), 5.79 (1H, s), 3.91 (6H, s), 3.89(6H, s).
2.8%
Stage #1: With boron trioxide In ethyl acetate at 85℃; for 0.666667 h; Stage #2: With triethyl borate In ethyl acetate at 85℃; for 3 h;
To a solution of 2,4-pentadione (12 ml, 117 mmol) in AcOEt was added boron trioxide (4.17 g, 59.9 mmol) at room temperature. After stirring for 40 min at 85 oC, 3,4-dimethoxybenzaldehyde (9.64 g, 58.1 mmol) and triethyl borate (5.0 ml, 29.4 mmol) were added to the reaction mixture. After stirring for 3 h at same temperature, the mixture was added to the n-BuNH2 (2.0 ml, 8.30 mmol). After stirring for 1 h at same temperature, to the reaction mixture was added 1 M HCl at 50 oC and extracted with AcOEt. The organic phase was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane/AcOEt, 4:1) to give 2 (112 mg, 2.8percent) as an orange powder. 1H NMR (400 MHz, CDCl3): 4.0 (s, 12H), 5.82 (s, 1H), 6.49 (d, 2H, J = 5.8 Hz), 6.88 (d, 2H, J = 8.4Hz), 7.07 (s, 1H), 7.16 (d, 2H, J = 8.4 Hz), 7.60 (d, 2H, J = 16 Hz). ESIHRMS m/z: C23H24O6 [M+H]+ calcd 397.1651, found 397.1608.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 360 - 367
[2] Patent: WO2018/149578, 2018, A1, . Location in patent: Page/Page column 16; 17
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5621 - 5626
[4] Journal of Mass Spectrometry, 1998, vol. 33, # 4, p. 319 - 327
[5] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 11, p. 3811 - 3820
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 23, p. 8260 - 8273
[7] Journal of Biological Chemistry, 2011, vol. 286, # 2, p. 1114 - 1124
48
[ 120-14-9 ]
[ 111-30-8 ]
[ 160096-59-3 ]
Yield
Reaction Conditions
Operation in experiment
5.6 g
With N-butylamine In N,N-dimethyl-formamide at 70℃; for 3 h; Inert atmosphere
The dimethoxy curcumin bulk drug is prepared by reference to the full synthetic route provided by the U.S. Patent (US005679864A). The preparation process is briefly described below. Methyl vanillin (23.3 g), boron oxide (4.66 g), anhydrous dimethylformamide (90 mL), pentanedione (7.2 mL) and dimethoxypropane (17.2 mL) were sequentially placed in 250 mL three-necked bottle, well-stoppered, after shaking evenly, slowly heated up to 70 ° C under N2 protection, until the solid matter was completely dissolved, n-butylamine (2.8 mL) was slowly added dropwise, and the reaction was completed in about 120 min, and the reaction was continued for about 1 h, the reaction solution was poured into 400 mL of boiling 5percent acetic acid solution while stirring, and was homogeneously stirred untill naturally cooled to room temperature, 200 mL of deionized water was added, well shaked, let stand for 2 days in a refrigerator at 4 ° C and pour off the upper layer solution. Acetonitrile aqueous solution (~63percent) was added, the lower layer of the viscous solid was dissolved under reflux for 30 min, filtered while hot, and the filtrate was placed in a refrigerator at 4 ° C for crystallization. Filtered, the obtained solid was repeatedly washed with a 60percent aqueous solution of acetonitrile and dried to give orange yellow needle crystals (5.6 g).
General procedure: Appropriate aldehyde (10.5 mmol) was added to the solution of <strong>[603-81-6]2,3-<strong>[603-81-6]diaminobenzoic acid</strong></strong> 6 (1.52 g, 10 mmol) in DMF (15 mL). The solution was heated to 80 C and then stirred for about 120 h. Then, the solution was cooled to room temperature. The precipitates were filtered, washed with ethanol and dried.
(a) Preparation of 4-(3',4'-dimethoxyphenyl)-4-oxobutyronitrile (111). A single portion of neat acrylonitrile (3.2 ml, 0.048 mol) and triethylamine (5 ml, 0.11 mol) was added to a stirred mixture of 3,4-dimethoxybenzaldehyde (7.8 g, 0.047 mol) and 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (5.3 g, 0.02 mol) in dry dimethylformamide (25 ml) under argon. The mixture was left overnight at room temperature. The reaction was diluted with water and extracted with ethyl acetate (3*100 ml). The organic extract was washed with water (3*100 ml), brine (3*100 ml) and the solvent was removed under reduced pressure to give an amber oil. Analysis by TLC (silica gel; ethyl acetate:hexanes, 1:1) revealed a mixture of three spots at Rf 0.80 (starting aldehyde), 0.50 (Compound 1) and 0.30 (unknown by-product). The sample was purified by column (flash) chromatography on silica gel 60 (230-400 mesh) and eluted with ethyl acetate:hexanes (1:1) to give the desired compound (2.26 g, 22percent) as a yellow solid. 1 H NMR (CDCl3) 2.78 (t, 2H, J=8 Hz), 3.33 (t, 2H, J=8 Hz), 3.96 (s, 3H), 3.98 (s, 3H), 6.90 (d, 1H, J=8.5 Hz), 7.52 (d, J=2 Hz, 2H), 7.58 (dd, J=2 and 8 Hz, 2H).
22%
With triethylamine; In N-methyl-acetamide;
(a) Preparation of 4-(3',4'-dimethoxyphenyl)-4-oxobutyronitrile (111). A single portion of neat acrylonitrile (3.2 ml, 0.048 mol) and triethylamine (5 ml, 0.11 mol) was added to a stirred mixture of 3,4-dimethoxybenzaldehyde (7.8 g, 0.047 mol) and 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (5.3 g, 0.02 mol) in dry dimethylformamide (25 ml) under argon. The mixture was left overnight at room temperature. The reaction was diluted with water and extracted with ethyl acetate (3*100 ml). The organic extract was washed with water (3*100 ml), brine (3*100 ml) and the solvent was removed under reduced pressure to give an amber oil. Analysis by TLC (silica gel; ethyl acetate:hexanes, 1:1) revealed a mixture of three spots at Rf 0.80 (starting aldehyde), 0.50 (Compound 1) and 0.30 (unknown by-product). The sample was purified by column (flash) chromatography on silica gel 60 (230-400 mesh) and eluted with ethyl acetate:hexanes (1:1) to give the desired compound (2.26 g, 22percent) as a yellow solid. 1H NMR (CDCl3) 2.78 (t, 2H, J=8 Hz), 3.33 (t, 2H, J=8 Hz), 3.96 (s, 3H), 3.98 (s, 3H), 6.90(d, 1H, J=8.5 Hz), 7.52 (d, J=2 Hz, 2H), 7.58 (dd, J=2 and 8 Hz, 2H).
1-(3,4-dimethoxyphenyl)-4-(2-naphthyl)butan-1,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; In N-methyl-acetamide;
Step A Preparation of 1-(3,4-dimethoxyphenyl)-4-(2-naphthyl)butan-1,4-dione Sodium acetate (2.38 g), 3-benzyl-4-methyl-5(2-hydroxyethyl)thiazolium chloride (3.78 g), 2-naphthaldehyde (10.92 g), 3,4-dimethoxybenzaldehyde (17.43 g), vinylsulfone (7.00 ml) and dimethylformamide (dry DMF, 35 ml) were stirred at room temperature for about 13 days. The reaction mixture was partitioned between chloroform and water and the layers separated. The pooled organic layers were washed with water, dried over anhydrous potassium carbonate and evaporated in vacuo to give about 24.9 g of an oil. The oil was chromatographed to give 1.8 g of crude product which was crystallized from methanol to give 623.2 mg of pure 1-(3,4-dimethoxyphenyl)-4-(2-naphthyl)butan-1,4-dione, m.p. 133° C.
EXAMPLE 26 In a 300-ml. three necked flask was placed 4.9 g. of sodium cyanide and 10 ml. of water to obtain a homogeneous solution. To the resuting solution was added 16.6 g. of 3,4-dimethoxybenzaldehyde dissolved in 40 ml. of methanol and then a solution of 9.7 g. of piperazine hexahydrate and 7.95 g. of <strong>[142-64-3]piperazine dihydrochloride</strong> in 30 ml. of water. The reaction mixture, from which crystalline precipitate separated upon heating, was stirred for about 1 hour at 60C. After the mixture was cooled, crystal to separate was collected by filtration, washed with water and methanol, and dried. There was obtained 22.8 g. of crystal having a melting point of 216 -218.5C. Recrystallization from chloroform-methanol afforded N,N'-bis-(alpha-cyano-3,4-dimethoxybenzyl)piperazine as a crystalline product melting at 216 -218C.
6-Hydroxy-3-(3,4-dimethoxybenzylidene)-4-chromanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.29 g (45%)
EXAMPLE 189 6-Hydroxy-3-(3,4-dimethoxybenzylidene)-4-chromanone By the method of Example 1, 5.00 g (30.5 mmol) of 6-hydroxy-4-chromanone and 5.06 g (30.5 mmol) of veratraldehyde gave 4.29 g (45%) of present title compound, tlc (66% ether-hexane) Rf 0.13.
General procedure: The desired compounds, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one analogues (1a- 1l) (Figure 1), were prepared by Knoevenagel condensation.With one exception, refluxing a solution of appropriate benzaldehydes and <strong>[556-90-1]pseudothiohydantoin</strong>in acetic acid in the presence of NaOAc produced (Z)-5-benzylidene-2-iminothiazolidin-4-ones as a single stereoisomer in yields of 41.4-94.1%. A Knoevenagel condensation between 2,4-dimethoxy benzaldehyde and <strong>[556-90-1]pseudothiohydantoin</strong> under the same conditions gave amixture of (E)- and (Z)-5-(2,4-dimethoxybenzylidene)-2-iminothiazolidin-4-ones. These compounds could not be easily separated by conventional silica gel column chromatography. Milder reaction conditions capable of accomplishing the Knoevenagel condensation were needed to synthesize only (Z)-stereoisomer. Interestingly,heating a solution of 2,4-dimethoxy benzaldehyde and <strong>[556-90-1]pseudothiohydantoin</strong> in ethanol:H2O (1:1) in the presence of 1.0 equiv. of piperidine as a base catalyst at 80 C afforded the corresponding (Z)-stereoisomer(1l) as a sole product. A suspension of an appropriate benzaldehyde (300 mg, 1.53-2.46 mmol), <strong>[556-90-1]pseudothiohydantoin</strong>(1.1 eq.), and sodium acetate (3.0 eq.) in acetic acid (1 mL/1 mmol of benzaldehyde) was refluxed for 3-7 h. The reaction mixture was cooled and water was added. The resulting precipitates were filtered, and washed with water and, if necessary, a small amountof methylene chloride or ethyl acetate, to produce (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-oneproducts (1a - 1k) in 41.4-94.1% yields. The resulting precipitates were filtered, and washed with water,ethyl acetate and methylene chloride to give (Z)-5-(2,4-dimethoxybenzylidene)-2-iminothiazolidin-4-one (1l) all final products were confirmed by 1H and 13C NMR spectroscopy and mass spectroscopy.
45%
To the magnetically stirred solution of 17 (232 mg, 2 mmol) in HOAc (7 mL), was added NaOAc (500 mg, 6 mmol). After 15 min 3,4-dimethoxybenzaldhyde (16a, 400 mg, 2.4 mmol) was added and the reaction mixture was heated under reflux for 72 h. The HOAc was removed under reduced pressure and the resultant solid was washed successively with water, methanol and EtOAc to obtain the desired products as solid. 10.2.1.1 5-(3,4-Dimethoxybenzylidene)-2-iminothiazolidin-4-one (14a) Yellow solid; mp > 200 C; 235 mg, 45% yield; IR (neat) numax = 3344, 2759, 1720, 1690, 1678 cm-1; 1H NMR (400 MHz, CD3SOCD3) delta = 9.35 (s, 1H), 9.09 (s, 1H), 7.54 (s, 1H), 7.08-7.16 (m, 3H), 3.80 (s, 6H); 13C NMR (100 MHz, CD3SOCD3): delta = 180.52, 175.39, 149.98, 148.81, 129.42, 126.62, 126.51, 122.77, 112.63, 111.98, 55.57, 55.38; HRMS (ESI-TOF): m/z calculated for C12H12N2O3S [M+Na]+, 287.0466; found 287.0461.
General procedure: A 250 mL round bottom flask was charged with 2 (1.0 equiv) and 3 (1.0 equiv) at 70 C, and the mixture was stirred under vacuum for 1 h. Methanol (100 mL) was added to the residue, and then NaBH4 (3.0 equiv) was added portionwise at the r.t. The mixture was refluxed for 4 h. Upon completion, as determined by TLC, the reaction mixture was concentrated in vacuo. The residue was dissolved in water (300 mL). The resulting aqueous phase was extracted with ethyl acetate (3 × 100 mL) and the combined organic layers were rinsed with saturated brines (100 mL) and dried (Na2SO4). Concentrated hydrochloric acid was added dropwise to adjust PH of the organic layer to 5-6, and filtered to give the hydrochlorate (5) without further purification.To a suspension of anhydrous CuSO4 (3.6 equiv) and 5 (1.0 equiv) in anhydrous formic acid (45 mL) was added glyoxal (40%, 2.0 equiv) at 100 C. The reaction mixture was stirred at 100 C for 5 h, concentrated hydrochloric acid (0.8 and 0.6 equiv) was added at 2 h and 4 h respectively during this process. Upon completion, as determined by TLC, the mixture was filtered. The filtrate was concentrated in vacuo. The residue (6) was dissolved in methanol (500 mL) and water (10 mL), CaO was added portionwise to adjust PH to 9-10. The suspension was stirred at the r.t. for 2 h, filtered and concentrated in vacuo. The resulting residues were purified via flash column chromatography using methanol/dichloromethane as the eluent, and then acidified by 10% HCl/ethanol to give 7.
General procedure: To a solution of the corresponding aromatic aldehyde (0.27 mmol) in EtOH (0.5 mL) was added urea (0.54 mmol) and CuSO4·5H2O (0.054 mmol). The mixture was stirred at 80 °C for 15 minutes before tetrahydrocurcumin or tetrahydrodemethoxycurcumin (0.27 mmol) was added. The reaction mixture was continued stirring for 24 hours and quenched with water (2 mL). The solution was washed with water (10 mL) and extracted with EtOAc (415 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford crude product as a yellow brown oil. Purification was accomplished by column chromatography eluting with 60percent-75percent EtOAc/hexane to furnish compounds 8-17.
With [gamma-Fe2O3-encapsulated-HAp-SO3H]; at 60℃; for 0.05h;
General procedure: [gamma-Fe2O3Hap-SO3H] was synthesized according to the procedures reported in Ref. [2]. Then to a mixture of 6-amino-2-(methylthio or ethylthio)pyrimidin-4(3H)-one (1 mmol), Meldrum?s acid (1 mmol) and aryl aldehydes (1 mmol) was added [gamma-Fe2O3Hap-SO3H] (10 mg, 0.9 mol%) and the reaction mixture was stirred mechanically at 60 C. After the completion of the reaction, which was monitored by TLC analysis, the reaction mixture was diluted with hot ethanol and the catalyst was easily separated from the reaction mixture by an external magnet. The product obtained was collected by filtration, washed with ethanol and recrystallized from appropriate solvent to furnish the desired pure product (4a-n).
In a round-bottom flask containing a magnetic stirrer, a mixture of aldehyde (1 mmol) and heteroaryl amine (1 mmol) was placed andstirred at about 80-85 8C for 20 min. Then <strong>[23612-48-8]2-methyl-7-azaindole</strong>(1 mmol) was added in portions, and the mixture was heated to 80-85 8C. Completion of the reaction was monitored by thin-layerchromatography (TLC) analysis. After completion, the reactionmixture was cooled to room temperature and a small quantity ofethanol was added. The solution was poured into ice-water, and theprecipitate formed was filtered, washed with an ice cold ethanol-water (1:1) mixture. The crude products were stirred in boiling nhexaneand filtered to afford the pure products.
General procedure: The mixture of <strong>[78364-55-3]6-fluoro-2-hydrazinylbenzo[d]thiazole</strong> (2) (0.01 mol) and benzalde-hyde/substituted benzaldehyde (0.01 mol) was reuxed in ethanol (15 ml) at 70?80 °C for 3 h. The separated product obtained was ltered off, washed withdistilled water and recrystallized from methanol to give the correspondinghydrazone. The product obtained was further dissolved in acetic acid (20 ml) atroom temperature followed by the addition of sodium acetate (0.5 g). Bromine(2 mmol) in acetic acid (10 ml) was added dropwise to the reuxing reactionmixture. After 1 h, the mixture was poured onto crushed ice (100 g). The precipitateobtained was ltered off and crystallized from ethanol-dimethylformamide (1:1) togive crystals of (3a?3t).
dimethyl ((3,4-dimethoxyphenyl)((2-methyl-3-(trifluoromethyl)phenyl)amino)methyl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With chitosan; In neat (no solvent); at 75℃; for 0.0666667h;Microwave irradiation; Green chemistry;
General procedure: An equimolar mixture of <strong>[54396-44-0]2-methyl-3-(trifluoromethyl)aniline</strong> (0.351 g, 0.002 mol), corresponding aldehyde (0.002 mol), dimethyl phosphite (0.18 ml, 0.002 mol) and chitosan catalyst (10 molpercent) were taken in a reaction glass tube, degassed for 10 min and microwave irradiated at 180 W for 2 min at 60 °C. The progress of the reaction was monitored by TLC using petroleum ether and ethyl acetate (3:7) as solvent. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water (2 x 15 ml) followed by brine (1 x 10 ml), dried over Na2SO4 and evaporated to dryness. The crude mass was purified by column chromatography on silicagel (100-200 mesh) by using a 7:3 mixture of ethyl acetate in hexane to afford the pure alpha-aminophosphonates.
2-chloro-N-(2-(cyclohexylamino)-1-(3,4-dimethoxyphenyl)-2-oxoethyl)-N-(4-(2-oxomorpholino)phenyl)-2-phenylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
General procedure: General Procedure for the Synthesis of IMCR Products 1a-f. A mixture of aromatic amine (1 mmol) andaromatic aldehyde (1 mmol) stirred at room temperature in methanol (3 mL) for 5 to 10 min afforded Schiffbase which further undergoes the reaction with chloroacetic acid (1 mmol) and isocyanide (1 mmol) at roomtemperature to gives 1a-f in affordable yields. After stirring at room temperature for 24 h, the solid wasfiltered out to obtain crude products then wash with 1-2 mL chilled methanol for purification which is ready touse for the next step.A post Ugi cyclisation of 1a-f were carried out by use of efficient reaction conditions by utilizing dry K2CO3 (2mmol), as a base and DMF (2 mL) solvent respectively under room temperature with portion wise addition of1a-f for 10 min which further heated at 100 oC for 2-4 hrs. The reacNon is monitored by TLC, aOer compleNonof reaction the resulting mixture was cooled to room temperature and poured on crushed ice. Collect solidand the residue was purified by flash column chromatography on silica gel by using hexane: EtOAc (95:5) as aeluent to afford the corresponding products 2a-f in 71-80% yields.
With pyridine; tetrabutyl-ammonium chloride; cerium triflate; at 20℃; for 24h;Glovebox; Sealed tube; Irradiation;
The reaction was carried out in a glove box, and lignin dimer 3 (0.1 mmol, 33.4 mg) and photocatalyst lanthanum triflate (5 mol%) were weighed.Auxiliary tetrabutylammonium chloride (5mol%),Nitrogen source di-tert-butyl azodicarboxylate (1 mmol) and 2.0 mL of pyridine were placed in a 10 ml pressure-resistant tube.The reaction pressure tube is sealed and placed under a purple lamp at 380 nm.After stirring for 24 hours, after the lignin dimer 3 is completely converted,After separation by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5, volume ratio), product 3,4-dimethoxybenzaldehyde (13.4 mg, yield 81%)And 1-[1-(2-methoxy)phenoxyethanol]-1,2-dicarboxylic acid diisopropyl ester-oxime(3) (28.3 mg, yield 71%).
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