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CAS No. : | 14737-89-4 | MDL No. : | MFCD00004387 |
Formula : | C11H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HJBWJAPEBGSQPR-GQCTYLIASA-N |
M.W : | 208.21 | Pubchem ID : | 717531 |
Synonyms : |
(E)-O-Methylferulic acid
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.18 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 56.1 |
TPSA : | 55.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.91 cm/s |
Log Po/w (iLOGP) : | 2.01 |
Log Po/w (XLOGP3) : | 2.34 |
Log Po/w (WLOGP) : | 1.69 |
Log Po/w (MLOGP) : | 1.3 |
Log Po/w (SILICOS-IT) : | 1.79 |
Consensus Log Po/w : | 1.83 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.64 |
Solubility : | 0.48 mg/ml ; 0.00231 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.15 |
Solubility : | 0.147 mg/ml ; 0.000707 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.12 |
Solubility : | 1.57 mg/ml ; 0.00753 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.04 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid; for 4h;Reflux; | 2-(3, 4-dimethoxyphenyl)cyclopropanecarboxylic acidConcentrated sulfuric acid (1.0 mL) was added to a solution of (£)-3,4- dimethoxycinnamic acid (2.0 g, 9.6 mmol) in MeOH (50 mL). The solution was heated to reflux for 4 h, cooled to rt and then quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, brine, dried and concentrated providing methyl ester (2.2 g, 95%). A cooled solution of the methyl ester (0.11 g, 0.49 mmol) and Pd(OAc)2 (6 mg, 0.027 mmol) in CH2CI2 (3 mL) and ether (3 mL) was treated with excess CH2N2 at 0 0C The suspension was filtered and the filtrate was concentrated. The crude residue was dissolved in MeOH (5 mL) and treated with 1 M NaOH (5 mL). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure to remove the MeOH. The aqueous phase was washed with 50% EtOAc/petrol, acidified with 1 M HCI and then extracted with EtOAc. The combined organic fractions were washed with water, brine, dried and concentrated providing 2-(3,4-dimethoxyphenyl)cyclopropanecarboxylic acid (96 mg, 87%) as a colourless crystalline solid; deltaH (500 MHz, DMSO-cfe) 1.36 (ddd, J = 5.0, J = 4.0, J = 2.0 Hz, 1H, CH), 1.62 (ddd, J = 2.0, J = 4.0, J = 2.0 Hz, 1H, CH)1 1.84 (ddd, J = 2.0, J = 4.0, J = 2.0 Hz, 1 H, CH), 2.57 (ddd, J = 2.0, J = 4.0, J = 3.0 Hz, 1 H, CH), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.65 (d, J5beta = 8.0, 1H, H6), 6.66 (s, 1 H, H2), 6.78 (d, J5i6 = 8.0 Hz, 1H, H5); deltac (125 MHz, DMSO-Cf6) 7.1 , 23.6, 26.9, 55.8, 55.9, 110.1 , 111.3, 118.2, 131.9, 147.9, 148.9, 179.8. |
95% | With sulfuric acid; at 65℃; for 12h; | (£)-Methyl 3-(3,4-dimethoxyphenyl)acrylate. To a stirred flask containing methanol (0.2 M, 190 mL) was added 3-(3,4-dimethoxyphenyl)acrylic acid (8.0 g, 38.4 mmol) followed by sulfuric acid (10 mol %, 0.21 mL, 0.38 g, ). The mixture was heated at reflux (65 C) for 12 hr. The mixture was cooled to rt and saturated NaHCC>3 was slowly added (20 mL). The solution was added to a separatory funnel containing brine (50 mL, sat. NaCl). The aqueous layer was extracted with methylene chloride (3 x 30 mL). The combined organic layers were dried (MgSO/t), concentrated, and submitted to silica gel chromatography (4: 1, hexanes/ethyl acetate) to access the desired methyl ester (8.1 g, 95%) as a colorless oil: Rf 0.25 (20% EtOAc/hexanes), NMR (300 MHz, CDC13) delta 7.65 (d, IH, J= 20 Hz), 7.10 (m, 2H), 6.88 (d, IH, 4 Hz), 6.34 (d, IH, 20 Hz), 3.91 (s, 6H), 3.80 (s, 3H), IR (cm" l) 3065, 2944, 1695. |
76% | With acetyl chloride; for 2.5h;Heating / reflux; | Monomer 1 , 3-(3',4'-Dimethoxy-phenyl)-acrylic acid methyl ester, was synthesized by reaction of 3-(3',4'-Dimethoxy-phenyl)-acrylic acid with methanol in the presence of acetic chloride. After refluxing for 2.5 h, the reaction mixture was concentrated by evaporation to 1/3 and the white solid was filtered and dried in vacuo to get the desired product in 76% yield as a white crystalline solid, mp.74-75 C. <n="30"/>ESI MS m/z: 223.0 [M+H] +; 1H NMR (300 MHz, CDCl3) delta: 7.64 (d, IH, J= 15.9 Hz, H-3), 7.1 l(dd, IH, J= 6.9, 2.1 Hz, H-6'), 7.05 (d, IH, J= 2.4 Hz, H-2'), 6.85 (d, IH, J= 8.4 Hz, H-5'), 6.32 (d, IH, J= 15.9 Hz, H-2), 3.92 (s, 6H, phenyl OCH3), 3.80 (s, 3H, ester OCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | With hydrogenchloride; zinc amalgam; In tetrahydrofuran; water; | General procedure: A mixture of zinc powder (25 g, 0.384 mol) and mercuric chloride(3.1 g, 0.0114 mol) was suspended in 100 mL of water in a 250 mLbeaker. The mixture was treated with 50 mL of con. HCl slowly dropwise and after completion of addition, the stirring was continued for15 min. The mixture was decanted to separate the solution and theremaining Zn-Hg amalgam was used for reduction. To a mixture of substituted cinnamic acid (1a-e, 0.134 mol), THF(150 mL) and 5 N HCl (100 mL) was added above freshly prepared Zn-Hg amalgam slowly portion wise. An additional 5 N HCl (50 mL) addedand the stirring continued for 2 h. After completion of reaction, asmonitored by TLC hexane/ethyl acetate (8:2), the reaction mixture waspoured into water (200 mL) and extracted with chloroform(2×400 mL), The organic layer was washed with brine solution, driedover Na2SO4 and concentrated. The crude residue was subjected to column chromatography on silica gel using hexane/ethyl acetate mixturesas eluents. The fractions were monitored using TLC and purecompound was obtained from the fractions eluted with ethyl acetate inhexane, 5%/95% (v/v). These fractions were combined and concentratedto obtained 3-(substituted-phenyl)-propionic acids (2a-e) asoily compounds with yields of 79-86%. |
82% | With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; under 3878.71 Torr; for 12h; | A solution of 1a (1.0 g, 4.8 mmol) in THF (20 mL) was hydrogenatedat 75 psi pressure in the presence of Pd/C (10%, 0.116 g) for 12 h. Usualwork-up gave 1b (0.83 g, 82%) as a colorless solid; RF=0.09 (silicagel, n-hexane/ethyl acetate, 4:1); m.p. 98 C (lit.: [33] 98-99 C); IR(ATR): nu=2935w, 1697s, 1591w, 1516m, 1463m, 1430m, 1343w,1306w, 1236s, 1146s, 1027s, 840m, 809s, 768m, 567m cm-1; UV-vis(MeOH): lambdamax (log epsilon)=202 (4.42), 229 (3.75), 280 (3.32) nm; 1H NMR(400 MHz, CDCl3): delta=6.80 (dd, J=8.4, 3.2 Hz, 1H, 6?-H), 6.76 (s, 1H,5?-H), 6.73 (d, J=5.5 Hz, 1H, 2?-H), 3.87 (s, 3H, 8?-H), 3.86 (s, 3H, 7?-H), 2.91 (td, J=7.8, 5.2 Hz, 2H, 3-H), 2.64 (td, J=7.7, 5.1 Hz, 2H, 2-H) ppm; 13C NMR (100 MHz, CDCl3): delta=177.9 (C-1), 149.1 (C-4?), 147.8 (C-3?), 132.9 (C-1?), 120.3 (C-5?), 115.5 (C-2?), 111.8 (C-6?), 56.1(C-8?), 56.0 (C-7?), 35.8 (C-3), 30.4 (C-2) ppm; MS (ESI, MeOH): m/z(%)=209.1 ([M-H]-, 100), 441 ([2M-2H+Na]-, 71); analysiscalcd for C11H14O4 (210.23): C 62.85, H 6.71; found C 62.65, H 6.92. |
With hydrogen;Raney Nickel; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; | Preparation of 74Step 1 . 3,4-dimethoxycinnamic acid (5 g, 24 mmol) was dissolved in THF (100 ml_). Raney Nickel was added to this solution under a N2 atmosphere. The reaction mixture was exposed to a hydrogen atmosphere and stirred 15 hours at room temperature. The reaction mixture was filtered over a cartridge packed with diatomateous earth and the solvent of the filtrate was removed under reduced pressure. The residue was used as such in the next step. LC-MS: Anal. Calcd. For CiiHu04: 210.09; found 209[M-H] |
With hydrogen; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; | 10127] Step 1. 3,4-dimethoxycinnamic acid (5 g, 24 mmol) was dissolved in THF (100 mE). Raney Nickel was added to this solution under a N2 atmosphere. The reaction mixture was exposed to a hydrogen atmosphere and stirred 15 hours at room temperature. The reaction mixture was filtered over a cartridge packed with diatomateous earth and the solvent of the filtrate was removed under reduced pressure. The residue was used as such in the next step.10128] EC-MS: Anal. Calcd. For C, ,H,404: 210.09; found209[M-H] | |
With 5%-palladium/activated carbon; hydrogen; In ethanol; at 35 - 40℃; for 12h;Autoclave; | 150 g of 20% sodium hydroxide aqueous solution was added to the reaction flask, and 118 g of ethyl 3,4-dimethoxycinnamate was added to the mixture. After stirring, the reaction mixture was heated at 60 C for 2 hours for hydrolysis, and the reaction was completed at 20 to 25 C. Concentrated hydrochloric acid to neutral; the solution was extracted with ethyl acetate 100 g * 2, and the organic layers were combined and dried. Filtered and concentrated to give 3,4-dimethoxycinnamic acid, which was dissolved by stirring with 450 g of ethanol. Ethanol solution was added to a 1 L autoclave, and then 1.2g of 5% palladium-carbon was added to 20 g of ethanol. The atmosphere was replaced with nitrogen three times, and hydrogen was kept at a temperature of 35 to 40 C for 12 hours. After the completion of hydrogen absorption, the nitrogen gas was replaced, and the palladium carbon was removed by filtration to be applied. The solution was concentrated under reduced pressure, and 360 g of deionized water was added to the solution, and the mixture was cooled to 0-5 C. Drying at 60 to 70C for 20 to 24 hours to obtain 96.8 g of 3,4-dimethoxybenzenepropionic acid; the molar yield is 92.2% and the purity of the liquid is 99.65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | A mixture of 3,4-dimethoxybenzaldehyde (1) (9.50 g,57.20 mmol), malonic acid (23.80 g, 228.80 mmol) and piperidine (1 mL) in pyridine (60 mL) was heated at 70C for about 6 h. Upon completion, pyridine was removed in vacuo. The residue obtained was dissolved in 15% solution of NaOH (100 mL), stirred at room temperature for 0.5 h, and extracted with ethyl acetate (EtOAc) (60 mL). The water phase was acidified with concentrated HCl to a pH value of less than 2. The resulting precipitate was filtered off, washed with water, and dried in vacuo to give (E)-3-(3,4-dimethoxyphenyl)acrylic acid (2) (10.70 g, 90%). mp:181-183C. | |
85% | With pyrrolidine; pyridine;Reflux; | 3,4-Dimethoxybenzaldehyde (5.0 g, 0.02 mol) was refluxed with malonic acid (8.0 g, 0.06 mol)in pyridine (50 mL) and few drops of tetrahydropyrrole as a catalyst for 20 h. The reactionmixture was acidified with dilute hydrochloric acid to attain pH 7. The precipitates of productobtained were settled down, filtered, washed with cold water and dried to afford 3,4-dimethoxycinnamic acid (2) as a light yellow solid. Yield: 85%, Rf: 0.22, m.p.: 130-1338C, IR(neat) y (cm21): 1650 (CvO acid). 1H NMR (DMSO, d ppm): 12.2 (1H, s, acid), 7.52 (1H, d,J 15.9 Hz, b-H), 7.32 (1H, d, J 1.8 Hz, HC-20), 7.20 (1H, m, HC-60), 6.96 (1H, d,J 8.4 Hz, HC-50), 6.4 (1H, d, J 15.9 Hz, a-H), 3.7-3.8 (6H, s,ZOMe). 13C NMR (DMSO, dppm): 168.3 (CvO acid), 151.2 (b-C), 111.9-151.2 (ArZC), 110.66 (a-C), 55.97-56.01(ZOMe); elemental analysis: found: C, 63.49, H, 5.81%; calcd for C11H12O4: C, 63.45; H,5.81%. |
82% | With piperidine; pyridine; for 4h;Reflux; | General procedure: A mixture of compound 1 (1 equiv, 10 mmol), malonic acid (1.2 equiv, 12 mmol) and two drops of piperidine in pyridine (25 mL) was refluxed for 4 h and evaporated to remove pyridine. The residue was suspended in H2O (30 mL) and extracted with EtOAc (2×50 mL) which was further purified by recrystallization to afford 2a-d. |
82% | With piperidine; In pyridine; for 4h;Reflux; | General procedure: A mixture of compound 1 (1 equiv, 10 mmol), malonic acid (1.2 equiv, 12 mmol) and two drops of piperidine inpyridine (25 mL) was refluxed for 4 h and evaporated to remove pyridine. The residue was suspended in H2O(30 mL) and extracted with EtOAc (2 9 50 mL) which was further purified by recrystallization to afford 2a-d. (E)-3-(3,4-dimethoxyphenyl)acrylic acid (2a) Yield 82 %. m.p. 181-183 C. ESIMS: m/z 208.0600 [M]+,calc. for C11H12O4 (208.21) (Brittelli et al., 1981). |
81% | A solution of 3,4-dimethoxybenzaldehyde (5.0 g, 30 mmol) and malonic acid (4.7 g, 45 mmol) in a mixture of piperidine (0.5 mL) and pyridine (15 mL) was heated to 120 C and stirred overnight. The mixture was cooled to rt and acidified with cone. HCI. The resulting precipitate was filtered and washed with water to give (£)-3-(3,4- dimethoxyphenyl)-2- propenoic acid (5.1 g, 81%) as a pale brown solid; <5"H (400 MHz, <n="52"/>DMSO-CZ6) 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 6.42 (d, J = 16.0 Hz, 1H, CH=CHCO2H), 6.96 (d, J5|6 = 8.0 Hz, 1 H, H5), 7.19 (d, J5,beta = 8.0 Hz, 1 H1 H6), 7.30 (s, 1 H, H2), 7.51 (d, J = 16.0 Hz, 1 H, CH=CHCO2H). | |
80% | Synthetic Examples; Example 1; Synthesis of l-bromo-6J-dimethoxyisoalphauinoline; Step 1.; A mixture of 3,4-dimethoxybenzaldehyde (30 g, 180.72 mmol), malonic acid (28.4 g, 273.08 nimol), and piperidine (3 mL) in pyridine (90 mL) was stirred at 120 0C for 6 hr. The reaction mixture was monitored by TLC (EtOAc/PE (1 :1, v/v)). Upon completion, the reaction mixture was cooled to room temperature, and the pH was then adjusted to 1 by the addition of concentrated HCl. The product was isolated by filtration, and the filter cake was washed with water. The solid was dried in an oven under reduced pressure to provide 30 g (80%) of (E)-3-(3,4-dimethoxyphenyl)acrylic acid as a light yellow solid. | |
80% | With piperidine; pyridine; at 120℃; for 4h; | General procedure: To a solution of the substituted benzaldehyde (1 eq.) and malonate(1.2 eq.) in pyridine (2.5 mL/mmol) at 120 C piperidine (0.04 eq.) wasadded, and the reaction mixture was heated under reflux for 4 h [31].The solvents were removed in vacuo as an azeotrope with toluene(3×70 mL). Water (100 mL) was added, and the aqueous phase wasextracted with ethyl acetate (3×100 mL), brine (1×100 mL), dried(MgSO4) and concentrated. Compounds 1a and 1c-1m were preparedfollowing procedure A. |
75.6% | With 1,4-diaza-bicyclo[2.2.2]octane; In N,N-dimethyl-formamide; at 110℃; for 2h; | General procedure: The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted benzaldehydes (1.0g, 1.0eq) in 100.0ml round bottom flask containing 15.0ml dimethylformide and malanoic acid (1.1eq). Diaza bicyclooctane (DABCO 1.0eq) was added as a catalyst and the temperature was raised to 110.0C and maintained for 2.0h. The reaction was monitored by thin layer chromatography. After the completion of the reaction the reaction mass was quenched into cold water 40.0ml and extracted with ethyl acetate 2×25ml. The organic layer was dried with anhydrous sodium sulfate and concentrated under high vacuum, the resulted solid was washed with hexane (5.0ml), suck dry for 15.0min and then dried under vacuum at 45C for 5.0h to yield the solid compound. |
With piperidine; In ethanol; for 8h;Reflux; | Malonic acid (0.05 M, 5.30 g) and veratraldehyde (0.05 M, 8.30 g) were added to a solutionof absolute ethyl alcohol with stirring, then piperidine (0.2 mL) was added. The mixturewas stirred and heated under reflux for 8 h. The solution was added in ice-water,precipitate was obtained and then dissolved in lye. The supernatant was obtained and thenacidification. The white precipitate was separated by filtration, washed three times withwater and dried at 50 C. Anal. Calcd for C11H12O4: C, 63.45; H, 5.81; N, 30.74%. Found:C, 63.23; H, 6.02; N, 30.95%. | |
With pyridine; In N,N-dimethyl-formamide; at 90℃; | General procedure: To a solution of the substituted benzaldehyde (50 mmol) and malonic acid (150 mmol) in DMF (30 mL) was added pyridine (50 mmol) and stirred for 3-5 h at 90 C. After adding water (60 mL), the reaction solution was acidified (pH 1) with concentrated hydrochloric acid and then was cooled to 0 C. Then the residue was filtered, washed with cold water (2×10mL) and dried in vacuum for 12 h to afford corresponding crude product 2 in yields ranging from 30.2 to 100.0%, which was used directly without further purification. | |
With piperidine; pyridine; at 90℃;Inert atmosphere; | General procedure: To a stirred solution of malonic acid (10 mmol) in pyridine(5 mL) and piperidine (3-5 drops) the corresponding aldehydes1a-p (8 mmol) were added. The resulting mixture was stirred at 90C for 8-12 h. The progress of the reaction was monitored byTLC analyses which indicated the disappearance of the starting material. After the completion of the reactions the reaction mixture were cooled to ambient temperature and the reaction mixture was neutralized with 1N HCl in ice bath resulting a white solid.This soled was filtered and washed three times with cold water.The recrystallization were done from aqueous ethanol (1:1)afforded the product 2a-p. | |
With pyridine; at 90℃; | General procedure: 7a-u were prepared by Knoevenagel condensation [45]. Briefly, 5mmol of different aldehydes (6a-u) and 10mmol malonic acid (1.04g) were stirred at 90C in 2mL pyridine solvent overnight. When the reaction was finished as monitored by TLC, 3M HCl was slowly dropped into the mixture until precipitation was complete. The formed precipitate was collected by filtration, washed with cold water and dried in vacuum, yielding compounds 7a-u. Intermediates 7c and 7d (1mmol) was further reacted with different substituted benzyl bromides (2.5mmol) in CH3CN with the presence of K2CO3 (2.0 equiv), followed by hydrolysis in 1M NaOH for 1h to give intermediates 7v-z, which were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | (E)-3,4-dimethoxycinnamic acid (208mg, 1,0mmol) was added to 14mul of triethylamine in 5ml of CH2Cl2 and stirred for 5 min. at room temperature. Thereafter, N-bromosuccinimide (214mg, 1.2mmol) was added and the reaction mixture stirred for another 10 min. at room temperature. CH2Cl2 was removed in vacuo and the residue purified by flash chromatography with silica gel (1:6 EtOAc/Hexanes) to afford (E)-beta-bromo-3,4-dimethoxystyrene (8) as an off-white solid, 90%. 1H NMR(400 MHz, CDCl3): delta7.031 (d, J = 13.93 Hz, 1H), 6.800-6.865 (m, 3H), 6.624 (d, J =13.92 Hz, 1H), 3.886 (s, 3H), 3.878 (s, 3H). 13C NMR (100 MHz, CDCl3): delta149.345, 149.150, 136.785, 129.034, 119.372, 111.213, 108.594, 104.258, 55.913, 55.866. | |
83% | With N-Bromosuccinimide; lithium acetate; In water; at 20℃; for 1h; | 4.10 (E)-4-(2-Bromovinyl)-1,2-dimethoxybenzene (6) To a solution of acrylic acid 5a (400 mg, 1.92 mmol) in MeCN: H2O (19:1, mL) was added LiOAc (25 mg, 0.38 mmol) and NIS (343 mg, 1.92 mmol) at room temperature. The yellow mixture was stirred at room temperature for 1 h before concentrated in vacuo on silica gel. The crude product was purified by flash column chromatography (petroleum ether: EtOAc 5:1) to afford 387 mg (83%) of product 6 as a white solid. Mp 61.8-63.2 C (hexane), lit. 17 66 C. Published data 17 were in accordance with ours: 1H NMR (CDCl3, 400 MHz): delta 7.03 (d, J=14.0 Hz, 1H), 6.86-6.80 (m, 3H), 6.62 (d, J=13.9 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3, 100 MHz): delta 149.2 (C), 149.0 (C), 136.7 (CH), 128.9 (C), 119.3 (CH), 111.1 (CH), 108.4 (CH), 104.2 (CH), 55.9 (CH3), 55.8 (CH3); IR (KBr) 3081 (w), 2953 (w), 2835 (m), 1602 (m), 1577 (w), 1512 (s), 1461 (m), 1438 (m), 1418 (m), 1328 (w), 1304 (w), 1263 (s), 1249 (m), 1208 (m), 1193 (m), 1155 (m), 1139 (s), 1037 (m), 1024 (m), 943 (m), 854 (w), 813 (w), 773 (m), 712 (w); Mass spectrum m/z (relative intensity %) 312.9 [M+Na]+ (100); HRMS (ESI) calcd for C10H11O2INa: 312.9696, found 312.9699. |
80% | General procedure: To a solution of cinnamic acid (20 mmol, 100 mol %) in CH2Cl2 (80 mL, technical grade) was added NEt3 (0.5 mmol, 5 mol %). The mixture was stirred for 5 min at room temperature, and NBS (12 mmol, 120 mol %) was added in small portions. After 20 min, CO2 evolution stopped indicating the completion of the reaction. CH2Cl2 was evaporated under reduced pressure and the remaining slush was purified by flash chromatography over silica gel (ethyl acetate/petroleum ether). |
General procedure: Triethylamine (7 muL) was added to a solution of alpha,beta-unsaturated aromatic carboxylic acid (1 mmol) in dichloromethane (3 mL). After the mixture was stirred for 5 min at room temperature, N-halosuccinimide (1.2 mmol) was added. The solution was stirred for 10 min, and solvent was removed under reduced pressure. The mixture was subjected to column chromatography over silica gel (60-120 mesh, eluent 1% ethyl acetate in hexane) to afford the pure trans-beta-halostyrenes. (E)-4-(2-Iodovinyl) biphenyl can be prepared from corresponding vinyl boronic acid by reported method.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With ammonium cerium(IV) nitrate; trifluoroacetic acid at 23℃; for 1h; Yield given; | |
79% | With ammonium cerium(IV) nitrate; trifluoroacetic acid at 23℃; for 1h; Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; In 1,4-dioxane; at 25℃; for 15h; | General procedure: To a round-bottom flask, cinnamic acid substrates (3.0 mmol) and CDMT (3.0 mmol) in dioxane (10 mL) were added, followed by that, NMM (3.0 mmol) was added to the reaction mixture. The resulted solution was stirred at room temperature for 15 h. The resulting mixture was cooled and then filtered using a syringe filter. Then the mass concentrated and further diluted with diethyl ether. The organic layer was washed with 5% citric acid and followed by 5% sodium bicarbonate. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting crude product was purified by simple column chromatography (eluant hexane/ethyl acetate). |
55% | General procedure: Under argon atmosphere, to a solution of the acid (1 eq.) in dryDCM (10 mL/mmol) at 0 C oxalyl chloride (3 eq.) and DMF (2 drops)were added. After stirring for 1 h at 0 C followed by 1 h at room temperaturethe solvent was removed in vacuo, and the residue was washedwith dry DCM (10 mL/mmol). The residue was re-dissolved in toluene(5 mL/mmol), pyridine (2 eq.) and the corresponding acid (1 eq.) wasadded. The mixture was stirred over night at room temperature. Usualaqueous work-up gave a residue that was washed with ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With lithium aluminium tetrahydride; In tetrahydrofuran; for 5.5h;Reflux; | To a stirred suspension of LiAlH4 (2.73 g, 71.94 mmol) in anhydrous THF (50 mL) was added 2 (10.00 g, 48.03 mmol) as a solid in portions over 30 min. After addition, the resulting reaction mixture was refluxed for 5 h, cooled to room temperature, and quenched with MeOH (20 mL). The resulting suspension was filtered under vacuum, washed in turn with EtOAc (100 mL) and brine, and dried over anhydrous Na2SO4. The organic extracts were concentrated in vacuo to yield a pale yellow oil (3, 7.80 g, 83%). 1H NMR (400 MHz,CDCl3) d 6.79 (d, J 8.1 Hz, 1H, H-5), 6.74 (d, J 6.1 Hz, 2H, H-2 andH-6), 3.86 (s, J 5.7 Hz, 6H, 2 OCH3), 3.67 (t, J 6.2 Hz, 2H,CH2OH), 2.66 (t, J 7.6 Hz, 2H, Ph-CH2), 1.88 (q, J 7.3 Hz, 2H,CH2CH2OH), 1.74 (s, 1H, CH2CH2OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; toluene; at 0℃; for 2h; | Monomer 3, a mixed anhydride, was prepared by reaction of 3-(3',4'-Dimethoxy-phenyl)-acrylic acid in toluene/CH2Cl2 (1: 1) in the presence Of Et3N. The solution was cooled to 0 0C, ethyl chloroformate (1.5 eq.) was added dropwise. After stirring at 0 0C for 2 h, the precipitate was filtered out. The filtrate was concentrated to get a relatively pure white solid, which was purified by a fast filtration through a thin silica gel pad and eluted with hexanes:ethyl acetate (1 :0 to 4: 1) to afford the desired product as a white solid in quantity. ESI MS m/z: 281.0 [M+H] +; 1H NMR (300 MHz, CDCl3) delta: 7.78 (d, IH, J= 15.9 Hz, H-3), 7.15(dd, IH, J= 8.4, 1.8 Hz, H-6'), 7.06 (d, IH, J= 1.8 Hz, H-2'), 6.89 (d, IH, J= 8.4 Hz, H-5'), 6.29 (d, IH, J= 15.9 Hz, H-2), 4.37 (q, 2H, J= 6.9 Hz, OCH2OB), 3.92 (d, 6H, J= 1.2 Hz, phenyl OCH3), 1.40 (t, 3H, J= 7.2, OCH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 23℃; for 16h; | To a solution of caffeic ester 20 (55 mg, 0.25 mmol, 1 equiv) in THF / H2O (2 mL / 1 mL) was added LiOH-H2O (21 mg, 0.50 mmol, 2 equiv) and the reaction mixture was stirred at 23 C for 16 h. The reaction mixture was quenched with a 0.5M aqueous solution of HCl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvents were removed under reduced pressure to yield the desired acid 21 (49 mg, 94%) as white solid. Rf 0.15 (Hex / EtOAc 1:1), UV + CAM; 1H NMR (delta, ppm) CDCl3, 300 MHz. 7.72 (d, J = 15.9 Hz, 1H), 7.11 (dd, J = 8.3, 1.9 Hz, 1H), 7.05 (brd, J = 2.0 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 15.9 Hz, 1H), 3.90 (s, 6H); 13C NMR (CDCl3, 75.4 MHz) delta: 172.9, 151.7, 149.4, 147.2, 127.2, 123.3, 115.1, 111.2, 109.9, 56.2, 56.1; HRMS (ESI): m/z calcd for C11H12O4 [M - H]- 207.0657, found 207.0650. |
77% | With potassium hydroxide; In methanol; at 60℃; for 18h; | 4.3 (E)-3-(3,4-Dimethoxyphenyl)acrylic acid (5a) To a solution of acrylate 4 (1.997 g, 8.98 mmol) in MeOH (50 mL) and water (5 mL) was added KOH (715 mg, 17.88 mmol). The reaction mixture was heated to 60 C for 18 h, before concentrated in vacuo. The residue was dissolved in water (50 mL), added 2 M aqueous NaOH solution (1 mL) and extracted with Et2O (2*60 mL). The water layer was adjusted to pH 0 by the addition of 6 M HCl (4 mL) and extracted a second time with CH2Cl2 (5*50 mL). The latter organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (petroleum ether: EtOAc 1:2) to afford 1.443 g (77%) of product 5a as a white solid. Mp 180.7-181.8 C (hexane), lit. 15 181-182 C. Published data 15 were in accordance with ours: 1H NMR (CDCl3, 400 MHz): delta 7.74 (d, J=15.9 Hz, 1H), 7.14 (dd, J=8.4, 1.96 Hz, 1H), 7.08 (d, J=1.92 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.33 (d, J=15.9 Hz, 1H), 3.93 (s, 6H); 13C NMR (CDCl3, 100 MHz): delta 172.4 (CO), 151.5 (C), 149.2 (C), 147.0 (CH), 127.0 (C), 123.2 (CH), 114.8 (CH), 111.0 (CH), 109.7 (CH), 56.0 (CH3), 55.9 (CH3); IR (KBr) 2840 (w), 1683 (s), 1625 (m), 1597 (m), 1517 (s), 1459 (m), 1427 (m), 1341 (m), 1299 (m), 1265 (s), 1211 (m), 1169 (w), 1142 (s), 1025 (m), 976 (w), 841 (m), 770 (w); Mass spectrum m/z (relative intensity %) 207.2 [M]- (100); HRMS (ESI) calcd for C11H11O4: 207.0663, found 207.0663. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: caffeic acid With sodium hydroxide In water Stage #2: dimethyl sulfate In water at 20℃; for 10h; Stage #3: With hydrogenchloride In water | |
78.8% | With sodium hydroxide for 6h; | |
78.8% | With sodium hydroxide In water for 3.5h; Heating; |
78% | With sodium hydroxide at 90℃; for 6.33333h; | 8 5.1.8. (E)-3-(3,4-Dimethoxyphenyl)-2-propenoic acid (13) Caffeic acid (18 g, 0.1 mol) was dissolved in cool 90 mL NaOH solution(4mol/L), in which process the inner temperature was requiredunder 20 °C. After Me2SO4 (20 mL) was added dropwise and stirred for20 min, 50 mL NaOH solution (4 mol/L) and 20 mL Me2SO4 weredropped into the reaction system constantaneously. The resultingmixture was slowly heated to 90 °C in 1 h and maintained at this temperaturefor 1 h, then the solution was refluxed for 2 h, after 50 mLNaOH solution (4 mol/L) was added, another 2 h of refluxing was applied.The pH of the resulting solution was regulated to 2 by concentratedHCl. Two to three hours later, mass brown solid were attainedby filtrating, and washed to neutrality with water. The gross was recrystallizedin EtOH and H2O to get 16.4 g (yield 78%) light yellowcrystal. 1H NMR (600 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.53 (d,J=15.9 Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 6.98 (d,J=8.2 Hz, 1H), 6.45 (dd, J=15.9, 2.3 Hz, 1H), 3.80 (dd, J=8.9,2.3 Hz, 6H). |
Stage #1: caffeic acid With sodium hydroxide In water at 20℃; Stage #2: dimethyl sulfate In water at 20℃; for 10h; | 16 Example 16; preparation of 17-(2'-(3", 4"-dimethylcaffeoyl amido)ethylamino)-17 -demethoxy geldanamycin(ZJH070413) 1.8g(0.01mol) caffeic acid is added into 15mL purified water and the resulted solution is adjusted to pH 13 using 30%NaOH to dissolve completely caffeic acid. 6g dimethyl sulfate (0.05mol) is added into the solution which is reacted at room temperature for 10h with stirring and adjusting pH to higher than 10 at intervals, then adjusting pH to 3 using 2N HCl. After filtering the resultant, the solid is washed with water until the water filtered out reaches a pH of 6-7. The solid is dried to obtain 3, 4-dimethyl caffeic acid. | |
With sodium hydroxide | ||
With sodium hydroxide In water at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: EDAC / dioxane; H2O 1.2: 35 percent / aq. NaOH / Heating 2.1: K2CO3 / dimethylformamide | ||
Multi-step reaction with 2 steps 1: 1) 1-<3-(dimethylamino)propyl>-3-ethylcarbodiimide hydrochloride, 2) 1N NaOH / 1) dioxane, H2O, 2) dioxane, H2O, reflux 2: K2CO3 / dimethylformamide / 50 °C | ||
Multi-step reaction with 4 steps 1.1: thionyl chloride / toluene / 16 h / 75 °C 2.1: pyridine / dichloromethane / 24 h / 20 °C 3.1: acetonitrile / Microwave irradiation 3.2: 5 h / 160 °C / Microwave irradiation 4.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In cyanoacetic acid; | 4-Hydroxyphenethyl 2-cyano-3-(3,4-dihydroxyphenyl)-2-propenoate (Compound 20) After the reduction of 3,4-dimethoxycinnamic acid to 3-(3,4-dimethoxyphenyl)propanol in the usual manner followed by condensation with cyanoacetic acid according to the procedure in Example 3, the product was demethylated with boron trichloride and condensed with 3,4-dihydroxybenzaldehyde to give the following compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With hydrogenchloride; triethylamine In <i>N</i>-methyl-acetamide; ethanol; water | 6 EXAMPLE 6 EXAMPLE 6 2 Grams of 3,4-dimethoxycinnamic acid were dissolved in a mixture of 20 ml of dry dimethylformamide and 1.5 g of triethylamine. To this solution was added under ice cooling and agitation 1.1 g of ethyl chlorocarbonate and the mixture was then reacted for one hour. To this mixture were added 10 ml of dimethylformamide containing 1.5 g of 3-aminobenzoic acid and the mixture was stirred for 2 hours. After completion of the reaction, the reaction liquid was concentrated approximately to 1/2 volume and poured into an aqueous solution of hydrochloric acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from an equivolume mixture of ethanol and water to obtain a yield of 50% 3-(3',4'-dimethoxycinnamoylamino)-benzoic acid having a melting point of 225°-226°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 g (59%) | With hydrogenchloride; thionyl chloride; In chloroform; water; Petroleum ether; benzene; | EXAMPLE III 3-Diethylamino-2,2-dimethylpropyl 3,4-dimethoxyphenylcinnamate hydrochloride 3,4-Dimethoxycinnamic acid (31.4 g, 0.15 mole) was added with rapid stirring to thionyl chloride (52.5 ml) and refluxed for 4 hours. The mixture was stripped of excess thionyl chloride under reduced pressure, benzene (100 ml) was added, and the mixture was again stripped of solvent. The residue was treated with a solution of <strong>[39067-45-3]3-diethylamino-2,2-dimethylpropanol</strong> (24.2 g, 0.15 mole) in benzene (500 ml), refluxed for 3 hours, cooled, diluted with petroleum ether (500 ml), and stored overnight at room temperature. The benzene-petroleum ether solution was decanted, the residue dissolved in H2 O (800 ml), and the solution adjusted to pH 8 with saturated aqueous K2 CO3 (60 ml). The product was extracted from the aqueous phase with benzene (800 ml) in portions and the extract dried overnight over MgSO4 and Darco. The solution was filtered and the filtrate adjusted to pH 3 with a solution of dry HCl in ether (cooled in ice bath). Petroleum ether (500 ml) was added and the product oiled out of solution. The benzene-petroleum ether solution was decanted, chloroform (5-0 ml) was added and the mixture was stripped to dryness under reduced pressure. This procedure was repeated three times and then the residue was washed with anhydrous ether (scratching induced crystallization). The product was collected by filtration, yield: 34 g (59%). A sample was recrystallized from ethyl acetate, m.p. 135-138. Anal. Calc'd for C20 H31 NO4.HCl: C, 62.24; H, 8.36; N, 3.63. Found: C, 62.43; H, 8.37; N, 3.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: To a suspension of the corresponding cinnamic acid (31a-31f) (6.67 mmol, 1.0 equiv) in 15 mL CH3CN at room temperature, was added HOBt (8 mmol, 1.2 equiv) in a single portion, followed by EDC (8 mmol, 1.2 equiv). The reaction was stirred at room temperature for 2 h, the time required for the complete consumption of cinnamic acid. The resulting mixture was then slowly added to a solution of hydrazine hydrate (13.34 mmol, 2.0 equiv) in 15 mL of CH3CN kept between 0 and 10 C. The reaction was usually completed upon the end of addition. Then, 15 mL of water was added. The reaction medium was extracted with ethyl acetate (3 × 30 mL) and aqueous sodium bicarbonate (1 × 50 mL). The organic phases were joined and the solvent was evaporated under reduced pressure to furnish the respective N-acylhydrazines (33a-33f), as described next. | |
73.4% | General procedure: The key intermediate acylhydrazine was synthesized by hydrazinolysis of carboxylic acid.1 The acid (1.0 mmol) was dissolved in DMF (10 mL), followed by HoBt and EDC·HCl as coupling agents. The reaction was conducted at room temperature. After the acid was completely converted to the active intermediate, a solution of 80% hydrazine hydrate (2.0 mmol) and DMF (1.0 mL) was slowly added to the mixture which was in ice-bath. After reacting for 0.5~1 h, distilled water (50 mL) was added. The resulted product was filtered, dried and recrystallized to obtain the intermediates C1-C8. Their structures were determined by 1H NMR and 13C NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dimethoxy-trans-cinnamic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.0833333h; Stage #2: 1,8-dihydroxy-3-hydroxymethyl-9,10-anthracenedione In dichloromethane at 20℃; | General procedure for synthesis of ester derivatives of aloe-emodin General procedure: Substituted benzoic acids or cinnamic acids (0.1 mmol) in dry CH2Cl2 (0.2 mL) were treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 20.6 mg, 0.1 mmol) and DMAP (1.0 mg, 0.006 mmol). The mixtures were stirred at room temperature for 5 min. Aloe-emodin (2, 5.4 mg, 0.02 mmol) was added, and stirring was continued at room temperature until the starting compound was consumed. The resulting solution was diluted with EtOAc (10 mL) and concentrated on a rotary evaporator. The final benzoate and cinnamate derivatives of aloe-emodin were purifiedby using preparative TLC (silica gel, 500 m; hexane/EtOAc, 4:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 24h; | Procedure for the synthesis of (E)-N-(9H-carbazol-3-yl)-3-(3,4-dimethoxyphenyl)acrylamide (BS 2) To a solution of 3,4-dimethoxycinnamic acid (0.66 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 0.83 mmol) and 4-dimethylaminopyridine (4-DMAP, 0.22 mmol) in tetrahydrofuran anhydrous (20 mL) was added 9H-carbazol-3-amine (3, 0.55 mmol). The reaction mixture was stirred at room temperature for 24 h. The crude mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain BS 2. Yield 76.5%, Yellow colored solid, mp: 194.6 , Rf = 0.18 (1:1 n-hexane-ethyl acetate); 1H NMR(400MHz, DMSO-d6): δH 11.20 (s, NH), 10.14 (s, NH), 8.53 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 16.4 Hz, 1H), 7.46 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 15.2 Hz, 1H), 3.84 (s, 3H, OCH3), 3.80(s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δC; 163.6, 150.3, 149.0, 140.4, 139.6, 136.4, 131.3, 127.7, 125.7, 122.4, 122.2, 121.6, 120.4, 120.1, 118.8, 118.4, 111.8, 111.1, 111.0, 110.9, 110.0, 55.5, 55.4; IT-TOF/MS: m/z = 395.1314 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: The corresponding acid (1mmol) and CDI (1.15mmol) were mixed into a microwave tube under nitrogen atmosphere. The tube was sealed up and 3mL of anhydrous THF were added using a syringe to dissolve the mixture (CO2↑). This solution was heated into a microwave reactor at 120C during 7min to complete the acid activation. Afterward, a solution of 1.2mmol of the corresponding amine in 2mL of THF was added with a syringe into the tube; this mixture was heated at 120C during 10min for NBP derivatives and 40min for DBMA hybrids. After solvent evaporation under reduced pressure, the crude was re-dissolved in 25mL of EtOAc and washed with water (3×5mL) and brine (3×5mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography using EtOAc:MeOH (9:1) or hexane/EtOAc (0→70%) as eluent. 4.2.1 (E)-N-(2-(1-Benzylpiperidin-4-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (1) (0028) From 3,4-dimethoxy cinnamic acid (0.100g, 0.48mmol) and 2-(1-benzylpiperidin-4-yl)ethan-1-amine (0.126g, 0.58mmol), hybrid 1 was obtained (0.170g, 87%) as a light yellow solid of mp: 108.1-110.5C. 1H NMR (500MHz, MeOD) δ 7.46 (d, J=15.7Hz, 1H, H3), 7.32 (s, 2H, Hm), 7.31 (s, 2H, Ho), 7.29-7.24 (m, 1H, Hp), 7.14 (d, J=2.0Hz, 1H, H5), 7.12 (ddd, J=8.2, 2.0, 0.5Hz, 1H, H9), 6.96 (d, J=8.2Hz, 1H, H8), 6.47 (d, J=15.7Hz, 1H, H2), 3.86 (s, 3H, H71), 3.85 (s, 3H, H61), 3.51 (s, 2H, Hγ), 3.35-3.32 (m, 2H, Hα), 2.90 (dt, J=12.1, 3.5Hz, 2H, H2′eq), 2.05-1.99 (m, 2H, H2′ax), 1.76-1.71 (m, 2H, H3′eq), 1.50 (dt, J=7.9, 6.6Hz, 2H, Hβ), 1.37 (dddd, J=16.4, 9.7, 6.4, 3.5Hz, 1H, H4′), 1.28 (qd, J=12.1, 3.5Hz, 2H, H3′ax). 13C NMR (126MHz, MeOD) δ 168.86 (C1), 152.20 (C6), 150.70 (C7), 141.56 (C3), 138.19 (Ci), 130.92 (Co), 129.36 (C4), 129.26 (Cm), 128.43 (Cp), 123.16 (C9), 119.67 (C2), 112.71 (C8), 111.31 (C5), 64.34 (Cγ), 56.42 (C61), 56.40 (C71), 54.64 (C2′), 38.10 (Cα), 37.10 (Cβ), 34.44 (C4′), 32.72 (C3′). HRMS [ESI+] m/z=408.2407 [M]+, Calcd for [C25H32N2O3]+ 408.2413. HPLC purity 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h;Inert atmosphere; | General procedure: The following procedure is the generalized synthetic procedure used for the synthesis of direct amide-linked benzoisoxazole derivatives. At room temperature, EDC (1.5 equiv) and a benzoisoxazole moiety (1) (1.1 equiv) were added to a solution of the corresponding carboxylic acid (4-9) in DCM. The reaction mixture was stirred for 4 h at room temperature. After the reaction was confirmed as completed by TLC, it was quenched by adding water. The resulting solution was extracted with DCM thrice and dried over anhydrous MgSO4. The solvent was removed under vacuum, and the crude product purified by silica gel column chromatography (DCM:MeOH = 9:1) to obtain the desired amide-linked compound (18-23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; | 3.12. tert-Butyl (S)-1-[(E)-3-(3,4-dimethoxyphenyl)propenoyl]pyrrolidine-2-carboxylate (5c) To a solution of HOBt (5.47 g, 40.5 mmol), L-proline tert-butyl ester (5.32 g, 31.1 mmol), 3,4-dimethoxycinnamic acid (6.48 g, 31.1 mmol) in THF (100 mL) was added DCC (8.34 g, 40.4 mmol) at 0 C. After stirring at room temperature for 5 h, the reaction mixture was filtered through Celite. The filtrate was poured into sat. NaHCO3 solution and extracted with EtOAc. The organic layerwas washed with sat. NH4Cl solution and brine, dried with anhyd MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel. Elution with hexane-EtOAc (1:1e1:6) gave 5c (8.56 g, 76%) as a colorless oil; [a]D22 -61 (c 0.73, CHCl3). IR (neat): 2969, 1737, 1650, 1597, 1514, 1422, 1265, 1154, 1024 cm1. 1H NMR (300 MHz, CDCl3, several peaks appeared separately as amide rotamers): d 1.43 (3H, s), 1.47 (6H, s), 1.89-2.36 (4H, m), 3.62-3.88 (2H, m), 3.90 (4H, s), 3.91 (2H, s), 4.50 (1H, m), 6.44 (1/3H, d, J = 15.4 Hz), 6.60 (2/3H, d, J = 15.4 Hz), 6.85 (1H, d, J = 8.1 Hz), 6.98-7.14 (2H, m), 7.63 (1/3H, d, J = 15.4 Hz), 7.65 (2/3H, d, J = 15.4 Hz). 13C NMR (125 MHz, CDCl3): d 22.8, 24.7, 27.9, 28.0, 29.2, 31.4, 46.7, 47.0, 55.9, 59.8, 60.3, 81.1, 82.0, 109.8, 110.0, 111.0, 116.0, 121.9, 128.2, 142.2, 142.5, 149.0, 150.5, 164.9, 165.4, 171.5, 171.8 cm1. HRMS (EI) [MNa] calcd for C20H27NNaO5: 384.1787; found: 384.1739. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 3,4-dimethoxy-trans-cinnamic acid With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 5℃; for 0.25h; Stage #2: N-(7-chloroquinolin-4-yl)ethylenediamine With benzotriazol-1-ol In tetrahydrofuran at 0 - 5℃; for 1.5h; | 4.4 General synthetic procedure for cinnamoyl compounds (9-14) General procedure: To the substituted cinnamic acid (1.0eq) derivatives (3-8) 15ml of tetrahydrofuran was added and cooled to 0-5°C, to this cooled solution 1.0eq of dicyclohexyl dicarbodimide (DCC) was added and stirred for 15min. Then (1.0eq of N-hydroxy benzo triazine) HOBT was added, stirred for 30 min and the solution of compound-2 (1.1eq) was added at 0-5°C for 60 min. The resulted mixture was maintained overnight at 25-30°C and the reaction was monitored by TLC. After completion of reaction the reaction mass was quenched into cold water 40ml and extracted with dichloro methane 2×25ml. The organic layer was dried with sodium sulfate, concentrated under high vacuum, charged into 10ml THF and kept at 0-5°C over night. The resulted solid was filtered under vacuum and also dried under vacuum at 45°C for 5h to obtain dried solid compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; | General Synthesis of Methyl (E)-4-(4-(3-argioacryloyl)piperazin-1-yl)benzoate 5a-i from (E)-3-argioacrylic acid 4a-i General procedure: To (E)-3-argioacrylic acid 4a-i (5 mmol), methyl 4-(piperazin-1-yl)benzoate 3 (5.55 mmol) and TBTU(1.35 g, 5.3 mmol) in acetonitrile (50 mL) was added DBU (4 mL, 5.35 mmol). After stirring 16 h atroom temperature, the resulting white percipitate 5a-i was removed by filtration, dried in vacuo andused in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 24h; | 3.2.1. General Procedure for One Pot Synthesis of Cinnamic Amides 1a-b, 2a-b and 3a-b General procedure: To a stirred solution of the appropriate cinnamic acid 1, 2 or 3 (1 equivalent) and propranololor atenolol (1.1 equivalents) in dichloromethane (25 mL), BOP (1.2 equivalents) and triethylamine(4 equivalents) were added [24,26]. The end of the reaction was monitored by TLC. After 24 h ofstirring at room temperature, the dichloromethane was removed under reduced pressure and ethylacetate (80 mL) was added to the residue. The resulted solution was washed with 10% citric acid(2 20 mL), 10% solution of NaHCO3 (3 20 mL), water (20 mL) and brine (2 20 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product waspurified by preparative thin layer chromatography (Prep TLC) or crystallized from the appropriatesolvent or triturated from diethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3,4-dimethoxy-trans-cinnamic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 20℃; for 2h; Stage #2: 8-aminooctan-1-ol In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 3,4-dimethoxy-trans-cinnamic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 20℃; for 2h; Stage #2: 10-amino-1-decanol In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | With sulfated montmorillonite K-10 In nitrobenzene at 100℃; Green chemistry; | General Procedure for the Synthesis of 4-Aryl-3,4-dihydrocoumarins 9-20 General procedure: A mixture of a substituted cinnamicacid (5 mmol) and a substituted phenol (5 mmol) in nitrobenzene (10 mL) was heated to 100C. Sulfated montmorilloniteK-10 (2 g) was added to the mixture after all reagents were dissolved, and the mixture was stirred at 100C for 3-12 h.The reaction process was monitored by TLC (CH2Cl2-CH3OH, 10:1). The suspension was directly filtered, and a suitableamount of petroleum ether was added to the filtrate. Then the mixture was cooled and stored or stirred under low temperaturefor a certain length of time to promote crystallization of the product. The crude product was recrystallized from EtOAc-PE toafford 9-20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; thionyl chloride | 2; 5 Preparation of 2,6-bis(3,4-dimethoxystyryl)benzo[1,2-4,5]bisoxazole Ferulic acid 5.2 gWas methylated with 17.8 g of dimethyl sulfate4.3 g of 3,4-dimethoxycinnamic acid was prepared,This was converted to pyridine,And acid chloride with thionyl chloride to give 3,4-dimethoxycinnamic acid chloride.To this was added 1.7 g of 2,6-dichloro-1,4-phenylenediamine and 100 ml of monochlorobenzene,And refluxed for 12 hours.After cooling down,The precipitate was filtered off,Washed to recover 1.8 g of a yellow solid.To 1.8 g of the above intermediate, 2.0 g of copper acetate,6 ml of pyridine and 20 ml of DMF were weighed, refluxed for 12 hours,After cooling down,The precipitate was filtered off,Column purification gave λ max 404 nm,To obtain the desired product having a melting point of 300 ° C. or higher. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | Methyl (E)-1-[3-(3,4-dimethoxyphenyl)acryloyl]aziridine-2-carboxylate (12b). Oxalyl chloride (0.14 ml, 1.59 mmol)and 3 drops of DMF were added to a stirred solution of3,4-dimethoxycinnamic acid (11b) (300 mg, 1.44 mmol) inCH2Cl2 (8 ml), and the mixture was stirred at roomtemperature for 2 h. The solvent and oxalyl chloride excesswere evaporated under reduced pressure to give desiredacid chloride as a yellow solid which was then dissolved inMeCN (2 ml) and added dropwise to a stirred solution ofmethyl aziridine-2-carboxylate (1b) (146 mg, 1.44 mmol)and Et3N (0.44 ml, 3.17 mmol) in MeCN (7 ml) at -5°Ctemperature. After 30 min, the ice bath was removed, andthe reaction mixture was stirred at room temperatureovernight. The precipitate was filtered off and washed withMe2CO. The solution was concentrated under reducedpressure, and the residue was purified by flash chromatographyon silica gel (eluent petroleum ether - EtOAc, 1:1).Yield 207 mg (49%), white solid, mp 103-105°C. 1H NMRspectrum (CDCl3), δ, ppm (J, Hz): 7.68 (1H, d, J = 15.9,CH=CHCO); 7.12 (1H, dd, J = 8.3, J = 2.0, H-6 Ar); 7.05(1H, d, J = 2.0, H-2 Ar); 6.87 (1H, d, J = 8.3, H-5 Ar); 6.49(1H, d, J = 15.9, CH=CHCO); 3.92 (3H, s, OCH3); 3.91(3H, s, OCH3); 3.79 (3H, s, OCH3); 3.23 (1H, dd, J = 5.8,J = 3.1, NCH); 2.68 (1H, dd, J = 3.1, J = 1.6) and 2.60 (1H,dd, J = 5.8, J = 1.6, NCH2). 13C NMR spectrum (CDCl3),δ, ppm: 176.5 (NC=O); 169.0 (NCC=O); 148.5 (C-4 Ar);146.9 (C-3 Ar); 145.1 (CH=CHCO); 126.9 (C-1 Ar); 123.5(CH=CHCO); 117.5 (C-6 Ar); 114.9 (C-5 Ar); 109.8 (C-2 Ar);56.1 (OCH3); 56.0 (OCH3); 52.8 (CO2CH3); 34.8 (C-2aziridine); 31.3 (C-3 aziridine). Mass spectrum, m/z (Irel, %):292 [M+H]+ (100). Found, %: C 61.41; H 5.79; N 4.66.C15H17NO5. Calculated, %: C 61.85; H 5.88; N 4.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | General procedure: <strong>[28957-04-2]Oridonin</strong> (100 mg, 0.27 mmol) wasmixed with 4-methoxycinnamic acid (48 mg, 0.27 mmol),EDCI(157 mg, 0.82 mmol) and DMAP(101 mg, 0.82 mmol) in drydichloromethane(10 mL) and stirred at room temperature overnight.The mixturewas poured into 1MHCl solution, and extractedwith dichloromethane. The organic layer was combined, washedwith water and saturated NaCl solutions, dried over anhydrousMgSO4, filtered, and concentrated in vacuo. The crude product waspurified by column chromatography to give the compound 20(122 mg, 86%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With 4-(dimethylamino)pyridine N-oxide; phenylboronic acid In neat (no solvent) at 200℃; for 0.5h; Microwave irradiation; chemoselective reaction; | Cinnamamide Derivatives 3 and 5; General Procedure General procedure: A mixture of carboxylic acid 1 (0.5 mmol), amine 2 or 4 (0.5 mmol),phenylboronic acid (5 mol%), and DMAPO (5 mol%) was placed in acylindrical quartz reactor (∅ = 1.1 cm). The reactor was then introducedinto an Anton Paar Monowave 300. The stirred mixture washeated at 200 °C (P = 100 W) for 15 min. After microwave dielectricheating, the crude reaction mixture was allowed to cool down to r.t.and partitioned between CH2Cl2 (5 mL) and sat. aq NaHCO3 (5 mL).The aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combinedorganic layers were washed with aq 1 N HCl (2 CH2Cl2 5 mL),dried (MgSO4), filtered, and concentrated under vacuum. The crudeproduct was purified using cold diisopropyl ether as a trituration solventor by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere; | 3.1.4. General Procedure of Hydroxyurea Analogs by Peptide Coupling General procedure: Et3N (TEA) (1 eq) was added dropwise to a stirred solution of hydroxyl urea (32) (1 eq) and the appropriate carboxylic acid (1 eq) in 5 mL of DMF at 0 °C. BOP (1 eq) dissolved in 10 mL of CH2Cl2was then added dropwise to the mixture under argon atmosphere at 0 °C. The mixture was stirred for 30 min at 0 °C and at room temperature for 2 h. Water (50 mL) was added followed by extraction with EtOAc (3 × 25 mL). The combined organic fractions were washed with brine, dried over MgSO4, decolorized with activated charcoal, filtered, and concentrated under vacuum. The resulting oil was purified by flash chromatography or filtered through celite if the product crystallizes during concentration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; Cooling with ice; | 2.2.2. General synthesis method of memantine hybrids (1-5) General procedure: The corresponding cinnamic/dihydro-p-coumaric acids (15.4 mmol), 2.09 g (15.4 mmol) HOBt and 2.95 g (15.4 mmol) EDC were dissolved in 25 mL CH2Cl2/DMF (1:1.5). The mixture was stirred for 6-8 min on an ice bath, and then a solution of 2.77 g (15.4 mmol) memantine hydrochloride and 1.77 mL (15.4 mmol) NMM in dry CH 2 Cl 2 (15 mL) was added. After one hour, the mixture was allowed to reach room temperature and stirred for an additional 23 h. Then, the solvents were removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The organic solution was subsequently washed with 5% NaHCO3 (3 ×50 mL), 1 M HCl (3 ×50 mL), and brine (3 ×50 mL). After the evaporation of ethyl acetate, the crude products were purified by column chromatography (HE/ EtOAc) and recrystallized from acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: thionyl chloride / 3 h / Reflux 2: triethylamine / dichloromethane / 4 h / 0 - 5 °C / Inert atmosphere 3: sodium hydroxide; water monomer / methanol |
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