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CAS No. : | 1866-39-3 | MDL No. : | MFCD00002697 |
Formula : | C10H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RURHILYUWQEGOS-VOTSOKGWSA-N |
M.W : | 162.19 | Pubchem ID : | 731767 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.1 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.08 |
TPSA : | 37.3 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) : | -5.52 cm/s |
Log Po/w (iLOGP) : | 1.79 |
Log Po/w (XLOGP3) : | 2.49 |
Log Po/w (WLOGP) : | 1.98 |
Log Po/w (MLOGP) : | 2.2 |
Log Po/w (SILICOS-IT) : | 2.18 |
Consensus Log Po/w : | 2.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.65 |
Solubility : | 0.361 mg/ml ; 0.00223 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.92 |
Solubility : | 0.196 mg/ml ; 0.00121 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.24 |
Solubility : | 0.938 mg/ml ; 0.00578 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.81 |
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 |
---|---|---|
palladium; In tetrahydrofuran; | EXAMPLE 5 4-(p-Methylhydrocinnamamido)benzoic acid, ethyl ester A solution of 65 g. of p-methylcinnamic acid, 1 g. of palladium on carbon catalyst, and 200 ml. of tetrahydrofuran is hydrogenated in a Parr apparatus at an initial pressure of 50 p.s.i., overnight. The mixture is filtered and the filtrate is evaporated, giving 65.2 g. of 3-(4-methylphenyl)propionic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid Inert atmosphere; Reflux; | |
With sulfuric acid for 5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sulfuric acid at 65℃; for 16h; | |
94% | With thionyl chloride at 0℃; for 6h; Inert atmosphere; Reflux; | |
93% | With sulfuric acid for 4h; Heating; |
93% | for 4h; Heating; | |
92% | With thionyl chloride at 40℃; for 3h; | |
58% | With sulfuric acid | |
With thionyl chloride | ||
Multistep reaction; | ||
With sulfuric acid Heating; | ||
With toluene-4-sulfonic acid for 12h; Heating; | ||
With thionyl chloride at 0℃; Reflux; | ||
With thionyl chloride at 0℃; Reflux; | ||
With thionyl chloride at 20℃; for 2h; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid at 66℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; | To a 0C stirring suspension of 4.22 g of the acid (26.02 mmol; 1.0 eqmol) in 50.0 mL of DCM, it was added 2.38 mL of oxalyl chloride (27.32 mmol; 1.05 eqmol) and then 60 uL of DMF (0.7806 mmol; 0.03 eqmol). The ice bath was removed and the reaction was allowed to stir at room temperature until gas evolution ceased (bubbler monitor).All the volatiles were then evaporated at the rotavap under high vacuum. 4.723 g (26.14 mmol; quant.) of a white solid were recovered. This material was used in the next step without any further purification. |
100% | With thionyl chloride; In N,N-dimethyl-formamide; for 4.0h;Reflux; | General procedure: To a solution of 1.2 equiv of substituted cinnamic acid 1a-l (5 mmol) in 5 equiv of thionyl chloride(3.6 mL), a catalytic amount of DMF was added. The reaction mixture was refluxed for 4 h, andthen, solvent was evaporated under vacuum to get the product 2a-l in the form of a solid residue inquantitative yield. The solid residue was directly added partially to an ice-cold stirred solution of1.0 equiv of tert-butyl (2-aminoethyl)carbamate or tert-butyl (3-aminopropyl)carbamate and 2.0 equivtriethylamine in DCM (20 mL). After the addition, the mixture was warmed to room temperature andstirred for 2 h. Then, DCM (20 mL) was added and washed with 0.2 M HCl (40 mL), H2O (40 mL),5% saturated. NaHCO3 (40 mL) and brine (40 mL), then dried over anhydrous magnesium sulfate.The solvent was removed in vacuo to give the corresponding cinnamamide derivatives 3a-l (65%-75%,from 1a-l) and 4a-g (59%-70%, from 1a-g) as a white solid. 3a-l, 4a-g (4 mmol) in DCM/TFA(9:1, 40 mL) were stirred at room temperature for 1 h. Solvents were removed in vacuo to yield 5a-l(100%) and 6a-g (100%) as a colorless oil. |
99.6% | With pyridine; thionyl chloride; In dichloromethane; at 20℃; for 3.5h; | 4 mmol of (E)-3-(4-methylphenyl)acrylic acid, 15 ml of dichloromethane, 1.5 ml of thionyl chloride and 1 drop of pyridine were placed in a 50 ml round bottom flask.After stirring at room temperature for 3.5 h, the solvent was evaporated.The yield was 99.6%, which was used in the next reaction without purification. |
89.6% | With thionyl chloride; In toluene; at 70℃; for 4.0h; | In a 100 mL three-necked bottle equipped with a gas absorption device and a reflux condenser,Join against4-Methylphenyl Acrylic Acid(16.2 g, 0.10 mol) and toluene (50 mL),Thionyl chloride (11.9 g, 0.10 mol) was added dropwise and slowly heated to 70C.Constant temperature reaction for 4 hours. After cooling, concentrate under reduced pressure to remove excess thionyl chloride.The residue was frozen to give a pale yellow solid which was recrystallized from dichloromethane.Obtained white crystals 16.2g, a yield of 89.6%. |
With thionyl chloride; In dichloromethane; | (a) To a stirred mixture of 100 g (0.62 moles) p-methylcinnamic acid in methylene chloride (about 30 ml), 88 g (0.74 moles) thionyl chloride was added dropwise. The reaction mixture was then refluxed for 24 hours. The methylene chloride was removed under reduced pressure and heat to give the corresponding p-methylcinnamic acid chloride. Fresh methylene chloride was added to the acid chloride; half of which was used in Step (b). | |
With thionyl chloride; In benzene; | A. 3-p-Tolyl-acryloyl chloride Thionyl chloride (9.44 mL, 129.5 mmol) is added dropwise to a solution of 3-p-tolyl-acrylic acid (20 g, 123.3 mmol) in benzene (50 mL) at 0 C. The resulting solution is allowed to warm to room temperature then heated to reflux for 2 hours. The mixture is concentrated to dryness on the rotovap to give the crude product (22.3 g, 123.3 mmol) which is taken onto the next step. 1H NMR (CDCl3, 300 MHz) delta7.80 (d, 1H), 7.50 (d, 2H), 7.26 (d, 2H), 6.58 (d, 1H), 2.40 (s, 3H). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 0 - 20℃; for 3.0h; | DMF (5 drops) was added to a solution of <strong>[1866-39-3]4-methylcinnamic acid</strong> (15,19g) in THF (100mL and oxalyl chloride (9.6mL) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. Oxalyl chloride (4.0mL) was further added. The mixture was further stirred at room temperature for 1 hour, and concentrated to dryness. The residue was dissolved in ethyl acetate (50mL), and the solution was added dropwise to a mixed solution of 25% aqueous ammonia (50mL)-ethyl acetate (20mL) under ice-cooling. The aqueous layer was salted out, and the organic layer was extracted with ethyl acetate. The extract was dried with magnesium sulfate, and concentrated under reduced pressure. The precipitates were washed with hexane and diethyl ether to obtain the title compound (11.63g) as colorless crystals. 1H-NMR (CDCl3) delta: 2.37 (3H, s), 5.56 (2H, brs), 6.41 (1H, d, J = 15.8), 7.18 (2H, d, J = 8.0), 7.42 (2H, d, J = 8.0), 7.62 (1H, d, J = 15.8). IR (KBr): 1671, 1601, 1518, 1397, 1254, 1123, 990, 816cm-1. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 0 - 20℃; for 3.0h; | To a THF (100 mL) solution of <strong>[1866-39-3]4-methylcinnamic acid</strong> (15.19 g), DMF (5 drops) was added and oxalyl chloride (9.6 mL) was further added thereto with ice-cooling, followed by stirring at room temperature for 2 hours. Oxalyl chloride (4.0 mL) was further added and, after stirring at room temperature for 1 hour, the mixture was concentrated to dryness. The residue was dissolved in ethyl acetate (50 mL) and the solution was added dropwise in a mixture of 25% ammonia water (50 mL) and ethyl acetate (20 mL) with ice-cooling. The aqueous layer was salted out and the organic layer was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The deposit was washed with hexane and diethyl ether to obtain the title compound (11.63 g) as colorless crystals. 1H-NMR (CDCl3) delta: 2.37 (3H, s), 5.56 (2H, brs), 6.41 (1H, d, J = 15.8), 7.18 (2H, d, J = 8.0), 7.42 (2H, d, J = 8.0), 7.62 (1H, d, J = 15.8). IR (KBr): 1671, 1601, 1518, 1397, 1254, 1123, 990, 816 cm-1. | |
With thionyl chloride; at 80℃; for 4.0h; | General procedure: The starting materials (acids 7-19) for the synthesis of amides should be activated in the first procedure: the compounds 7-19 (1.0 mM) and SOCl2 (6-10 mL) were mixed and stirred at reflux 80Cfor 4 h. The reaction mixture was cooled and evaporated to give reactive acyl chloride obtained as an oil, which would be dissolved in ethyl acetate (5-6 mL) in the next step. | |
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 50℃; for 1.0h; | 5.50 g (0.034 mol) of 4-methylcinammic acid, 61 ml of toluene and 0.27 g (3.7 mmol) g of N,N-dimethylormamide are provided and mixed with 4.8 g (0.041 mol) of thionyl chloride. Stirring takes place for 1 hour followed by heating to 50 C. The toluene and excess thionyl chloride are drawn off under vacuum. Then 18 ml of toluene and 4.8 g (0.037 mol) of ethyldiisopropylamine are added at 60 C. A solution of 6.8 g (0.037 mol) of cyclohexyl-2-pyridylamine in toluene is added and stirred for 1 hour at 60 C. Hydrolysis with water is performed and 2-methyltetrahydrofuran is added. The organic phase is separated and washed with water, 1 N NaOH and again with water. The organic phase is rotated and the residue crystallised from MTBE. The crystallised solid is drawn off, washed with MTBE and dried, wherein the desired compound is obtained.Yield: 62% | |
With thionyl chloride; N,N-dimethyl-formamide; at 60℃; for 2.0h; | General procedure: The carboxylic acid (6.5mmol) was dissolved in excess thionyl chloride (10ml) and two drops of DMF. The mixture was kept 60C for 2h and excess thionyl chloride was evaporated. The freshly prepared acyl chloride was then dissolved in 15ml of THF and the resulting solution was added to the mixture of 9a, 9b or 9c (5.5mmol) and sodium bicarbonate (13.5mmol).The resulting mixture was stirred for 8h at room temperature. After removing the solvent, the mixture was acidified with 1M HCl and the final product was purified by recrystallization in water/ethanol. | |
With thionyl chloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 4.0h;Reflux; | General procedure: The mixture of appropriate substituted trans-cinnamic acid(3 mmol), thionyl chloride (6 mmol) and DMF (1 drop) in dry 1,2-dichloroethane (10 ml) were refluxed for 4 h under anhydrous conditions. Volatiles were then removed under reduced pressure at 50 C. The residue (acid chloride) was dissolved in 1,2-dichloroethane (5 ml). This solution was added dropwise to an ice-cold stirred solution of 6 (2 mmol) and triethylamine (9 mmol) in 1,2-dichloroethane (20 ml) over 10 min under anhydrous conditions. The reaction mixture was stirred for an additional 17 h at room temperature. Upon completion of the reaction (monitored byTLC, solvent system 10% MeOH in DCM), the reaction mixture was washed successively with a saturated NaHCO3 solution (50 ml) and water (2 50 ml). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was rotary-evaporated to dryness to yield the crude product which was column-chromatographed on silica gel (eluent 2% MeOH in DCM) to obtain the pure product. | |
With thionyl chloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 4.0h;Reflux; | General procedure: The mixture of appropriate substituted trans-cinnamic acid (3mmol), thionyl chloride (6mmol) and DMF (1 drop) in dry 1,2-dichloroethane (10ml) were refluxed for 4h under anhydrous conditions. Volatiles were then removed under reduced pressure at 50C. The residue (acid chloride) was dissolved in 1,2-dichloroethane (5ml). This solution was added dropwise to an ice-cold stirred solution of 6 (2mmol) and triethylamine (9mmol) in 1,2-dichloroethane (20ml) over 10min under anhydrous conditions. The reaction mixture was stirred for an additional 17h at room temperature. Upon completion of the reaction (monitored by TLC, solvent system 10% MeOH in DCM), the reaction mixture was washed successively with a saturated NaHCO3 solution (50ml) and water (2×50ml). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was rotary-evaporated to dryness to yield the crude product which was column-chromatographed on silica gel (eluent 2% MeOH in DCM) to obtain the pure product. | |
With thionyl chloride; triethylamine; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 12.0h; | General procedure: Different substituted carboxylic acid (5mmol) and SOCl2 (7.5mmol) were dissolved into CH2Cl2 (10 mL)solvent, two drops of N, N-dimethylformamide (DMF) ascatalyst and triethylamine (TEA) (5mmol) as acid-bindingagent were added into the above solution. The reaction wasexecuted for 12 h at room temperature under continuousstirring, which was detected by TLC. Then, the redundantCH2Cl2 solvent has been removed by reduced pressuredistillation at 40?C. Finally, the crude product of differentsubstituted acryloyl chlorides was obtained. | |
With thionyl chloride; In toluene; for 5.0h;Reflux; | Syntheses of the tested compounds were carried out according to Scheme 1. The compounds were obtained by means of N-acylation of aminoalkanols by means of substituted cinnamic acid chlorides.20-22 4-Chloro, 4-methyl, and 2-methylcinnamic acid chlorides were obtained in the reactions of 4-chloro, 4-methyl, and 2-methylcinnamic acid with 10% excess of thionyl chloride in toluene. The reagents were refluxed for 5 h, then the solvent was evaporated under reduced pressure. In case of 4-Cl and 4-CH3-cinnamic acid chlorides the oily residues were crystallized from n-hexane what resulted in obtaining yellowish-white products, while 2-CH3-cinnamic acid chloride was not obtained in crystalline form and was used as a brown liquid. | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane;Reflux; Inert atmosphere; Schlenk technique; | General procedure: Cinnamic acid derivatives 1a-n (1 equiv.) was dissolved inthionyl chloride (SOCl2, 5 equiv.), the reaction mixturewas refluxedin the presence of sufficient amount of DMF as the catalyst for3-5 h. The solvent was removed by reduced pressure distillation toobtain the product 2a-n in the form of solid residue. Meanwhile,bergenin (1 equiv.) and K2CO3 (3 equiv.) were dissolved in dry DMFat 0 C and benzyl bromide (3 equiv.) was added. After the mixturewas stirred for 12 h at room temperature, the compound 4 wasobtained through extraction with ethyl acetate, drying with anhydroussodium sulfate and desolventizing by evaporated in vacuo.The compound 4 was directly added to an ice-cold stirred solutionof above solid residue in dry pyridine (200 mg/mL). Thenwarm the mixture to room temperature and stir for 20 h with CH2Cl2 addedand DMAP as a catalytic. After completion of the reaction (monitoredby TLC: ethyl acetate/petroleum ether 2:1), the mixturewashydrogenated by Pd/C under H2 atmosphere for 15 h. The mixturewas filtered, evaporated under vacuum and purified using columnchromatography to afford the compound 5a-n (Scheme 1). | |
With thionyl chloride; at 20℃; for 1.0h; | General procedure: The different substituted cinnamic acid derivatives (1, 5 mmol) were dissolved in SOCl2 (10 mL) and stirred in room temperature for 1 h. The solution was concentrated under vacuum to obtain product 2 as yellow oil. The corresponding cinnamic acid chloride was dissolved in dry dichloromethane (5 mL). The solution was added dropwise to a solution of piperazine prepared from piperazine (10 mmol) dissolved in glacial acetic acid (20 mL). The reaction solution was adjusted to pH 7-9 by 40% NaOH, and then extracted with dichloromethane (3 ). The organic phase was washed with saturated sodium chloride (3 ). The organic layer was separated and dried over anhydrous magnesium sulphate,filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with dichloromethane methanol(50:1) to give the desired product 3a-3h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dibromamine-T; potassium carbonate; In acetonitrile; at 20℃; for 0.08333330000000001h; | General procedure: To a solution of cinnamic acid (1 mmol) in CH3CN (2 mL), TsNBr2 (1.1 mmol) and K2CO3 (2 mmol) was added and stirred at room temperature. After completion of the reaction (monitored by TLC), water was added. The aqueous layer was extracted using dichloromethane (30 mL) and dried over anhydrous Na2SO4. The crude product was purified by flash chromatography using petroleum ether as eluent. |
76% | With ammonium bromide; In water; acetonitrile; at 75℃; for 1.0h;Electrochemical reaction; | General procedure: Substrate 1 (0.5mmol), NH4Br (3mmol) were added to an undivided cell which equipped with platinum anode and cathode. Followed by addition of MeCN (7mL) and H2O (3mL). The mixture was electrolyzed under continuous stirring at 75C under a constant current of 40mA for 1h. The solution was cooled to r.t., condensed under vacuum, extracted with DCM (3×10mL), washed with saturated sodium chloride solution. And the organic layers were dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=50:1-30:1) to afford the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | With tributyl-amine; In N,N-dimethyl-formamide; at 90℃; for 3.0h; | General procedure: In a 50 mL of round bottomed flask, PP-N-Pd (0.015 g), acrylic acid (1.5 mmol), iodobenzene (1.0 mmol), (n-Bu)3N (3.0 mmol) and solvent (0.2 mL) were added. The mixture was stirred and heated to 90 C in air for 3 h. After the reaction mixture was cooled to room temperature, H2O (25 mL) and Na2CO3 (1.0 g) were added. The mixture was stirred for 10 min, and then PP-N-Pd was separated by filtration. The filtrate was treated with 3 M HCl (5 mL) and the precipitate appeared. Then, the precipitate was filtered, washed with H2O and dried in air to give the product. |
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1.0h; | General procedure: In a typical experiment, a mixture of aryl halide (1.0 mmol), acrylic acid (1.5 mmol), K2CO3 (3.0 mmol), DMF (5.0 mL), and Fe3O4/SiO2/HPG-OPPh2-PNP catalyst (0.025 g, 0.95 mol % Pd) was charged in a 25 mL round-bottom flask and stirred at 100 C. The end of reaction was monitored by TLC. After completion of the reaction, the mixture was cooled down to room temperature and the catalyst was separated with a magnet and washed with diethyl ether (2×10 mL), deionized water (2×10 mL), and dried under vacuum for the next run. The resultant residual mixture diluted with H2O (20 mL) and aqueous layer was acidified using diluted aqueous HCl. The organic material was then extracted twice (2×15 mL) with diethyl ether. The organic fraction was dried over MgSO4, and removing the solvent leaving the crude product. The pure product was obtained by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h; | |
In N,N-dimethyl-formamide Inert atmosphere; | General procedure for the synthesis of allyl alcohols. Procedure1 General procedure: 4-Substituted cinnamic acid (10 mmol) and potassium carbonate(1.38 g, 10 mmol) were suspended in dimethylformamide(10 mL). Methyl iodide (2.13 g, 0.93 mL, 15 mmol) was added in oneportion and the mixture was stirred for 2 d or until completeconversion was observed by TLC. After addition of aqueous saturatedammonium chloride (ca. 10 mL), the mixture was stirred for30 min, then it was extracted with diethyl ether twice (225 mL).The combined organic phases were washed twice with brine, thendried over Na2SO4. After removing the solvent under reducedpressure, the ester was obtained as an off-white solid, which wasused in the next step without further purification. | |
Stage #1: trans-p-methylcinnamic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 20℃; for 1h; Stage #2: methyl iodide In toluene at 20℃; | General procedure of synthesis of cinnamic acid esters General procedure: According to method II [23] [4a, 5a, 7a, 8a, 14a, 15a, 16a, 17a]:15 mmols of cinnamic acid were dissolved in 45 ml of dried toluene.Next, 15 mmols of DBU were added to the mixture and stirred inroom temperature for 1 h. After that time 15 mmols of iodomethanewere added and stirring was continued for at least 20 h.Then, 20 ml of toluene was added and mixture was washed twicewith 70 ml of 0.5% NaOH and 70 ml of water. Organic layer wasdried with anhydrous sodium sulfate. Finally, the solvent wasevaporated. |
With caesium carbonate In acetone for 4h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine In acetonitrile for 0.166667h; microwave irradiation, cooling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With copper(II) nitrate; In acetonitrile; at 110℃; for 8.0h;Sealed tube; Green chemistry; | General procedure: A 25-mL Schlenk tube was charged with alpha,beta-unsaturated acid (0.4 mmol), Cu(NO3)2 (0.48 mmol), and CH3CN (2 mL). The tube was sealed, then the mixture was stirred under air at 110 C for 8 h. After completion of the reaction as monitored by thin-layer chromatography (TLC), H2O (5 mL) was added. The mixture was extracted with dichloromethane (3 X 4 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (10 mL) and water (10 mL), dried over anhydrous Na2SO4, then concentrated by rotary evaporator. Finally, the residue was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 6:1) to provide the desired products (3). (E)-(2-Nitrovinyl)benzene (3a) [18, 19, 21] |
96% | With chloro-trimethyl-silane; copper(II) nitrate trihydrate; In acetonitrile; at 100℃; for 2.0h; | General procedure: In a pressure tube, to a solution of alpha,beta-unsaturated carboxylic acid (0.5 mmol, 1 equiv) and copper(II) nitrate trihydrate (423 mg, 1.75 mmol, 3.5 equiv) in dry acetonitrile (3 mL), chlorotrimethylsilane (65 mg, 0.6 mmol, 1.2 equiv) was added. The reaction mixture was stirred vigorously at 100 C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution and organics were extracted using dichloromethane. Organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, giving the corresponding products in pure form in excellent yields. |
86% | With ferric nitrate; for 0.5h;Milling; | General procedure: Known amounts of unsaturated acid (0.1 mol), PEG (0.02 mol) and Fe(III) or Mn(II) nitrate (0.12 mol) were taken in a mortar and ground with a pestle till the reaction mixture became homogeneous. After completion of the reaction, as confirmed by TLC, about 2 % Na2CO3 solution was added to the reaction mixture till it is neutralized. Reaction product was extracted by dichloromethane (DCM) or dichloroethane (DCE), dried with sodium sulfate and purified by column chromatography. Binary solvent mixture of ethyl acetate and hexane (3:7) was used as eluent to obtain pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2 / 5 percent Pd/C / ethyl acetate 2: MeOH | ||
Multi-step reaction with 2 steps 1: 92 percent / thionyl chloride / 3 h / 40 °C 2: 90 percent / H2 / 10percent Pd/C / methanol / 15 h / 45 °C / 1551.4 Torr | ||
Multi-step reaction with 2 steps 1: hydrogen; palladium 10% on activated carbon / ethanol / 5 h / 1794.37 Torr 2: thionyl chloride / 1 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: HCl / diethyl ether / Heating 2: H2 / PtO2 / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 79 percent / H2 / 10percent Pd/C / ethanol / 1 h / 760 Torr 2: thionyl chloride / 4 h / Heating 3: AlCl3 / CS2 / 1.) 5 deg C, 30 min, 2.) reflux, 10 min 4: 61 percent / zinc amalgam, aq. HCl / toluene / 16 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Table 1 shows some examples that are encompassed by the general formula (I) and in Table 2 the data are indicated for identification of these compounds. The examples 1-36, 44-63 and 65-74 have been prepared according to method A, examples 37-39 according to method B, examples 40-42 according to method C, example 64 according to method F and the enantiomerically pure compounds 75-78 by resolution of the racemic mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In methanol | 2 Preparation of 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester EXAMPLE 2 Preparation of 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester A suspension of 300 g of p-methylcinnamic acid (J. Chem. Soc., Chem. Comm., 471, 1976) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled and filtered to give as a white solid, p-methylcinnamic acid methyl ester, mp 55°-56° C. NMR (DMSOd6) δ=7.36 (d, J=16 Hz, 1H); 7.36 (dd, J1 =30 Hz, J2 =7 Hz, 4H); 6.48 (d, J=16 Hz, 1H); 3.70 (s, 3H); 2.32 (s, 3H). IR (cm-1) 3061, 3028, 2949, 1713, 1634, 1607, 1570, 1516, 1438. | |
With sulfuric acid In methanol | 3 Preparation of 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester EXAMPLE 3 Preparation of 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester A suspension of 300 g of p-methylcinnamic acid (J. Chem. Soc., Chem. Comm., 471, 1976) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled and filtered to give as a white solid, p-methylcinnamic acid methyl ester, mp 55°-56° C. NMR (DMSOd6) δ=7.36 (d, J=16 Hz, 1H); 7.36 (dd, J1 =30 Hz, J2 =7 Hz, 4H); 6.48 (d, J=16 Hz, 1H); 3.70 (s, 3H); 2.32 (s, 3H). IR (cm-1) 3061, 3028, 2949, 1713, 1634, 1607, 1570, 1516, 1438. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium acetate; sodium nitrite; In water; acetone; | (a) 2-Chloro-4-methoxy-4'-methylstilbene A mixture of 62.5 g. (0.4 m) of <strong>[29242-84-0]2-chloro-4-methoxyaniline</strong>, 120 ml. of concentrated hydrochloric acid and 20 ml. of water was heated to boiling and then cooled in ice. There was then added 120 g. of ice followed by a solution of 28 g. (0.4 m) of sodium nitrite in 60 ml. of water over a 15 minute period. This mixture was stirred for 15 minutes, filtered, and 88 g. of sodium acetate was added. The resulting solution of diazotized compound was added to a stirred suspension of 65 g. (0.4 m) of 4-methylcinnamic acid in 1200 ml. of acetone. Cupric chloride (20 g.) was then added, and the reaction mixture was stirred for three hours and allowed to stand for 2.5 days. The reaction mixture was diluted with water, and the solid product collected and recrystallized from toluene to give 35.2 g. of 2-chloro-4-methoxy-4'-methylstilbene, m.p. 144-145 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 70℃; | General procedure: A mixture of alpha,beta-unsaturated aromatic or aliphatic acid (10 mmol), CH3SO2Bt (10 mmol) and Et3N (15 mmol) were refluxed in dry THF (50 mL) overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2 (100 mL). The organic phase was washed with brine (3 times) and dried over anhydrous Na2SO4. The organic phase was concentrated under vacuum to give a crude product, which could be further purified by recrystallization from a proper solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.9% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 50 - 60℃; for 24h; | General procedure: Equimolar amount of <strong>[3366-95-8]secnidazole</strong> (1.0 mmol) and cinnamic acid (1.0 mmol) were dissolved in dichloromethane, DCC (1.5 mmol) and DMAP (0.5 mmol) as catalyst and stirred at 50-60 C for 24 h. The reaction mixture was extracted with ethyl acetate and saturated sodium bicarbonate, respectively. Then, the organic layer was collected and crystallized to get the product (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With ammonia at 25℃; aq. buffer; Enzymatic reaction; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Reflux; | General procedure: Compounds 6a-10e were synthesized by coupling substituted 2-amino-1,3,4-thiadiazoles with cinnamic acids, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 8-10 h. The products were extracted with ethyl acetate. The extract was washed successively with 10% HCl, saturated NaHCO3 and water, respectively, then dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography using petroleum ether and ethyl acetate (3:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane Reflux; | 4.4. General procedure for synthesis of target compounds 6a-10e General procedure: Compounds 6a-10e were synthesized by coupling substituted 2-amino-1,3,4-thiadiazoles with cinnamic acids, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 8-10 h. The products were extracted with ethyl acetate. The extract was washed successively with 10% HCl, saturated NaHCO3 and water, respectively, then dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography using petroleum ether and ethyl acetate (3:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: trans-p-methylcinnamic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.333333h; Stage #2: 4-amino-7-chloroquinoline In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; | 4.16. General procedure for the synthesis of compounds 9a-k General procedure: The relevant cinnamic acid (1.1 eq), PyBOP (1.1 eq), DIEA (2 eq.) and DCM (2 mL) were mixed in a round bottom flask and put under stirring for 20 min. Then, a solution of 3 (0.250 g, 1.40 mmol) in DMF (2 mL) was added and the reaction allowed to proceed for one day at room temperature. Following, the reaction mixture was diluted with 14 mL of DCM and sequentially washed with 1% aq. HCl (3 × 18 mL) and 5% aq. Na2CO3 (3 × 18 mL). Finally, the organic layer was dried with anhydrous Na2SO4, filtered, and evaporated to dryness In all cases, the crude product had to be purified by column liquid chromatography on silica, using DCM/Me2CO 6:1 v/v as eluent. Target compounds were isolated as solids, with analytical and spectral data given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Inert atmosphere; | II. Experimental Procedure General procedure: (E)-3-(4-ethylphenyl)acrylic acid (100 mg, 0.567 mmol), 3-((ethylimino)methyleneamino)-N,N-dimethylpropan-1-aminium chloride (163 mg, 0. 851 mmol), and N,N-dimethylpyridin-4-amine (13 mg, 0.19 mmol) were dissolved in dichloromethane (10 mL). N-ethyl-N-isopropylpropan-2-amine (161 mg, 1.248 mmol) was added followed by 4,5-dihydrothiazol-2-amine (64 mg, 0.624 mmol). The reaction mixture was stirred for 12 hours at room temperature. The reaction was concentrated under vacuum. Purification by column chromatography provided (E)-N-(4,5-dihydrothiazol-2-yl)-3-(4-ethylphenyl)acrylamide as a white powder (58 mg, 40% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tert.-butylhydroperoxide; nickel(II) acetate tetrahydrate In water at 100℃; for 16h; | Typical Procedure General procedure: To a mixture of cinnamic acid (0.148 g,1 mmol), Ni(OAc)2·4H2O (25 mg, 0.1 mmol), and N,Ndimethylacetamide(2 mL), tert-butyl hydroperoxide (0.39g, 3 mmol, 70% in water) was added at r.t. dropwise. Theresulting mixture was heated to 100 °C for 16 h, then themixture was added to dichloromethane (40 mL) and washedwith water and saturated brine. The organic solution wasdried with anhydrous magnesium sulfate and the desiredproduct was separated on a silica gel column (petroleumether-EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tetrabutylammonium perchlorate; acetic acid In water; acetonitrile at 20℃; for 2h; Electrolysis; regioselective reaction; | |
76% | With manganese (II) acetate tetrahydrate In dimethyl sulfoxide at 110℃; for 12h; | 1. General Procedure: General procedure: To a 25 ml round bottom flask were added cinnamic acid (0.5 mmol) , aromatic sulfinic acidsodium salt (1.5 mmol), Mn(OAc)2•4H2O(6.13 mg, 0.025 mmol) and DMSO (2ml). The round bottom flask was stirred under air at 110 °C for 12 h. The reaction mixture was cooled to roomtemperature and washed three times with saturated sodium chloride, extracted with EtOAc, andconcentrated in vacuo. The resulting residue was purified by flash column chromatography usinghexanes:EtOAc (8:1) as the eluent. All compounds are characterized by 1H NMR, 13C NMR,LRMS and their comparison to literature values |
73% | With palladium diacetate; silver carbonate; 1,4-di(diphenylphosphino)-butane In N,N-dimethyl-formamide at 75℃; for 6h; Inert atmosphere; Sealed tube; |
54% | With potassium iodide; copper(II) oxide In dimethyl sulfoxide at 100℃; for 24h; Sealed tube; Green chemistry; stereospecific reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dmap; potassium carbonate In dichloromethane Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; potassium carbonate In dichloromethane Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 1h; Reflux; | 12 4.4. General procedure for the synthesis of 5-phenyl-1H-pyrazolderivatives (5a-5x) General procedure: Compounds 5a-5x were synthesized by coupling substituted 3a-3c with cinnamic acids, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 1-3 h. The products were extracted with ethyl acetate. The extract was washed successively with 5% HCl, then evaporated and purified by column chromatography over silica gel to give the compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1,10-Phenanthroline; palladium diacetate; silver carbonate In dimethyl sulfoxide at 130℃; for 72h; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tert.-butylhydroperoxide; iodine In water; toluene at 90℃; for 12h; | 4.2. General procedure for preparation of iodine-mediateddecarboxylation between cinnamic acid and sodium benzenesulfinate General procedure: A 25 mL tube was charged with cinnamic acid (0.3 mmol), sodiumbenzene sulfinate (1.2 mmol), iodine (2 equiv), TBHP in H2O(0.6 mmol) and toluene (2 mL). The resulting reaction mixture waskept stirring at 90 C for 12 h. Upon completion of the reaction, thereaction mixturewas cooled to room temperature. After removal ofthe solvent, the residue was subjected to column chromatographyon silica gel using ethyl acetate and petroleum ether mixtures toafford the desired product in high purity. |
79% | With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 20℃; for 12h; Irradiation; | |
58% | With [bis(acetoxy)iodo]benzene In N,N-dimethyl-formamide at 100℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water for 0.666667h; Sonication; Green chemistry; | 2.3. Ultrasound-promoted synthesis of propanamide derivatives(4 and 5) General procedure: The carboxylic acid derivative (2) (1.0 mmol), 2-oxopropyl benzoate (3) (1 mmol), isocyanide (1) (1 mmol) and water (7 mL) were added into a 25 mL round bottomed flask. The reaction mixture was sonicated under 100 W for the period of time (the reaction was monitored by TLC). The solvent was eliminated under decreased pressure, and the products were generated without any purification (4 and 5). The authenticity of the samples (4a-4i and 5a-5i) was established by their 1H NMR, 13C NMR, FT-IR, elemental analyses and MS. The characterization data of the compounds are given below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84 % ee | With ammonium bisulphate; EncP wild type enzyme at 55℃; for 22h; Enzymatic reaction; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium bromide In N,N-dimethyl-formamide at 130℃; for 12h; Schlenk technique; chemoselective reaction; | 4.2 General procedure for KBr-mediated methylation of carboxylic acid with dimethyl malonate General procedure: To a Schlenk tube equipped with a magnetic stir bar were added under air, carboxylic acid (0.3 mmol), dimethyl malonate (1.8 mmol) and KBr (0.09 mmol) in DMF (2 mL). The resultant reaction mixture was kept stirring at the required temperature for 12 h. After indicated reaction time, the mixture was cooled down to room temperature. It was poured into ethyl acetate, then washed with water, extracted with ethyl acetate, dried by anhydrous Na2SO4, then filtered and evaporated under vacuum, the residue was purified by flash column chromatography (petroleum ether or petroleum ether/ethyl acetate) to afford the corresponding coupling products with high purity. |
96% | With potassium bromide In N,N-dimethyl-formamide at 130℃; for 12h; Schlenk technique; | 2 In a Schlenk test tube, 4-methylcinnamic acid (0.3 mmol) Potassium bromide (0.09 mol), And N, N-dimethylamide (2 mL), Dimethyl malonate (l.Smmol) was added to the micro-injector and the system was sealed and heated in an oil bath at 130 ° C for about 12 hours. After the reaction, the reaction was quenched by the addition of 4 mL of water and then quenched with acetic acid (10 mL X3). The organic phases were combined and dried over anhydrous sodium sulphate and concentrated by a simple column chromatography (eluent using petroleum ether (60-90 ° C)), To give the product methyl 4-methyl cinnamate in a yield of 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: trans-p-methylcinnamic acid With toluene-4-sulfonic acid In ethanol for 3h; Schlenk technique; Inert atmosphere; Reflux; Stage #2: With diisobutylaluminium hydride In tetrahydrofuran at -78 - 20℃; for 2h; Inert atmosphere; Schlenk technique; Stage #3: 7-hydroxy-2-methylquinoline With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 20h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.5% | Stage #1: trans-p-methylcinnamic acid With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 5℃; for 0.25h; Stage #2: N-(7-chloroquinolin-4-yl)ethylenediamine With benzotriazol-1-ol 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. 4.4.1 Compound- (E)-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-p-tolylacrylamide (9) White solid; Yield: 60.5%, 1HNMR (CDCl3+DMSO-d6), 300MHz; δ:8.35(d, 1H, J=6.52Hz), 8.20 (bs, NH), 8.01(d, 1H, J=12Hz), 7.73(t, 1H, J=2.8Hz), 7.47(d, 1H, J=21Hz), 7.34(m, 3H), 7.21(bs, NH), 7.10(d, 1H, J=10.4), 6.48(d, 1H, J=21) 6.37(d, 1H, J=7.2), 3.59-3.57(m, 2H), 3.39-3.37(m, 2H), 2.28(s, 3H).; C13NMR DMSO-d6, 75MHz: δ 169.01, 150.80, 147.95, 141.16, 139.97, 135.05, 131.66, 129.23, 127.52, 126.54, 125.09, 118.75 MS: ESI (m/z) 366.3[M+H]+ and Anal. Calcd. for C21H20ClN3O: C,68.94; H, 5.51; N, 11.49; Found: C,68.98; H, 5.52; N, 11.42. |
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 |
---|---|---|
75% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 2.5h; Inert atmosphere; | 3 Example 3: Preparation of 3-(2-acetamidoethyl)-1H-indol-5-yl (E)-3-(4-methylphenyl)acrylate (Compound 3) General procedure: To a solution of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)acetamide (1 eq) and Et3N (1.5 eq) in CH2Cl2 (0.057 M) under argon, a solution of the corresponding acrylic acid (1.2 eq) and HATU (1.5 eq) in dry CH2Cl2 (0.057 M) was added dropwise. The resulting solution was stirred at room temperature. When the reaction was finished (TLC) it was quenched with distilled water and allowed to stir for 15 min. Thereafter, the mixture was extracted three times with CH2Cl2 (3 x 20 mL). The organic layer was washed with brine, filtrated and dried over anhydrous MgSO4. The resulting solid was purified by flash chromatography on silica gel using CH2Cl2/MeOH mixtures as eluent. Following general procedure A, N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)acetamide (100 mg, 0.458 mmol) and Et3N (95.8 μL, 0.687 mmol)) in CH2Cl2 (8 mL), (E)-3-(p-tolyl)acrylic acid (0.089 g, 0.550 mmol) and HATU (261.2 g, 0.687 mmol) in CH2Cl2 (8 mL), 2.5 h, flash chromatography on silica gel (CH2Cl2:MeOH 0-2 %) to afford compound 3 as a brown solid (0.124 g, 75 % yield). MP: 170-172 °C; IR (KBr) v 3344, 3252, 2932, 1703, 1628, 1554, 1483, 1326, 1170, 810. 1H NMR (CDCl3, 300 MHz) δH 8.35 (1H, Sbr, NH), 7.79 (1H, d, J = 16,0, 3'-H), 7.42 (2H, d, J = 8.0 Hz, 2"-H), 7.27 (1H, d, J = 2.5 Hz, 4-H), 7.25 (1H, d, J = 8.9 Hz, 7-H), 7.16 (2H, d, J = 8.0 Hz, 3"-H), 6.93 (1H, s, 2-H), 6.90 (1H, dd, J = 8.9 Hz, J = 2.5 Hz; 6-H), 6.55 (1H, d, J = 16.0 Hz, 2'-H), 5.90 (1H, Sbr, NH), 3.48-3.43 (2H, m, CH2CH2NHCOCH3), 2.83 (2H, t, J = 7.37 Hz, CH2CH2NHCOCH3), 2.33 (3H, s, CH3-Ph), 1.85 (3H, s, CH2CH2NHCOCH3). 13C NMR (CDCl3, 75 MHz) δC 170.7, 166.8, 146.3, 144.2, 141.1, 134.3, 131.5, 129.7, 128.3, 127.7, 123.6, 116.5, 116.2, 112.9, 111.8, 110.8, 39.9, 25.1, 23.0, 21.5. MS (API-ES+) m/z: [(M+H)+] 363.1713; [(M+Na)+] 385.1517. Anal. calcd. for C22H22N2O3: C: 72.91 %; H: 6.12 %; N: 7.73 %; found: C: 72.76 %; H: 6.29 %; N: 7.68 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With urea; at 140℃; for 2h;Green chemistry; | General procedure: A 10-mL test-tube was equipped with magnetic stirring bar and charged with 1 mmol cinnamic acid and 6 mL DES, heated at 140 C in a preheated oil bath for 2 hours, then the mixture was cooled to room temperature, extracted with ethyl acetate (3*15 mL), combined and evaporated under vacuum. Pure product was obtained by silica gel column chromatography with petroleum ether and ethyl acetate. All the compounds, after purification, were weighted and characterized by MS, 1H NMR, 13C NMR, and then compared them with the spectral data of authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 1H-imidazole at 140℃; for 2h; Green chemistry; | Typical Procedure for the esterification of carboxylic acid in DES General procedure: A 10-mL test-tube was equipped with magnetic stirring bar and charged with 1 mmol cinnamic acid and 6 mL DES, heated at 140 °C in a preheated oil bath for 2 hours, then the mixture was cooled to room temperature, extracted with ethyl acetate (3*15 mL), combined and evaporated under vacuum. Pure product was obtained by silica gel column chromatography with petroleum ether and ethyl acetate. All the compounds, after purification, were weighted and characterized by MS, 1H NMR, 13C NMR, and then compared them with the spectral data of authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 3-methylimidazolinium hydrogensulfate; copper(II) acetate monohydrate at 70℃; for 24h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(I) oxide; silver carbonate In chlorobenzene at 140℃; for 18h; | 6.A; 6.B he synthesis of 10-benzoquinoline-4-methylbenzoate comprises the following steps: A. 0.2 mmol of benzoquinoline and 0.3 mmol of 4-methylcinnamic acid were placed in a reaction tube, and then 0.04 mmol of Cu2O, 0.4 mmol of Ag2CO3, and 3 mL of PhCl were sequentially added, and the reaction was stirred at 140 ° C for 18 hours.B. The product was extracted with EtOAc. EtOAc. A yellow solid was obtained. The results were confirmed to be 10-benzoquinoline-4-methylbenzoate as shown in Fig. 7a and Fig. 7b. Yield 65% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | General method of the synthesis of amides (XIIa-m). General procedure: The mixture of corresponding acid (XIa-m) (1 mmol),cyanopyrrolidine tosylate (IX) (0.27 g, 1 mmol), andEt3N (0.28 mL, 2 mmol) in DMF (10 mL) were stirredin an inert atmosphere at room temperature ffor 24 h.The reaction mixture was poured into 40 mL of water,and the product was extracted with ethyl acetate (3 ×10 mL). The combined organic layers were washedsuccessively by water (10 mL) and saturated sodiumchloride (10 mL) and dried over MgSO4. The precipitatewas filtered off, and the solution was evaporatedunder reduced pressure. The residue was purified bycolumn chromatography using a chloroform-methanolmixture (10 : 1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In dichloromethane; at 20℃; for 5h; | General procedure: 1.2 equiv. of acid (benzoic acid or bibenzoic acid) was added to the solution of 10 mL triethylamine and 30 mL acetonitrile ordichloromethane of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 equiv),HBTU or TBTU (2.4 mmol). The mixture was stirred at room temperaturefor 5 h. After TLC detection, the solvent was removedunder reduced pressure. Sodium chloride solution (30 mL) wasadded to the residue and extracted with ethyl acetate (3 40 mL).The combined organic layer was washed twice with saturated sodiumchloride (30 mL). And dried by anhydrous MgSO4, the solventwas removed under reduced pressure after filtering and removingMgSO4, and the crude product was purified by column chromatographyto obtain the corresponding intermediates 12a and 12b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; at 30℃; for 168.0h;pH 10.0; | General procedure: The reaction mixtures containing substituted (E)-cinnamic acids(2a-s, 5 mM) in NH2CO2NH4 (3 M, pH 9.1) supplemented with PzaPAL(50 Xg mL-1) or in NH3 (6 M, pH 10) supplemented with PcPAL (50 XgmL-1) were incubated at 30 C. Samples (50 XL) taken at different timepoints (17, 40, 64, and 168 h) from the reaction mixtures were quenchedby adding an equal volume of MeOH, vortexed and centrifuged(13,000 rpm, 2 min). The supernatant was transferred to a 0.22 Xmfilter and used directly for HPLC analysis to determine conversion andee values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With dihydrogen peroxide; recombinant Curvularia inaequalis vanadium-dependent chloroperoxidase; potassium bromide In dimethyl sulfoxide at 30℃; for 10h; Green chemistry; Enzymatic reaction; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃; | 4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39. |
26% | With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃; | 4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃; | 4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39. |
37% | With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃; | 4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39. |
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
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P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
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P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
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P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
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P285 | In case of inadequate ventilation wear respiratory protection. |
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P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
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P314 | Get medical advice/attention if you feel unwell. |
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P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
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P350 | Gently wash with plenty of soap and water. |
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P362 | Take off contaminated clothing and wash before reuse. |
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P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
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P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
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P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
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P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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