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CAS No. : | 830-09-1 | MDL No. : | MFCD00004398 |
Formula : | C10H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AFDXODALSZRGIH-QPJJXVBHSA-N |
M.W : | 178.19 | Pubchem ID : | 699414 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.1 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 49.6 |
TPSA : | 46.53 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) : | -5.48 cm/s |
Log Po/w (iLOGP) : | 1.68 |
Log Po/w (XLOGP3) : | 2.68 |
Log Po/w (WLOGP) : | 1.68 |
Log Po/w (MLOGP) : | 1.59 |
Log Po/w (SILICOS-IT) : | 1.73 |
Consensus Log Po/w : | 1.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.78 |
Solubility : | 0.298 mg/ml ; 0.00167 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.31 |
Solubility : | 0.0874 mg/ml ; 0.00049 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.99 |
Solubility : | 1.84 mg/ml ; 0.0103 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.69 |
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 |
---|---|---|
95.2% | With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 20℃; for 5 h; | To a solution of 3-(4-methoxyphenyl)acrylic acid (15, 14.7 mmol) in THF (50 mL) was added a catalytic amount of 10percent palladium on activated carbon to carry out hydrogenation, followed by stirring for 5 h at room temperature. The mixture was filtered, and the filtrate was concentrated in vacuo to give a white solid with a yield of 95.2percent, mp 102-103 °C |
95.2% | With palladium 10% on activated carbon In tetrahydrofuran; methanol at 20℃; for 5 h; | Plus p-methoxycinnamic acid(11a, 14.7 mmol), tetrahydrofuran (50 mL),Methanol (20 mL),Catalytic amount of 10percent Pd / C, hydrogen, The reaction was stirred at room temperature for 5 h. The reaction was terminated and the solid was filtered off. The solution was concentrated to dryness under reduced pressure to give a white solid, 95.2percent yield, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydroxide In methanol; water at 20℃; for 24h; | General procedure for the synthesis of 4a-c. General procedure: In a 100 mL flat bottomflask with magnetic stirrer 0.1127 g of sodium hydroxide (NaOH) (2.0 Eq), 10 mLof MeOH/H2O in an 8/2 ratio and 0.26 g (1.0 Eq) of ester 3a-cwere added. The solution was stirred at room temperature for 24 h andsubsequently brought to pH = 2.0 with concentrated hydrochloric acid (HCl)dropwise. The solution was stirred for another 30 min and then MeOH wasevaporated under vacuum and EtOAc added to perform EtOAc:H2Oliquid-liquid extractions. The organic phase was dried with anhydrous Na2SO4and the solvent evaporated under vacuum to obtain a white solid. This solid waswashed three times with 15 ml of hexane with a vacuum filtration, allowing itto dry inside the extraction hood. |
64% | Stage #1: ethyl p-methoxycinnamate With sodium hydroxide In ethanol Stage #2: With hydrogenchloride In water | |
With potassium hydroxide In tetrahydrofuran; water for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 20℃; for 5h; | 4.1.16. 3-(4-Methoxyphenyl)propanoic acid (16) To a solution of 3-(4-methoxyphenyl)acrylic acid (15, 14.7 mmol) in THF (50 mL) was added a catalytic amount of 10% palladium on activated carbon to carry out hydrogenation, followed by stirring for 5 h at room temperature. The mixture was filtered, and the filtrate was concentrated in vacuo to give a white solid with a yield of 95.2%, mp 102-103 °C |
95.4% | With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 2h; | |
95.2% | With palladium 10% on activated carbon In tetrahydrofuran; methanol at 20℃; for 5h; | 38 Preparation of p-methoxyphenylpropionic acid (12a) Plus p-methoxycinnamic acid(11a, 14.7 mmol), tetrahydrofuran (50 mL),Methanol (20 mL),Catalytic amount of 10% Pd / C, hydrogen, The reaction was stirred at room temperature for 5 h. The reaction was terminated and the solid was filtered off. The solution was concentrated to dryness under reduced pressure to give a white solid, 95.2% yield, |
92% | With hydrazine hydrate In ethanol for 5.5h; Reflux; | |
90% | With sodium tetrahydroborate; sodium hydroxide In water at 20 - 60℃; | |
88% | With palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction; | |
61.2% | ||
With sodium amalgam; water | ||
With sodium amalgam | ||
With sodium amalgam | ||
With carbon dioxide; hydrogen at 50℃; for 0.0833333h; | ||
With nickel; hydrazine hydrate; aluminium; sodium hydroxide | ||
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; for 12h; | ||
With palladium on activated charcoal; hydrogen | ||
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With bromine In dichloromethane for 4h; | 2,3-Dibromo-3-(4-methoxy-phenyl)-propionic acid (1b) (procedure 2) Compound 1a (19.44 g, 0.094 mol) and dichloromethane 90 ml were added to thereaction flask. Cooling to below 20 C, the solution was stirred for 2 h. Liquid bromine(15.41 g, 0.096 mol) was added into dropping funnel and dropped into the reaction solution.After that, the solution was stirred for 4 h. The compound 1b was obtained bydried in room temperature. Yield: 85%. |
With bromine | ||
With chloroform; bromine |
With carbon disulfide; bromine | ||
With bromination | ||
With bromine In chloroform for 0.5h; Cooling with ice; | ||
With bromine In chloroform at 0℃; for 0.333333h; | ||
With bromine In chloroform at 0℃; for 0.333333h; Inert atmosphere; Sealed tube; | ||
With bromine In chloroform at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With thionyl chloride In 1,2-dichloro-ethane for 3h; Heating; | |
83% | With thionyl chloride | |
With phosphorus pentachloride |
With thionyl chloride In benzene for 2h; Heating; | ||
With thionyl chloride In chloroform for 2h; Heating; | ||
With thionyl chloride; N,N-dimethyl-formamide In benzene at 50℃; for 1h; | ||
With thionyl chloride | ||
With thionyl chloride at 80℃; for 2h; | ||
With oxalyl dichloride In benzene at 20℃; for 2h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; | ||
With pyridine; thionyl chloride In ethyl acetate | ||
With thionyl chloride at 80℃; for 5h; | ||
With oxalyl dichloride In dichloromethane at 25℃; | ||
With thionyl chloride for 2h; Reflux; | ||
With pyridine; trichlorophosphate | ||
With oxalyl dichloride In dichloromethane at 20℃; for 5h; | ||
With thionyl chloride; N,N-dimethyl-formamide In benzene at 70 - 80℃; | ||
With thionyl chloride Reflux; | ||
With oxalyl dichloride In diethyl ether; N,N-dimethyl-formamide at 20℃; | ||
With thionyl chloride In dichloromethane for 1.5h; Reflux; | ||
With thionyl chloride | ||
With thionyl chloride Reflux; | ||
With oxalyl dichloride In dichloromethane for 3h; | 1.2 General Procedure for the Synthesis of Substituted Cinnamoyl Chloride General procedure: Oxalyl chloride (1 ml) was added to the dichloromethane (10 ml) solutions of substituted cinnamic acid (2 mmol). The reaction mixture was stirred until the bubbling stopped (approximately 3 hours), and vaporized in vacuo. The cinnamoyl chloride was used directly without purification. | |
With thionyl chloride Reflux; | ||
With thionyl chloride Heating; | ||
With thionyl chloride for 3h; Reflux; | General procedure: Compound 10 was prepared by a procedure similar to that of Lu and co-workers, and Nagao and co-workers. A solution of octanoic acid (4.43g, 30.74mmol) and thionyl chloride (20mL) was heated under reflux for 3h. The excess thionyl chloride was removed in vacuo and the crude octanoyl chloride taken through to the next step without further purification. A solution of 2 (12.0g, 21.55mmol), triethylamine (4.6mL, 33.3mmol), dimethylaminopyridine (0.26g, 2.16mmol) and crude octanoyl chloride in dimethylformamide (150mL) was then stirred at room temperature for 3h. The mixture was then diluted with ethyl acetate (200mL) and washed with water (200mL). The separated aqueous phase was further extracted with ethyl acetate (2×100mL) and the combined organic phases washed with brine (4×100mL), dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate 2:1) afforded 10 as an off-white solid (9.92g, 14.66mmol, 68%). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; Cooling; | ||
With thionyl chloride In toluene at 60℃; for 18h; | 1 Synthesis of Trimethoxysilylpropyl-P-Methoxycinnamamide 100 g of p-methoxycinnamic acid (Aldrich) was dissolved in 500 mL of toluene and 100 mL of thionyl chloride (Oriental Chemical Industries) was slowly added thereto. After stirring at 60° C. for 18 hours, all volatile substances were removed by evaporation under reduced pressure while maintaining temperature at 80° C. or lower. After adding 500 mL of toluene to the product, a mixture of 80 g of triethylamine (Aldrich) and 100 g of 3-aminopropyltrimethoxysilane (Aldrich) was slowly added dropwsie to the resulting solution. Thus obtained mixture was stirred continuously for about 5 hours and cooled to room temperature. After removing the formed salt by filtration under reduced pressure and removing toluene under reduced pressure, trimethoxysilylpropyl-p-methoxycinnamide was obtained. Purity of the synthesized precursor was measured by silica thin-layer chromatography | |
With thionyl chloride In benzene for 1h; Reflux; | 1.1.1.General procedure for acylation of morphinamine derivatives (8a-e): General procedure: The appropriate carboxylic acid (1.2 molar equivalents) was mixed with benzene (5mL) and thionyl chloride (0.5 mL) and refluxed for 1 h. The solution was evaporated to dryness under reduced pressure and then dissolved in dichloromethane (10 mL). 6β-morphinamine (4) (1.0molar equivalent) and triethylamine (0.4 mL) were added and stirred for 2 hrs at room temperature. The solvent was evaporated under reduced pressure, methanol (10 mL) and Na2CO3 (0.5 g) were added and the mixture stirred overnight. The resulting slurry was neutralized with 20 % aq. acetic acid and extracted with chloroform. The organic phase was dried and evaporated to dryness. The crude products were purified by column chromatography using chloroform-methanol 9:1 isocratic eluent and crystallized from hexane to yield crystalline pale yellow products 8a-e (20-60% yields). | |
With thionyl chloride for 6h; | ||
With 1,3,5-trichloro-2,4,6-triazine; triethylamine In acetonitrile at 20℃; for 1h; | 4.1. General procedure for the synthesis of substitutedphenylcinnamide derivatives 3 (a-y) General procedure: Substituted cinnamic acids (2a-y) were synthesized by Knoevenagel condensation of corresponding aldehydes (0.01 mol) and monoethyl malonate (0.01 mol) according to literature procedure [30]. A stirred solution of the suitable cinnamic acid (0.01 mol) in acetonitrile was treated with 2,4,6-trichloro-1,3,5-triazine (0.01 mol) and Et3N (0.02 mol). A slight exotherm (1-2 °C) was observed, and most of the solid was dissolved. The reaction mixture thickened noticeably after 20-40 min. After the mixturewas stirred for further 1 h at ambient temperature, the aminereagent (0.02 mol) was added, and a second exotherm of 2-4 °C was noticed. The reaction mixture was stirred at 40 °C and on completion (TLC examination) was cooled to room temperature and filtered. The solid was washed with a minimal amount of solvent; the filtrates were combined and washed with 1 M sodium hydroxide solution and finally with water. The organic layer was dried over sodium sulphate, and the solvent was removed by vaporation under reduced pressure. The residue was dried under vacuum to yield the amide product and recrystallized from ethanol to afford the products (3aey) in yields mentioned against each. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; | ||
With thionyl chloride | General procedure: Synthesis: 4-Hydroxycinnamic acid and the 4-n-alkoxycinnamic acids, as well as the corresponding acid chlorides (A), were prepared using the appropriate n-alkyl halides and subsequently using thionyl chloride by the modified method of Dave andVora [4]. α-3-Hydroxy phenyl β-4-nitro benzoylethylene (B)was prepared by an established method [5c]. Components (A) and(B) were condensed in dry cold pyridine to obtain final products. 4-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, malonic acid, piperidine, pyridine, thionylchloride, alkyl halides,methanol, KOH, ethanol, and 4-nitroacetophenpone required for synthesis were used as received. The final products were all purified and crystallized from alcohol until they gave constant transition temperatures. The synthetic route to the novel series is outlined in Scheme 1. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2.16667h; Inert atmosphere; | ||
With thionyl chloride Heating; | 4.3. General procedure for the synthesis of initial cinnamides (amides of 3-arylpropenoic acids) 1a-j General procedure: Chloro anhydride of the corresponding cinnamic acid (10 mmol), preliminary prepared by heating of acid with SOCl2, was quenched with solution of amine (30 mmol) in dioxane (10 mL) at room temperature with vigorous stirring for 10 min. Then reaction mixture was diluted with water (50 mL), acidified by concentrated aqueous hydrochloric acid. Reaction product was extracted with chloroform (3×50mL). The extracts were combined, washed with water (3×20 mL), and dried over Na2SO4. The solvent was distilled off under reduced pressure. The residue was purified by recrystallization from ethanol. | |
With thionyl chloride In dichloromethane for 3h; Reflux; | ||
With thionyl chloride In dichloromethane at 20℃; for 24h; | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 4h; | ||
With thionyl chloride at 60℃; for 3h; | ||
With thionyl chloride In toluene at 70℃; Large scale; | 1 Example 1 Example 1 In a 50-L reactor, 2.5 kg of 4-methoxycinnamic acid and 11 kg of toluene were placed to give a suspension. This suspension was combined with 1.75 kg of thionyl chloride (1.05 times the mole of 4-methoxycinnamic acid) added dropwise while maintaining the reactor inside temperature at 70±2° C. After the dropwise addition, the reaction was continued until the conversion from 4-methoxycinnamic acid reached 99% or more. After the completion of reaction, about two-tenths of toluene were distilled off together with unreacted thionyl chloride and an acidic gas at 60° C. under reduced pressure. After the concentration, the resulting mixture was combined with toluene in an amount equal to the distilled-off amount and yielded 15 kg of a solution of 4-methoxycinnamoyl chloride in toluene. | |
With thionyl chloride In chloroform for 0.5h; Reflux; | 2.2. Procedure for preparation of D12, D13 General procedure: To a stirred solution of 3,4-dimethoxycinnamic acid (5.0 g,24.1 mmol) in chloroform (50 mL) was added dropwise thionylchloride (3.2 g, 26.5 mmol, 1.1 equiv). The reaction mixture was heated under reux for 30 min, then cooled, and the solvent evaporated under reduced pressure to give the corresponding acyl chloride, which was dissolved in chloroform (50 mL). The solution of acyl chloride was added slowly to a solution of hydroxylamine hydrochloride (2.64 g, 38.0 mmol) and triethylamine (10.45 mL,74.9 mmol) in chloroform (50 mL), stirred at 0 °C. The reaction mixture was stirred at 0 C for 20 min, and then stirred at room temperature for 40 min. The solvent was removed under reduced pressure, and to the residue was added 1 M aqueous sodium hydroxide solution (50 mL). The mixture was ltered through a Buchner funnel and acidied with concentrated HCl to pH 4, precipitating the hydroxamic acid, which was recovered by filtration and then recrystallized from hot ethanol to give the product D12 aspale yellow crystals (4.71 g, 84%). | |
With oxalyl dichloride In tetrahydrofuran at 60 - 70℃; for 4h; | General procedure for the synthesis of intermediates 6e-6m General procedure: In a double necked round bottom flask (RB flask), 1.94 g(10 mmol) of the compounds 2e-2m obtained in step 1 was takenand dissolved in 30 mL of tetrahydrofuran (THF). 2 mL (20 mmol)of oxalyl chloride was subsequently added to the RB flask usingdropper. The refluxing was performed for 4 h at 60-70 C. The solutionwas dried carefully under reduced pressure using rota vapourand the product obtained was used directly in the next step | |
With thionyl chloride at 60℃; for 3h; | General procedure: An 50 mL anhydrous flask was charged withmagnetic stir bar, cinnamic acid (5 mmol, 0.74 g) and SOCl2 (5 mL).After stirring at 60 C for 3 h, the redundant SOCl2 was evaporatedunder reduced pressure and then the liquid was dropwise addedinto another flask containing N-methylaniline (10 mmol, 1.07 g)dissolved in anhydrous CH2Cl2 (20 mL). The mixture was stirredfor 1 h at room temperature. The organic phase was then washedby aqueous HCl and aqueous K2CO3, then dried by anhydrousNa2SO4. After evaporating the CH2Cl2, the N-methyl-N-phenylcinnamamidewas obtained in 97% yield and used in the next stepdirectly. | |
With thionyl chloride Reflux; | Synthesis of p-n-alkoxy cinnamoyl chloride General procedure: P-n-alkoxycinnamic acid is prepared from p-hydroxycinnamic acid and corresponding alkyl halide by the modified method of Dave and Vora [3]. N-alkoxycinnamic acid is refluxed with excess of freshly distilled thionyl chloride until the evolution of SO2 gas ceased. Excess of thionyl chloride is distilled off and the corresponding acid chloride is left behind and preservedin moisture free atmosphere without purification for further reaction. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 5.11 General procedure for the preparation of compounds 9a-n General procedure: Oxalyl chloride (2.0mmol) was added drop-wise to a stirred mixture of compounds 8a-n (1.0mmol) and DMF (0.02mmol) in dichloromethane (16mL) in room temperature for 10min, and the mixture was distilled and dissolved in dichloromethane (16mL) immediately. The solution was used for the next step without further purification. | |
With thionyl chloride In toluene at 80℃; for 5h; | ||
With thionyl chloride at 75℃; for 2h; | General procedure: Compounds A11-A15, A17, A18, A20-A22, B1-B12, C7-C10 and C13-C20 were preparedaccording to method B in Fig 1 by reaction of the corresponding acyl chloride and thecorresponding alcohol. The general procedure was as follows. The mixture of cinnamic acid orcinnamic acids with substituents on the phenyl ring (0.10 mol) and 30 mL thionyl chloridewas refluxed at 75°C for 2 h. The excess thionyl chloride was removed under reduced pressure.After the residue was dissolved in 10 mL DCM, the corresponding alcohol (10 mmol) wasadded at 0°C. The solution was stirred at 0°C for 1 h, and then washed with water (3 × 30 mL)followed by 5% Na2CO3 aqueous solution, and dried over anhydrous sodium sulfate. After filtration,the solvent was removed under reduced pressure. The residue was purified by silica gelcolumn chromatography ( 40 mm × L 40 cm) to afford the desired product. | |
With phosphorus pentachloride at 20℃; for 0.5h; | 8.1 In the first step, 0.05 mol of 4-methyl benzene acrylate is added to the reaction vesselAnd 0.075mol of phosphorus pentachloride,Stir the reaction at room temperature for 30 min; | |
With thionyl chloride Reflux; | General synthetic procedure for 3-phenyl acryloylchloride (4a-4j) General procedure: A mixture of various substituted cinnamic acid (0.01 mol) and thionyl chloride (10.0 ml) was heated under reflux condition and stirred for 4-5 h. The progress of the reaction was monitored by TLC. After the completion of the reaction,the unreacted thionyl chloride was removed under reduced pressure by distillation, and then remaining residue was used for further step without recrystallization. Similarly, other compounds were also prepared. | |
With thionyl chloride In dichloromethane at 0 - 60℃; for 5h; | Synthesis of phenylpropanoid-conjugated derivatives: General procedure: SOCl2 (1.0 mL) wasadded to a solution of phenylpropanoic acid (1.15 mmol) in DCM (5 mL) at 0oC.After stirring at 60oC for 5 h, the resultant solution was concentratedin vacuo and then dissolved in DCM (5mL). Compound 5 or 6 or 7 or 8 (0.38 mmol) and K2CO3(0.38 mmol) were added into the resultant solution. Reaction was heated at 50oCand stirred for 17 h. The resultant solution was poured into distilled water,partitioned with EtOAc, and washed with 10% HCl aq., sat. NaHCO3aq., and brine. The organic layer was dried over anhydrous Na2SO4and concentrated in vacuo. Theresidue was purified using silica gel column chromatography eluted with n-hexane/EtOAc (1/1) to afford thedesired compound. In the case of 9, 10, 11, 12, 16, and 17, TBS group(s) was(were) removed using TBAF (1M in THF) for 15min. | |
With thionyl chloride Reflux; Schlenk technique; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide for 2h; | ||
With thionyl chloride In 1,2-dichloro-ethane for 3h; Reflux; | 8 P-methoxycinnamoyl chloride 9.8 g of p-methoxycinnamic acid was added to a 250 ml reaction flask.20 g of dichloroethane and 13.1 g of thionyl chloride were heated to reflux.Maintain reflux reaction for 3 hours,Unreacted thionyl chloride and dichloroethane were distilled off. P-methoxycinnamoyl chloride is obtained.After the concentrate was dissolved in 40 g of dichloroethane, the next step was directly carried out. | |
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; | ||
With thionyl chloride at 20℃; for 1h; | ||
With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 5℃; for 1h; | 6.2 In a fume hood, 61.42 g (0.008 mol) of VI was added to a 50 mL pear-shaped bottle, 0.25 mL of N, N-dimethylformamide (DMF) was added dropwise, and the temperature of the ice bath was reduced to 0-5 ° C. Slowly add 2.00 mL (0.021 mol) of oxalyl chloride, and the addition is completed within 10 minutes. After dripping, the ice bath was removed, and the reaction was continued for 1 h until the solution was clear, and no gas was generated in the system. The excess solvent and oxalyl chloride were distilled off using a rotary evaporator to obtain VII6. 16 mL of dichloromethane was added to dissolve and sealed for later use. | |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; | 2 The synthesis process is as follows: at 0 ° C, SOCl2 (2.4 mmol) and DMF (2 drops) are added to p-methoxycinnamic acid (2.0 mmol) in anhydrous DCM (5 mL), and the reaction mixture is at room temperature Stir for 5h. After the reaction is completed, the substituted cinnamoyl chloride is obtained by concentration. At 0 ° C, 4-hydroxycoumarin (1.6 mmol) and DIEA (3.2 mmol) were added to dry DCM (5 mL), and then p-methoxycinnamoyl chloride dissolved in dry DCM (5 mL) Add slowly to the reaction system. After 30 minutes, the reaction was moved to room temperature and proceeded. Follow the reaction by TLC until the reaction is complete. The reaction was quenched with saturated sodium bicarbonate, then extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous Na2SO4, and finally purified by column chromatography. The yield was 52.8%. | |
With thionyl chloride In dichloromethane Reflux; | ||
With thionyl chloride for 2h; Reflux; | 5.9 General procedure for the preparation of 8a-e, 16a-e General procedure: The mixture of cinnamic acid derivatives (1.2mmol) and thionyl chloride (5mL) was refluxed for 2h and then the thionyl chloride was evaporated under vacuum to obtain corresponding cinnamoyl chloride. The solution of cinnamoyl chloride (1mmol) in dry dichloromethane (1mL) was added dropwise to the solution of 4-dimethylaminopyridine (0.1mmol, 12mg) and pyridine (1mmol, 0.08mL) in dry dichloromethane (5mL) at 0°C under argon atmosphere. After 15min, the solution of compound 7 or 15 (0.9mmol) in dry dichloromethane (1mL) was slowly added. The reaction was stirred for another 2hat r.t. Then, dichloromethane was added and washed with HCl (1M). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from methanol and water to give the final products. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.5h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.2h; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide for 24h; Reflux; | 4.2.2.4. General procedure for synthesis of cinnamic acid-piperazine hybrids(4a - 4e). General procedure: Synthetic scheme is shown in Scheme 2. Substituted cinnamic acid (1 mol) was taken in organic solvent (dichloromethane,DCM) and thionyl chloride (1.2 mol) was added followed by addition ofcatalytic amount of dimethylformamide (DMF). The reaction mixturewas refluxed for 24 h. Completion of reaction was monitored by TLC(Hexane:Ethyl acetate:methanol; 3:2:0.5). After completion of reaction,solvent was evaporated to remove excess of thionyl chloride and to getcinnamoyl chloride in the form of an amorphous powder. Unsubstitutedpiperazine (3 mol) was dissolved in DCM and triethylamine (TEA) (3equivalent) was added to it and stirred at 0 C. Substituted cinnamoylchloride (1 mol) was dissolved in DCM and added dropwise to abovestirred solution at 0 C. Completion of reaction was monitored by TLC(Hexane : Ethyl acetate : methanol; 3:2:0.5). After completion, theprecipitate obtained was filtered and washed with water. The resultingsolid product was suspended in 5% sodium bicarbonate solution toremove any acid impurity. The final product was recrystallized from absolute alcohol. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 24h; | 4.1.2. The synthesis of piperlongumine analogs [28,29] General procedure: Oxalyl chloride (6 mmol) and a catalytic amount of DMF (0.01 equiv)was added to the solution of substituted cinnamic acids (2 mmol) in dryCH2Cl2 (4 mL). The solution was stirred at room temperature for 24 h,and then the solvent was concentrated in vacuo. The residue was dried under high vacuum and dissolved in dry CH2Cl2 (5 mL). After addingtriethylamine (6 mmol) and lactam (2.4 mmol), the mixture was stirredat room temperature for 24 h before quenched with saturated aqueousNH4Cl and extracted with ethyl acetate. The combined organic phaseswere washed with brine, dried over Na2SO4, and concentrated in vacuo.Then the crude products were purified with a silica gel column (5/1,Petroleum ether (60-90)/Ethyl acetate). Their structures wereconfirmed by 1H and 13C NMR spectroscopy (Bruker Avance500 spectrometers,Germany), and HRMS (Waters UPLC G2-XS QTof). (SeeSupporting Information Section 2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide; water at 100℃; for 1.5h; | |
90% | With tetrabutylammomium bromide; sodium carbonate In water at 90℃; for 22h; Green chemistry; | |
88.1% | Stage #1: acrylic acid With sodium carbonate In water Stage #2: With copper (II) carbonate hydroxide In water for 0.166667h; Autoclave; Stage #3: 1-bromo-4-methoxy-benzene Further stages; | 1-2; 1-6 Example 2 Salt formation reaction:Add 20.6g (0.19mol) of Na2CO3 to a 0.5L clean batcher.150g of tap water, start stirring, and slowly add 26g (0.36mol) of acrylic acid,After the addition is complete, keep stirring until there are no bubbles in the kettle, and it is clear and transparent.Coupling reaction: Add the prepared sodium acrylate solution to a 1L clean autoclave.Add 9.97 mg of Cu2 (OH) 2CO3 (150.80 ppm rel.to BA) and keep stirring for 10 min. Add 15.0g (0.18mol) of NaHCO3 and 250g of tap water to the autoclave.Maintain stirring for 10 min. Add 56g (0.30mol) to the autoclaveP-Bromoanisole (BA)And 4.2mg (23.3 × 10-6mol) BHA, close the feeding port of the autoclave,Replace 5 times with N2, raise the temperature to 160 ° C, and keep the reaction until the pressure no longer increases.It takes about 2h.With stirring during the reaction, the stirring speed was maintained at 1000 r / min. Turn off the heating device,Turn on the condensed water to lower the temperature to 85 ° C, evacuate the pressure in the reactor, and open the discharge port.Add 100 g of tap water and keep stirring for 20 min, and pump out the contents of the kettle.Crystallization: transfer the reaction material to a four-necked flask, add 1 g of activated carbon, and raise the temperature to 90 ° C.Keep incubation for 30 min, and filter. The filtrate was transferred into the acidification kettle, and stirring was started.Acidify 39.4g 55% H2SO4 to pH = 1-2, and keep stirring for 30min.Suction filtration gave crude p-methoxycinnamic acid and the filtrate.Recrystallization: Add crude p-methoxycinnamic acid to a dry and clean four-necked flaskAnd 200 g of isooctanol, and the temperature was raised to 145 ° C. After the crude p-methoxycinnamic acid was completely dissolved,Slowly lower the temperature to 100 ° C, precipitate the crystals, and incubate the crystals for 1 h. Reduce the temperature to 30 and keep it for 1h. After filtration, the filtrate was used to recover isooctanol, the filter cake was rinsed with 100 g of isooctanol (10 ° C), and the filtrate was used for the next batch of recrystallization. The filter cake was dried to constant weight to obtain 47.20 g of finished p-methoxycinnamic acid with a yield of 88.1% and an HPLC content of 99.7823%. |
88% | With water; C31H28Br2N4Pd; potassium hydroxide at 120℃; for 6h; | 3.7. Mizoroki-Heck coupling reactions of aryl bromides with different acrylates using Pd-BNH3 catalyst. Scope of the substrates General procedure: The Mizoroki-Heck cross-coupling reactions of 4-bromoanisole (1a)methyl acrylate (4a), acrylic acid (4b), and acrylamide (4a) were investigated (Table 8, entries 1-6) using Pd-BNH3 catalyst (Equation 3).As mentioned above (Scheme 4), under the experimental reaction conditions(KOH, H2O, 120 °C), the methyl acrylate (4a) and acrylamide(4c) are hydrolyzed into potassium acrylate (4b’) prior to their engagement in the cross-coupling reactions to produce the carboxylic acids 5aa and 6aa after the acidic workup. As expected, the Mizoroki-Heck cross-coupling reactions of 4-bromoanisole with methyl acrylate(4a) (Table 8, entry 1), acrylic acid (4b) (Table 8, entry 3), and acrylamide(4c) (Table 8, entry 5) in i-PrOH/H2O gave excellent overall yields (92-96%) and very good selectivity towards the cinnamic acidderivative 5aa (75-79%). When the same reactions were carried out in DMF/H2O as a solvent system, the overall yields remained very high(85-88%) (Table 8, entries 2, 4, and 6) with the production of the cinnamic acid derivative 5aa as the sole product. The attempts to produce the hydrocinnamic acid derivative 6aa as a major product have not yetbeen successful. Further studies and research will be adopted to solvethis challenging task. |
85% | With potassium carbonate In water for 1.66667h; Reflux; Green chemistry; | |
83% | Stage #1: acrylic acid With potassium <i>tert</i>-butylate In water at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 1-bromo-4-methoxy-benzene With C16H21Br2N3Pd In water at 120℃; for 24h; Inert atmosphere; Sealed tube; | 4.2.1. General procedure for the NHC-Pd(II) complex 1-catalyzed Mizoroki-Heck reaction General procedure: (If olefin is acrylic acid) Under N2 atmosphere, acrylic acid 3a (1.5 mmol), KOtBu (3.0 equiv) and H2O (2.0 mL) were added into a seal tube and the mixture was stirred at room temperature for 10 min. Then NHC-Pd(II) complex 1 (1.0 mol %) and aryl halides 2 (1.0 mmol) were added. The mixture was stirred vigorously at 120 °C (for bromides) or 100 °C (for iodides) for 24 h. After cooling to room temperature, HCl (4 M) was dropped into the reaction mixture to reach a pH of 1, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by a flash column chromatography (SiO2) to give the pure product. |
78% | With triethylamine In N,N-dimethyl-formamide at 80℃; for 8h; | |
77% | With sodium hydrogencarbonate In water at 130℃; for 24h; | |
75% | With potassium carbonate In water at 90℃; for 0.833333h; | |
70% | With tributyl-amine In N,N-dimethyl-formamide at 110℃; for 10h; | |
68% | With tetrabutylammomium bromide; sodium carbonate In water at 90℃; for 18h; | |
44% | With tributyl-amine In N,N-dimethyl-formamide at 135℃; for 7h; Reflux; | |
With sodium carbonate In water at 100℃; Yield given; | ||
With triethylamine In water | 12.a Preparation of p-octyl methoxy cinnamte in the presence of an organic base Step a): The following reagents: 12 g of water, 12.75 g of triethylamine (126 mmole), 8.4 g of p-bromo anisole (45 mmole), 3.9 g of acrylic acid (54 mmole) and 0.0003 g of palladium chloride were fed into a reaction autoclave and the vessel was sealed. The mixture was magnetically stirred and heated in an oil bath to 125°-130° C. for two hours. The reaction vessel was cooled to about 50° C. and the catalyst was removed by filtration. The product, p-methoxy cinnamic acid, was isolated by precipitation from the clear reaction mixture with about 130 ml of H2 SO4 (40%) and filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tributyl-amine In N,N-dimethyl-formamide at 90℃; for 7h; Reflux; | |
96% | With potassium hydroxide In water at 90℃; for 5h; | |
95% | Stage #1: acrylic acid With potassium <i>tert</i>-butylate In water at 20℃; for 0.166667h; Inert atmosphere; Stage #2: para-iodoanisole With C16H21Br2N3Pd In water at 100℃; for 24h; Inert atmosphere; Sealed tube; | 4.2.1. General procedure for the NHC-Pd(II) complex 1-catalyzed Mizoroki-Heck reaction General procedure: (If olefin is acrylic acid) Under N2 atmosphere, acrylic acid 3a (1.5 mmol), KOtBu (3.0 equiv) and H2O (2.0 mL) were added into a seal tube and the mixture was stirred at room temperature for 10 min. Then NHC-Pd(II) complex 1 (1.0 mol %) and aryl halides 2 (1.0 mmol) were added. The mixture was stirred vigorously at 120 °C (for bromides) or 100 °C (for iodides) for 24 h. After cooling to room temperature, HCl (4 M) was dropped into the reaction mixture to reach a pH of 1, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by a flash column chromatography (SiO2) to give the pure product. |
95% | With tetra-(n-butyl)ammonium iodide; potassium hydroxide In methanol at 80℃; for 24h; | |
95.7% | With triethylamine In N,N-dimethyl-formamide at 110℃; for 7h; | |
95% | With triethylamine In N,N-dimethyl-formamide at 120℃; for 6h; Green chemistry; | |
93% | With tributyl-amine; potassium carbonate In N,N-dimethyl-formamide Green chemistry; | Typical procedure for the Heck reaction General procedure: In a typical reaction, aryl halides (9 mmol), phenylethylene (15 mmol) (or acrylic acid), tributylamine (30 mmol) and DMF (10 mL) were placed in a round-bottomed flask with 1.47 mol% AOFs-Ni(0) as catalyst. The reaction was carried out in a temperature controlled oil bath. After completion of the reaction, the mixture was cooled to room temperature. Then the AOFs-Ni(0) was separated from the mixture by filtration and washed sequentially with hot ethanol and reused in thenext reaction. The filtrate was extracted with ethyl acetate (30 mL) and washed with distilled water (3 × 15 mL). The solvent was then removed by rotary evaporation to give a crude product. The crude product was purified by column chromatography on H 60-silica powder using mixed solvent (petroleum ether/ethyl acetate = 3/1). The pure products were characterised by melting point, 1H NMR, HRMS and GC-MS spectroscopy. |
91% | With potassium carbonate In water at 90℃; for 8h; | |
90% | With tributyl-amine In N,N-dimethyl-formamide at 110℃; for 2.5h; | |
85% | With sodium carbonate In water at 100℃; for 24h; | |
84% | With potassium phosphate tribasic trihydrate In N,N-dimethyl-formamide at 130℃; for 10h; Green chemistry; | |
80% | With sodium hydrogencarbonate In water at 130℃; for 8h; | |
With sodium carbonate In water at 100℃; Yield given; | ||
93.2 %Chromat. | With N-Methyldicyclohexylamine In N,N-dimethyl-formamide at 95℃; for 3h; | |
With potassium carbonate In water at 90℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With chloro-trimethyl-silane at 20℃; | 1 (E)-1-methoxy-4-[3-(prop-2-yn-1-yloxy)prop-1-en-1-yl]benzene (11d): Made via route 1, starting from the carboxylic acid 11a. The first two steps were carried out according to a literature procedure, and the 1H-NMR spectra of the products were consistent with those which were reported. 2 For the first step, 180 mg of carboxylic acid 11a, was combined with 0.270 mL of TMSCl in 5 mL of ethanol, and the product ester 11b was obtained in 94% yield (193 mg). The subsequent reduction step was carried out using 193 mg of ester 11b, 2.1 mL of 1M DIBAL-H in hexanes, and 2.3 mL of toluene. The product was purified using a 3:7 ethyl acetate/hexanes and the isolated yield was 64% (98.5 mg). The WES was carried out using 95.5 mg of alcohol 11c dissolved in 1.5 mL of THF, 38.2 mg of sodium hydride suspended in 1.2 mL of THF, and 0.10 mL of propargyl bromide solution. The reaction was quenched with 1.7 mL of sat. NH4Cl (aq) solution and the product was isolated as a colorless liquid using 1:10 ethyl acetate/hexanes eluent in 81% yield (95.5 mg). |
86.2% | With sulfuric acid at 95℃; | 3 Example 3 Example 3-Reagents and conditions:A)EtOH, H2O, conc. H2SO4, 95 ° C overnightB)DIBAL-H, DCM, -70 ° C rt;C)NaNO2, AcOH-H2O, rt, 3h;D)Day - Martin oxidizer, DCM, rt, overnight;E)NH4OH-HCl, pyridine, EtOH, 95 ° C, 3 h;F)SOCl2, DMF, rt, overnightG)L-methionine, methanesulfonic acid, 60 ° C.Compound 10 (10 g, 56.2 mmol) was dissolved in ethanol,Adding concentrated sulfuric acid as catalyst for stirring at 95 ° C overnight,TLC tracks the degree of completion of the reaction,After completion of the reaction with sodium bicarbonate and,Ethyl acetate extraction,The solvent was removed by concentration to give compound 11 (10 g, 86.2%) as an oil;Compound 11 (10 g, 48.5 mmol, 1 eq) was dissolved in DCM,At -70 & lt; 0 & gt; C,Diba-H reductant (1.5 M) (81 mL, 121.4 mmol, 2.5 eq) was slowly added dropwise,After dripping,And then at room temperature for 1h,TLC tracks the degree of completion of the reaction,After completion of the reaction,At -20 ° C,Compound 12 (5 g, 62.5%) was obtained by quenching, extracting, extracting and concentrating the solvent with dilute hydrochloric acid;Compound 12 (5 g, 30.5 mmol, 1 eq) was dissolved in acetic acid (10 mL)An aqueous solution of NaNO2 (4.2 g, 61 mmol, 2 eq) was then slowly added,The color of the reaction solution slowly turns yellow,Followed by stirring at room temperature overnight,TLC tracks the degree of completion of the reaction,(FWH-222) (2g, 30%) was obtained by column chromatography after neutralization, extraction and concentration of solvent.after that,Compound 13 (2 g, 9.0 mmol, 1 eq) was dissolved in DCM,Add a Day-Martin oxidant (4.6 g, 10.8 mmol, 1.2 eq)The reaction was stirred overnight at room temperature,TLC tracks the degree of completion of the reaction,After the completion of the reaction, the solvent was removed by suction filtration, neutralization, extraction and steaming to obtain pale yellow compound 14 (1.5 g, 75%);Compound 14 (1.5 g, 6.8 mmol, 1 eq) was then dissolved in ethanol,Hydroxylamine hydrochloride (0.56 g, 8.2 mmol, 1.2 eq), pyridine (0.65 g, 8.2 mmol, 1.2 eq)After heating, the temperature was raised to 95 and the reaction was refluxed for 3 h,TLC tracks the degree of completion of the reaction,After the completion of the reaction by steaming to remove ethanol, pickling, extraction, steaming and steaming to goRemoval of the solvent gave the yellow compound 15 (0.8 g, 50%);after that,Compound 15 (0.8 g, 3.4 mmol, 1 eq) was dissolved in DMF,Slowly dropwise SOCl2 (1.62 g, 13.6 mmol, 4 eq)The reaction was stirred overnight at room temperature,TLC tracks the degree of completion of the reaction,After the reaction, the solvent was removed by neutralization, extraction and steaming, and the residue was isolated by column chromatography to give pale yellow compound 7 (0.4 g, 54.1%).At last,Compound 16 (0.4 g, 1.8 mmol, 1 eq) was dissolved in methanesulfonic acid (5 mL)L-methionine (0.41 g, 2.8 mmol, 1.5 eq) was added at 60 ° C for 3 h,TLC tracks the degree of completion of the reaction,After the completion of the reaction to take neutralization, extraction, saturated salt water and anhydrous sodium sulfate drying,Concentration gave compound 17 (FWH-203) (0.2 g, 54%).Compound 17 (50 mg, 0.25 mmol, 1.0 eq) was dissolved in DMF (2 mL), cesium carbonate (96.4 mg, 0.30 mmol, 1.2 eq) was added successively,1,3-dibromopropane (42.7 mg, 0.25 mmol, 1.0 eq).Heated to 40 ° C,TLC to track the degree of completion of the assay,After completion of the reaction,The reaction solution was diluted with ethyl acetate (50 mL)Washed,Collect organic phase to concentrate to obtain crude,Column chromatography (PE: EA = 10: 1 to 4: 1) gave compound 18 (FWH-324) (30 mg, 41.7%). |
44% | With sulfuric acid for 3h; | 2.3. Synthesis of the esters General procedure: The ester derivatives (b-f) were synthesized following classicFischer esterification [18] using 1 mmol of the corresponding acid,0.1 mL of concentrated sulfuric acid and the corresponding alcohol assolvent. The reaction proceeded for 3 h or until no more acid was observedin TLC. The reaction mixture was neutralized with aqueousNaHCO3 saturated solution, and the solvent excess was evaporatedunder reduced pressure. The residue was taken up in 10 mL ethylacetate and washed with 3x10 mL of saturated NaHCO3 solution and10 mL of water. The organic layer was dried with anhydrous Na2SO4.The desired compounds were further purified in a silica gel columnchromatography, using hexane:ethyl acetate as eluent. |
With hydrogenchloride In diethyl ether Heating; | ||
With toluene-4-sulfonic acid Heating; | ||
With chloro-trimethyl-silane at 25℃; for 12h; Inert atmosphere; | ||
With chloro-trimethyl-silane at 20℃; for 24h; | ||
With hydrogenchloride In water for 8h; Reflux; | ||
With thionyl chloride at 82℃; for 2h; | 2.2 Add to 250ml three-necked reaction flask7.12 g (40 mmol)4-methoxyphenylacrylic acid,100 ml (1717 mmol) of anhydrous ethanol,4.4 ml (60 mmol) of thionyl chloride was added dropwise,Heated to 82 ° C,Reflux reaction for 2 hours,Until the originalMaterial points completely disappear,Stop the reaction cooling 10min,The reaction solution was concentrated,Add 50ml ice water,4 refrigerator cooling precipitation of light red solid,The crude 4-methoxyphenyl acrylate was filtered off,Directly for the next step. | |
With thionyl chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With H-Y zeolite In toluene for 4h; Heating; | |
78% | With iodine at 120 - 130℃; for 1.5h; Neat (no solvent); | General procedure for the synthesis of dihydrocoumarins: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over anhydrous sodium sulphate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
78% | With iodine In neat (no solvent) at 120 - 130℃; for 1.5h; | 4.2.1 General procedure for the synthesis of dihydrocoumarins General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
78% | With iodine In neat (no solvent) at 120 - 130℃; for 1.5h; | 4.2.1. General procedure for the synthesis of dihydrocoumarins. General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With iodine In neat (no solvent) at 120 - 130℃; for 1h; | 4.2.1 General procedure for the synthesis of dihydrocoumarins General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
83% | With iodine In neat (no solvent) at 120 - 130℃; for 1h; | 4.2.1. General procedure for the synthesis of dihydrocoumarins. General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
75% | With H-Y zeolite In toluene for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With boron trichloride Stage #2: methanol | |
99% | With thionyl chloride at 20℃; for 19h; Cooling with ice; Inert atmosphere; | |
97.8% | With thionyl chloride for 4h; Reflux; |
88% | With hydrogenchloride Reflux; | |
87% | With thionyl chloride at 20℃; for 1h; Cooling; | Synthesis of Methyl3-(4-methoxyphenyl)acrylate (2) To a ice-cold solution of 4-Methoxy cinnamic acid (2 g, 11.2 mmol) in methanol (20 mL), SOCl2 (1 mL) was added drop wise and the reaction mixture was stirred at room temperature for 1h. After completion of the reaction, methanol was removed under vacuum and water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate twice and combined organic layer was dried over anhydrous Na2SO4. The solvent was then evaporated under reduced pressure and the crude product was purified with column chromatography (petroleum ether /ethylacetate) (4:1) to afford pure product as a white solid |
79% | With sulfuric acid for 4h; | |
77% | With sulfuric acid for 3h; | 2.3. Synthesis of the esters General procedure: The ester derivatives (b-f) were synthesized following classicFischer esterification [18] using 1 mmol of the corresponding acid,0.1 mL of concentrated sulfuric acid and the corresponding alcohol assolvent. The reaction proceeded for 3 h or until no more acid was observedin TLC. The reaction mixture was neutralized with aqueousNaHCO3 saturated solution, and the solvent excess was evaporatedunder reduced pressure. The residue was taken up in 10 mL ethylacetate and washed with 3x10 mL of saturated NaHCO3 solution and10 mL of water. The organic layer was dried with anhydrous Na2SO4.The desired compounds were further purified in a silica gel columnchromatography, using hexane:ethyl acetate as eluent. |
With toluene-4-sulfonic acid Reflux; | ||
With sulfuric acid for 12h; Reflux; | ||
With sulfuric acid | ||
With hydrogenchloride In water for 8h; Reflux; | ||
497mg | With sulfuric acid for 7h; Inert atmosphere; Cooling with ice; Reflux; | 7.1.i (1) methyl 3-(4-methoxyphenyl)-4-nitrobutanoate (i) Under an argon atmosphere, to a solution of 4-methoxycinnamic acid (502 mg) in methanol (10.0 mL) was added under ice-cooling sulfuric acid (500 µL), and the mixture was heated under reflux for 7 hr. The reaction mixture was allowed to cool, pure water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) to give methyl 4-methoxycinnamate (497 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogenchloride In chloroform; water at 80℃; for 10h; | 4.2 New compounds General procedure: Samples of tertiary phosphines and substituted cinnamic acids were dissolved in chloroform and 1 drop of concentrated hydrochloric acid solution was added. The reactions were carried out at a temperature of 80C in a water bath with a reverse refrigerator. Heated 10h. Upon completion of the reaction, the solvent was distilled in a Schott funnel. The precipitate was washed with diethyl ether and dried in vacuum. |
In chloroform at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: acetic acid With sodium tetrahydroborate at 20 - 100℃; for 2h; Stage #2: 4-methoxy-benzaldehyde In 1-methyl-pyrrolidin-2-one at 185 - 190℃; for 12h; | |
55% | Stage #1: acetic acid With sodium tetrahydroborate at 10 - 100℃; for 1.5h; Stage #2: 4-methoxy-benzaldehyde In 1-methyl-pyrrolidin-2-one at 185 - 190℃; for 10h; Reflux; | General procedure for the synthesis of acrylic acids General procedure: Acrylic acids 3a-f were prepared according to Chiriac et al.10 A 500 mL three necked round bottom flask equipped with a reflux condenser carrying calcium chloride guard tube, kept in ice-bath, was charged with acetic acid (0.7 mol). Under stirring, sodium borohydride (0.133 mol) was added slowly in small portions into the flask. During this the temperature was maintained below 10°C. The mixture was stirred for half hour at RT and then for one hour at 90-100°C in an oil bath. To this solution, aldehyde (0.1 mol) was added and then N-methyl pyrrolidone (9.91 g) was added as solvent. This solution was refluxed at 185-90°C for 10 hr in an oil bath. After cooling to RT, the above reaction mixture was treated with 50 mL of water and then with saturated sodium bicarbonate solution with vigorous shaking. There was an alkaline reaction and after completion of the reaction it was filtered. To remove the unreactive aldehyde, the filtrate was distilled under vacuum, until the distillate was no longer cloudy. The solution was treated with hydrochloric acid solution (2.7 N) till there was no further reaction. The precipitates of acid were obtained. Absence of spot of aldehyde on thin layer chromatographic plates revealed the homogeneity of acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogen bromide; sodium nitrite In water; acetonitrile at 20℃; for 4h; | Representative procedure for bromodecarboxylation of α,β-unsaturated carboxylic acid (Table 1, entry 1) General procedure: In a stirred solution of cinnamic acid (0.3 gm, 2.0 mmol) in freshly distilled acetonitrile (10 mL) 48% aqueous solution of HBr (4.0 mmol) was added. To this reaction mixture was added aqueous solution of NaNO2 (20 mL, 2.5 M). The flask was immediately covered with an air filled balloon (1 L) and the stirring was continued at room temperature. After completion of the reaction (TLC), CHCl3 (10 mL) was added. The organic layer was separated and washed with aqueous solution of NaHCO3 (2 × 20 mL), followed by water (3 × 20 mL), finally dried over anhyd Na2SO4 and was concentrated in vacuum. The remaining residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 9:1) to yield pure bromostyrene. |
85% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With triethylamine In dichloromethane at 20℃; for 0.0833333h; Stage #2: With N-Bromosuccinimide In dichloromethane for 0.333333h; | |
83% | With sodium molybdate dihydrate; dihydrogen peroxide; potassium bromide In water at 25℃; | 1. Synthesis of the Bromides General procedure: To a suspension of α,β-unsaturated aromatic carboxylic acid (20.0 mmol) and KBr (4.76 g, 40.0 mmol) a solution of Na2MoO4*2H2O (242.0 mg, 1.0 mmol) in water (5.0 mL) and H2O2 (15.0 mL) was added dropwise at room temperature (25 °C). A rapid reaction took place and the temperature immediately rose to a high temperature within 30 min. The reaction mixture was stirred for a period time until it was cooled down. And then the product as well as the unreacted acid were extracted with CH2Cl2 (20 mL) for 3 times. The corresponding (E)-β-bromostyrene 1 was separated from the starting material by column chromatography in good yield.[1] |
Multi-step reaction with 2 steps 2: NaHCO3 / acetone | ||
Multi-step reaction with 2 steps 1: bromination 2: NaHCO3 / CH2Cl2 | ||
16.6 g | With N-Bromosuccinimide In water; acetonitrile at 100℃; for 0.15h; Microwave irradiation; | |
Stage #1: 3-(4'-methoxyphenyl)propenoic acid With lithium acetate In water; acetonitrile at 20℃; for 0.0833333h; Stage #2: With N-Bromosuccinimide In water; acetonitrile | Synthesis of substituted beta bromostyrenes2 General procedure: α,β-Unsaturated cinnamic acid (300mg, 2mmol) was added to a solution of lithium acetate (13mg, 0.2mmol) in4.5mL of acetonitrile:water (97:3v/v). After the mixture was stirred for 5min at RT, N-bromosuccinimide (370mg,2.1mmol) was added as a solid portion wise. Reaction progress was monitored by TLC. Usual workup followed bysilicagel column chromatography afforded the pure haloalkene.Thestereoselectivity (E:Z) was measured by GC-MS. | |
With Oxone; triethylamine hydrobromide In dichloromethane at 20℃; for 4h; | 2.1 General procedure for the synthesis of enyne derivatives(12a-h) General procedure: To a stirred solution of O-silylated ferulic acid (10a) (1 equiv mol) in dry CH2Cl2, triethylammonium bromide (TEAB) (1.2 equiv mol) and oxone (1.2 equiv mol) were sequentially added. The reaction is stirred for 4 h at room temperature, quenched with Na2SO3 and washed with CH2Cl2. The organic layers were washed with NaHCO3 satd sol, dried over Na2SO4, filtered and evaporated. The residue was purified by GCC on silica gel (PE/EtOAc 95:5 as eluant) to afford 11a as pure compound (73%). | |
Stage #1: 3-(4'-methoxyphenyl)propenoic acid With triethylamine In dichloromethane at 20℃; for 0.0833333h; Stage #2: With N-Bromosuccinimide In dichloromethane | ||
With N-Bromosuccinimide; lithium acetate In water; acetonitrile at 80℃; Inert atmosphere; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With oxalyl dichloride In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 3.25h; Stage #2: With ammonia In tetrahydrofuran; DMF (N,N-dimethyl-formamide); water at 0 - 5℃; for 0.75h; | 1 Example 1; 1- [4- (4- {2- [2- (4-METHOXY-PHENYL)-VINYL]-OXAZOL-4-YLMETHOXY}-PHENYL)-BUTYL]- 1H- [1, 2,3] triazole 44.5 ml (351 mmol) oxalyl chloride was added dropwise at 0°C within 45 min. to a suspension of 50.0 g (281 mmol) 3- (4-METHOXYPHENYL)-ACRYLIC acid in 300 TL tetrahydrofuran and 3.0 ml N, N-dimethyl formamide. Stirring was continued at 0- 5°C for 30 min. and thereafter for 2 h at room temperature. The resulting solution was cooled to 0-5°C again and then added within 15 min. to 750 ml of a 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40°C in vacuo. 48.8 g (98%) 3- (4- METHOXYPHENYL)-ACRYLAMIDE were obtained. |
65% | With pyridine; potassium cyanate; 2-chloro-1-methyl-pyridinium iodide; water In acetonitrile for 6h; Reflux; Green chemistry; | 3.1. Preparation of Benzamide from Benzoic Acid UsingMukaiyama Reagent as Typical Procedure General procedure: A suspension of Mukaiyama reagent (0.511 g, 2 mmol),potassium isocyanate (0.242 g, 3 mmol), benzoic acid (0.122g, 1 mmol) and pyridine (0.16 g, 2 mmol) in 1% aqueousacetonitrile (7 mL) was magnetically stirred at reflux conditions.After completion of the reaction (10 min) and evaporationof acetonitrile, aqueous HCl (5%, 10 mL) was addedand the organic layer extracted with CH2Cl2 (3 × 5 mL). Thecombined organic extracts were dried over Na2SO4, filtered,and concentrated. Purification of the crude product by shortcolumn chromatography on silica gel (hexane/EtOAc 5:3)provided benzamide (0.107 g, 88%) as a white solid: mp127-129oC (lit. [18] 127oC); 1H NMR (DMSO-d6, 250 MHz)8.11 (brs, 2H), 7.65 (d, J = 8.0 Hz, 2H, H-2',6'), 7.32 (t, J =7.8 Hz, 2H, H-3',5'), 7.05 (t, J = 7.4 Hz, 1H, H-4'). |
33% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5h; | 4.2.3 4.2. Typical procedure for the primary amidation of 3-phenylpropanoic acid 1a with NH4Cl General procedure: To a colorless solution of 75mg (0.50mmol) of 3-phenylpropanoic acid 1a in 10mL of THF were added at 0°C 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) was added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 72mg (96% yield) of 3-phenylpropanamide 2a. 4.2.3 4-Methoxycinnamamide 2c 30 mg (33%); colorless powder; mp: 198-201 °C; 1H NMR (400 MHz, MeOD-d4): δ 3.82 (s, 3H, CH3), 6.49 (d, J = 15.9 Hz, 1H, CHCO), 7.50 (d, J = 15.9 Hz, 1H, CHC6H5), 6.94, 7.51 (d, d, J = 8.7, 8.7 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, MeOD-d4): δ 55.9, 115.4, 118.8, 128.8, 130.6, 142.6, 162.7, 171.5; IR (KBr, vmax/cm-1) = 3361 (CONH), 3166 (CONH), 1684 (CON), 1662 (CON); HRMS (ESI-TOF): Calcd for C10H11NO2Na (M+Na)+: 200.0682, found: 200.0673. |
Multi-step reaction with 2 steps 1: PCl5 2: alcoholic ammonia | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.5 h / 0 °C 2: ammonium chloride / tetrahydrofuran; water / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Bases: K2 CO3 Into a mechanically stirred, jacketed autoclave was fed a solution of Acrylic acid (73.6 gr., 1.02 mol) and K2 CO3 (116 gr., 0.84 mole) in water (600 mL) followed by Palladium Chloride (5 mg) and 4-Bromo anisole (112 gr., 0.59 mol). The autoclave was sealed and heated to 150 C. (oil bath temperature) while stirring for 3.25 hours. The heating was discontinued and the vessel was allowed to cool to 90 C. Upon opening, the catalyst was filtered off the mixture. An acidified aliquot of the filtrate was analyzed by qualitative HPLC showing a 89.3% conversion of 4-Bromo anisole to p-methoxy cinnamic acid. The filtrate was acidified to a pH of about 1, by means of concentrated HCl. The precipitate which formed was collected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium <i>tert</i>-butylate; copper(l) chloride; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In tetrahydrofuran at 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine; Iron(III) nitrate nonahydrate In toluene at 100℃; for 12h; | Typical Procedure General procedure: The mixture of α,β-Unsaturated Acids (0.5 mmol), Fe(NO3)3 (1.0 mmol), Pyridine (0.5 mmol) and toluene (2 ml) was stirred at 100 °C for 12 h. After cooling to r.t., the reaction mixture was washed with H2O (10 ml), and extracted by ethyl acetate for three times. The obtained top organic layer was dried with anhydrous MgSO4. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EA/n-Hexane=15%) to afford pure product. |
67% | With ammonium cerium (IV) nitrate; sodium nitrite for 0.166667h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3 2-carboxy-1-methylethyl-4'-methoxycinnamate was synthesised according to reaction scheme (7) below. A 250-ML round-bottomed flask equipped with a reflux condenser was charged with 150 ML of DMSO and 9 g of 4-methoxycinnamic acid. 6 g of thionyl chloride was added into the flask in a nitrogen atmosphere and stirred. 5 g of 3-hydroxybutyric acid was slowly added into the mixture, heated slowly to about 60 C. while stirring it, and reacted for 5 hours.The reaction mixture was cooled to room temperature, and the reaction product was poured into excess distilled water to precipitate it.The resulting precipitates were filtered, washed several times with distilled water, and recrystallized using a solvent mixture of chloroform and ethanol to provide 8.5 g of 2-carboxy-1-methylethyl-4'-methoxycinnamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere; | 2. General procedure for the synthesis of compounds 1-3, 5-8 General procedure: Synthesis of serotonin derivatives (1-3, 5-8) were accomplished according to published method (Koyama et al., 2006). First, triethylamine (230 ml, 1.65 mmol), 1-hydroxybenzotriazole (223 mg, 1.65 mmol) and EDC (290 mL, 1.65 mmol) were added to a solution serotonin hydrochloride (350 mg, 1.65 mmol) and cinnamic acid derivatives (1.50 mmol) in dinethylformamide (1.5 ml) and dichloromethane (10 ml). After the mixture was stirred over night at room temperature under nitrogen, it was concentrated in vacuo. The residue was treated with water (15 ml) and extracted withethyl acetate (3 x 10 ml). The organic extract was washed successively with 5 % citric acid solution (3 x 20 ml), saturated sodium hydrogencarbonate solution (3 x 30 ml), and brine (50 ml). The extract was dried over Na2SO4 and concentrated to yield a solid (yield 64.9 % - 96.1 %). |
79.2% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | |
79.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.8% | 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 |
---|---|---|
92% | 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 |
---|---|---|
76% | 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 |
---|---|---|
58.5% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: With sodium tetrahydroborate at 0℃; for 0.5h; Stage #3: With methanol at 20℃; | 7 Take p-methoxycinnamic acid (1.0 g, 5.6 mmol) in a two-necked flask, add 10 mL of anhydrous THF in a N2 atmosphere, and slowly add triethylamine (0.57 g, 5.6 mmol) dropwise for more than 2 minutes at 0°C. After reacting for 5 min, ClCOOCH2CH3 (0.61 g, 5.6 mmol) was slowly added dropwise for more than 5 min. A white precipitate appeared in the reaction solution, filtered, NaBH4 (1.48g, 39.0mmol) was added to the filtrate in batches under stirring at 0°C, and reacted for more than 30 minutes. After the reaction was completed, 10 mL of methanol was slowly added to quench, and the reaction was carried out overnight at room temperature. Adjust the pH of the reaction solution to acidity with concentrated hydrochloric acid, add 10 mL of purified water, extract three times with CH2Cl2 (3×10 mL), enrich the organic layer, add anhydrous sodium sulfate and spin dry, proceed to silica gel (200 mesh-300 mesh) column layer After precipitation and separation, the eluent is petroleum ether: acetone=7:1 or chloroform: methanol=100:1. After vacuum drying, 1 g of the target product is obtained, and the yield is 58.5%. |
Multi-step reaction with 2 steps 1: sulfuric acid 2: lithium aluminium tetrahydride; aluminum (III) chloride | ||
With diisobutylaluminium hydride Inert atmosphere; |
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.5 h / -7 °C 2: sodium tetrahydroborate / methanol; tetrahydrofuran / 2 h / 10 °C | ||
Multi-step reaction with 2 steps 1: chloro-trimethyl-silane / 20 °C 2: diisobutylaluminium hydride / toluene; hexane / 3 h / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium hydroxide In ethanol; water monomer at 50 - 70℃; for 7h; | 3-(4-Methoxy-phenyl)-acrylic acid (1a) (procedure 1) Under stirring condition, anhydrous ethanol (115 ml), water (150 ml), cinnamic acid(17.22 g, 0.105 mol) and potassium hydroxide (17.64 g, 0.315 mol) were added to 1 Lreaction flask and then heated to complete dissolution. After heating to 50 C, methylbromide (29.85 g, 0.314 mol) was dropped into the solution. Maintain temperature at60-70 C, this solution was stirred for 7 h. The compound 1a was obtained throughacidified, washed to neutral and dried. Yield: 87%. |
With potassium hydroxide In methanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sulfated montmorillonite K-10 In nitrobenzene at 100℃; | |
62.2% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With boron trifluoride diethyl etherate; trichlorophosphate at 0℃; for 0.25h; Stage #2: 2-hydroxyresorcinol at 20℃; | |
62.2% | With boron trifluoride diethyl etherate; trichlorophosphate at 0 - 20℃; |
59.4% | With sulfuric acid-modified montmorillonite K-10 In nitrobenzene at 100℃; for 10h; | 5 Example 5: Preparation of 4-(4'-methoxyphenyl)-7,8-dihydroxy-3,4-dihydrocoumarin The 4-methoxyphenylacrylic acid was prepared in the same manner as in Example II. In the 100ml three-mouth reaction bottle, 0.89 g (5 mmol) of 4-methoxyphenylacrylic acid was added. Then, 0.69 g (5.5 mmol) of pyrogallol and 10 ml (98 mmol) of nitrobenzene were added then stirred evenly, heating to 100 °C. Then, 2 g of sulfuric acid-modified montmorillonite K-10 was added. The reaction was complete after 10 hours. The filtrate was added with 20 ml of petroleum ether, and the overnight natural crystallization was carried out. The reaction mixture was suction filtered and washed with 20 ml of petroleum ether. The precipitate was washed with ethyl acetate , Dried in a vacuum oven to obtain 0.85 g pure yellow product in a yield of 59.4%. |
With montmorillonite K-10 at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium phosphate; iodine In acetonitrile at 100℃; for 16h; Inert atmosphere; | |
Stage #1: 3-(4'-methoxyphenyl)propenoic acid With lithium acetate In water; acetonitrile at 20℃; for 0.0833333h; Stage #2: With N-iodo-succinimide In water; acetonitrile at 20℃; | 3.3. General procedure for preparation of vinyl halides11 General procedure: β-Unsaturated carboxylic acid (1.48 g, 10 mmol) was added to a solution of LiOAc (0.07 g, 1 mmol) in MeCN/H2O (97:3 v/v, 30 mL). After the mixture was stirred for 5 min at room temperature, 1-iodopyrrolidine-2,5-dione (2.25 g, 10 mmol) was added. Usual workup by flash column chromatography on silica gel to afford the 1-((E)-2-bromovinyl)benzene 2a (1.36 g, 85%). | |
With N-iodo-succinimide; triethylamine In dichloromethane |
Multi-step reaction with 2 steps 1: potassium bromide; sodium molybdate dihydrate; dihydrogen peroxide / water / 25 °C 2: potassium iodide; copper(I) oxide; <i>L</i>-proline / ethanol / 24 h / 110 °C / Schlenk technique; Sealed tube; Inert atmosphere; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: N1-(7-chloroquinolin-4-yl)butane-1,4-diamine In N,N-dimethyl-formamide at 20℃; for 24h; | |
Stage #1: 3-(4'-methoxyphenyl)propenoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: N1-(7-chloroquinolin-4-yl)butane-1,4-diamine In N,N-dimethyl-formamide at 20℃; for 24h; | ||
Stage #1: 3-(4'-methoxyphenyl)propenoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: N1-(7-chloroquinolin-4-yl)butane-1,4-diamine In N,N-dimethyl-formamide at 0℃; for 24h; | 1. Detailed synthetic procedures for compounds 4-10 General procedure: Chemistry. Compounds 4-10 were synthesized following methodologies previously reported and the analytical and structural data was in agreement with formerly published data.1, 2 Briefly, 4,7-dichloroquinoline or 4-chloropyridine, respectively, was reacted at 100 ºC for 2 to 3 h with 10 molar equivalents (eq) of the respective diaminoalkane to afford the resultant amine; the reaction mixture was then brought to room temperature and diluted with dichlorometane (DCM), and the solution washed with 5% aqueous Na2CO3. The organic layer was isolated and dried over anhydrous Na2SO4, filtered, and the filtrate evaporated to dryness. In the case of the morpholine derivative, 2 eq of morpholine were reacted with 1 eq of 1-(N-phthaloyl)amino-4-bromobutane for 1 day to yield N-(N-phthaloyl)aminobutylmorpholine; after the previously described extraction process, the phthalimide group of the latter compound was removed with hydrazine in ethanol to afford the desired amine. Following, the respective cinnamic acid was activated in N,N-dimethylformamide (DMF), using 2 eq of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 2 eq of N,N-diethyl-N-isopropylamine (DIEA) at 0 oC for 10 min. Subsequently, the corresponding amine was added and the mixture was left to react for 1 day. The mixture was then diluted in DCM, washed with 5% aqueous Na2CO3 and the organic layer collected, dried over Na2SO4, filtered, and the filtrate evaporated to dryness. The crude product was further purified by column liquid chromatography on silica, using a mixture of ethyl acetate and methanol (8:2 v/v) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium azide; trichloroacetonitrile; triphenylphosphine In acetonitrile at 20℃; for 1.5h; Inert atmosphere; | Procedures for the synthesis of parazoanthine A (1) and its O-Me-analog (2) and spectral data of the synthetic intermediates. Compound 5a: 4-Methoxy-cinnamic acid (4a) (0.6 g, 3.37 mmol), triphenylphosphine (1.62 g, 6.74 mmol) and sodium azide (0.24 g, 4.04 mmol) were dissolved in anhydrous acetonitrile (6 mL) under argon; trichloroacetonitrile (0.964 g, 6.74 mmol) was added dropwise at room temperature; the reaction mixture was stirred for 1.5 h and was evaporated under reduced pressure; the residue was purified by silica gel chromatography using a gradient of petroleum ether/ethyl acetate to give compound 5a (0.46 g, 2.63 mmol, 78%) as a pale yellow oil; 1H-NMR (CDCl3, 400 MHz): d 7.73 (1H, d, J= 16.1 Hz), 7.46 (2H, d, J= 8.42 Hz), 6.90 (2H, d, J= 8.42 Hz), 6.31 (1H, d, J=16.1 Hz), 3.78 (3H, s, OCH3); 13C-NMR (CDCl3, 75 MHz): d 173.1 (C), 160.1 (C), 146.9 (CH), 130.8 (CH), 116.3 (CH), 116.1 (CH), 56.8 (OCH3); HRESIMS m/z 226.0596 [M+Na]+ (calcd for C10H9N3O2Na, 226.0592). |
78% | With sodium azide; triphenylphosphine In acetonitrile at 20℃; for 1.5h; Inert atmosphere; | Compound 2a 4-Methoxy-cinnamic acid (1a) (0.6 g, 3.37 mmol), triphenylphosphine (1.62 g, 6.74 mmol) and sodium azide (0.24 g, 4.04 mmol) were dissolved in anhydrous acetonitrile (6 mL) under argon; trichloroacetonitrile (0.964 g, 6.74 mmol) was added dropwise at room temperature; the reaction mixture was stirred for 1.5 h and was evaporated under reduced pressure; the residue was purified by silica gel chromatography using a gradient of petroleum ether/ethyl acetate to give compound 2a (0.46 g, 2.63 mmol, 78%) as a pale yellow oil; 1H-NMR (CDCl3, 400 MHz): d 7.73 (1H, d, J= 16.1 Hz), 7.46 (2H, d, J= 8.42 Hz), 6.90 (2H, d, J= 8.42 Hz), 6.31 (1H, d, J=16.1 Hz), 3.78(3H, s, OCH3); 13C-NMR (CDCl3, 75 MHz): d 173.1 (C), 160.1 (C), 146.9 (CH), 130.8 (CH), 116.3 (CH), 116.1 (CH), 56.8 (OCH3); HRESIMS m/z 226.0596 [M+Na]+ (calcd for C10H9N3O2Na, 226.0592). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tert.-butylhydroperoxide; copper(ll) sulfate pentahydrate; Langlois reagent In dichloromethane; water at 50℃; for 6h; stereospecific reaction; | |
65% | With tert.-butylhydroperoxide; silver (II) carbonate; Langlois reagent; copper(l) chloride In water; 1,2-dichloro-ethane at 0 - 70℃; for 24h; stereoselective reaction; | Decarboxylative Trifluoromethylation of α,β-UnsaturatedAcids (Scheme 2); General Procedure General procedure: To a solution of substrate 1 (0.2 mmol, 1 equiv), CuCl (4 mg, 0.04mmol, 1 equiv), Ag2CO3 (33 mg, 0.12 mmol, 0.6 equiv), andNaSO2CF3 (93.6 mg, 0.6 mmol, 3.0 equiv) in DCE (2 mL) at 0 C,was slowly added TBHP (70% in water, 136 L, 1.0 mmol, 5.0equiv) with stirring. The reaction was allowed to warm to 70 C andthen stirred for 24 h. The resulting mixture was extracted withEtOAc (3 ~ 8 mL) and the combined organic layers were dried withNa2SO4 and then concentrated under vacuum. After evaporation,the residue was purified by column chromatography using silica gel(300.400 mesh; PE.EtOAc, 100:120:1). |
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% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 24h; | 4.1.11 5-(α-Hydroxy-α-2-pyridylbenzyl)-N-[2′-(4’’-isopropylcinnamoyloxy)ethyl]-7-(α-2-pyridyl benzylidene)-5-norbornene-2,3-dicarboximide (29) General procedure: Compound 29 was prepared by a procedure similar to that of Schwartz and co-workers. To a solution of 2 (1.0g, 1.80mmol), 4-isopropylcinnamic acid (0.22g, 1.13mmol), triethylamine (0.47mL, 3.40mmol) and dimethylaminopyridine (12mg, 0.10mmol) in dichloromethane (15mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.24g, 1.24mmol), and the mixture stirred at room temperature for 24h. The reaction mixture was then diluted with dichloromethane (75mL) and washed with brine (2×100mL). The aqueous phase was adjusted to pH 7 with a 10% aqueous solution of citric acid, and the organic phase further washed with brine (2×100mL). The aqueous phase was then extracted with dichloromethane (2×100mL) and the combined organic extracts dried over anhydrous sodium sulfate and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate 1:3) afforded 29 as an off-white solid (0.55g, 0.75mmol, 73%). mp 95-100°C; 1H NMR (300MHz, CDCl3) δ 1.24-1.26 (6H, m, CH(CH3)2), 2.87-2.96 (1H, m, CH(CH3)2), 3.33-3.90 (4.67H, m, NCH2CH2O, H-2, H-3, U/H-1, V/H-1, W/H-4), 3.94 (0.33H, m, Y/H-4), 4.13 (0.13H, m, U/H-4), 4.28-4.35 (2.36H, m, NCH2CH2O, V/H-4), 4.6-4.49 (0.51H, m, W/H-1, Y/H-1), 5.53 (0.36H, dd, J=3.4 and 1.2Hz, V/H-6), 5.56 (0.33H, dd, J=3.4 and 1.2Hz, Y/H-6), 5.62 (0.69H, s), 5.68 (0.31H, s), 6.03 (0.13H, dd, J=3.4 and 1.2Hz, U/H-6), 6.05 (0.18H, dd, J=3.4 and 1.2Hz, W/H-6), 6.23 (0.31H, d, J=15.8Hz, COCH=CH), 6.31 (0.69H, d, J=15.8Hz, COCH=CH), 6.70-7.66 (21H, m, Ar and COCH=CH), 8.41-8.63 (2H, m, αPyr); mp 95-100°C; νmax(NaCl) cm-1 1174, 1250 (C-O ester), 1585 (C=O imide), 1696 (C=O ester); m/z (ESI, 70eV) (Found: MNa+ 750.2939), C47H41N3NaO5 requires 750.2938 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.6% | Stage #1: [(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-(3-amino)tetrahydro-2H-pyran-2,4,5-triyl]triacetate hydrochloride With triethylamine In dichloromethane at 20℃; for 1h; Cooling with ice; Stage #2: 3-(4'-methoxyphenyl)propenoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 36h; | 12 N-(1,3,4,6-Tetra-O-acetyl-2-deoxy-β-d-galactopyranosyl)-3-(4-methoxyphenyl)-2-propenamide (10g) G2-NH2·HCl (0.5 g, 1.3 mmol) was suspended in anhydrous CH2Cl2 (20 mL). Et3N (0.17 mL, 1.30 mmol) was added to this mixture while cooling in an ice bath, and the resulting solution was stirred at room temperature for 1 h. To this solution, HOBt (0.21 g, 1.56 mmol), 4-Methoxycinnamic acid (0.28 g, 1.56 mmol), and EDCI (0.30 g, 1.56 mmol) were added successively, and the reaction mixture was stirred at room temperature for 36 h. Then the mixture was washed with water (20 mL * 2), saturated aqueous NaHCO3 (20 mL * 2), and brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column by use of petroleum ether-acetic ether (1:1, v/v) to give compound 10g as a white solid (0.32 g, 48.6%), mp181-183 °C; +25.68 (c 0.19, CHCl3); 1H NMR (300 MHz, CDCl3) δ (ppm): 7.57 (1H, d, J = 15.6 Hz, -CH=), 7.44 (2H, d, J = 8.7 Hz, ArH), 6.89 (2H, d, J = 8.7 Hz, ArH), 6.18 (1H, d, J = 15.3 Hz, -CH=), 5.78 (1H, d, J = 8.7 Hz, NH), 5.57 (1H, d, J = 9.6 Hz, H-1), 5.41 (1H, d, J = 2.7 Hz, H-4), 5.17 (1H, dd, J = 3.3 Hz, J = 11.3 Hz, H-3), 4.63 (1H, dd, J = 9.3 Hz, J = 10.5 Hz, H-2), 4.23-4.04 (3H, m, H-5, H-6a, H-6b), 3.83 (3H, s, OCH3), 2.19, 2.11, 2.05, 2.00 (each 3H, each s, 4 * OAc); IR (cm-1): 3329 (NH), 2974, 2941 (CH), 1745 (ester, C=O), 1659 (amide, C=O), 1630 (C=C), 1538, 1451, 1370, 1221, 1080, 1041; MS(ESI(-)70 V, m/z): 506.0 [M-H]-; Anal. Calcd for C24H29NO11: C, 56.80, H, 5.76, N, 2.76. Found: C, 56.95, H, 5.85, N, 2.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;Reflux; | General procedure: A stirred solution of compound 4-amino-N-(pyrimidin-2-yl)benzenesulfonamide (1 mmol) in CH2Cl2 (50 mL) wastreated with the appropriate substituted cinnamic acid,EDC·HCl (0.15 mmol), HOBt (0.05 mmol) and refluxedovernight. Then purification with recrystallization affordedthe corresponding compound as white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: 1,2:3,4-di-O-isopropylidene-5R-(+)-proto-quercitol In dichloromethane at 20℃; Inert atmosphere; | 4.1.5. General coupling reaction between bis-acetonides andcinnamic or silylated cinnamate derivatives General procedure: To a solution of 1, 2, 3, 4 and 5 (2.5 eq) in CH2Cl2 (5 mL) were added N,N'-dicyclohexylcarbodiimide (DCC, 2.7 eq) and 4-dimethylaminopyridine (DMAP, catalytic amount). The reaction mixture was stirred at 0 °C for 30 min. 10 or 11 (1 eq) in CH2Cl2 was added dropwise at room temperature under N2 gas. The product was filtrated and solvent was removed under reduced pressure. The crude product was subsequently purified by silica gel column to afford bis-acetonides 1R-5R. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tetrabutylammomium bromide; potassium carbonate; palladium In water at 170℃; for 0.25h; Microwave irradiation; | |
93% | With tetrabutylammomium bromide; potassium carbonate In water at 170℃; for 0.333333h; Microwave irradiation; | |
85% | With water; C31H28Br2N4Pd; potassium hydroxide at 120℃; for 6h; | 3.7. Mizoroki-Heck coupling reactions of aryl bromides with different acrylates using Pd-BNH3 catalyst. Scope of the substrates The Mizoroki-Heck cross-coupling reactions of 4-bromoanisole (1a)methyl acrylate (4a), acrylic acid (4b), and acrylamide (4a) were investigated (Table 8, entries 1-6) using Pd-BNH3 catalyst (Equation 3).As mentioned above (Scheme 4), under the experimental reaction conditions(KOH, H2O, 120 °C), the methyl acrylate (4a) and acrylamide(4c) are hydrolyzed into potassium acrylate (4b’) prior to their engagement in the cross-coupling reactions to produce the carboxylic acids 5aa and 6aa after the acidic workup. As expected, the Mizoroki-Heck cross-coupling reactions of 4-bromoanisole with methyl acrylate(4a) (Table 8, entry 1), acrylic acid (4b) (Table 8, entry 3), and acrylamide(4c) (Table 8, entry 5) in i-PrOH/H2O gave excellent overall yields (92-96%) and very good selectivity towards the cinnamic acidderivative 5aa (75-79%). When the same reactions were carried out in DMF/H2O as a solvent system, the overall yields remained very high(85-88%) (Table 8, entries 2, 4, and 6) with the production of the cinnamic acid derivative 5aa as the sole product. The attempts to produce the hydrocinnamic acid derivative 6aa as a major product have not yetbeen successful. Further studies and research will be adopted to solvethis challenging task. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sulfuric acid Inert atmosphere; Reflux; | |
96% | With sulfuric acid at 70℃; for 3.5h; Reflux; | 2 Example 2 Synthesis of Methyl Esters from Cinnamic Acids [0294] (E)-methyl 3-(4-methoxyphenyl)acrylate: In a round bottom flask, 4-methoxycinnamic acid (3.14 g, 17 mmol, 1 eq) was suspended in methanol (20 mL). Sulfuric acid (650 μL) was added dropwise. The reaction was brought to 70° C. and allowed to reflux for 3.5 hours, until starting material was consumed as observed by TLC. The crude reaction mixture was poured on ice water (30 mL). The organic products were extracted with ether (1×60 mL, 2×30 mL), washed with brine (30 mL) and dried using anhydrous MgSO4. The crude product was concentrated in vacuo. The desired (E)-methyl 3-(4-methoxyphenyl)acrylate was isolated by flash chromatography using 5:1 hexanes:ethyl acetate to afford a white solid in 96% yield (3.241 g). 1H NMR (300 MHz, CDCl3): δ7.61 (1H, d, J=15.9 Hz), 7.41 (2H, d, J=8.7 Hz), 6.84 (2H, d, J=8.7 Hz), 6.27 (1H, d, J=15.9 Hz), 3.83 (3H, s), 3.79 (3H, s). 13C NMR (75 MHz, CDCl3): δ167.8, 161.6, 144.6, 129.9, 127.2, 115.3, 114.4, 55.4, 51.6. |
92% | With sulfuric acid Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dihydrogen peroxide; vanadium pentoxide In water monomer; acetonitrile at 20℃; for 24h; Inert atmosphere; Green chemistry; | |
87% | With potassium peroxomonosulfate; 3,4,5,6-tetramethyl-2-iodobenzoic acid In water monomer; acetonitrile for 36h; | |
40% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With oxygen; ozone; acetic acid In water monomer at 0 - 10℃; for 1.16667h; Stage #2: With dihydrogen peroxide In water monomer at 15 - 95℃; for 3h; | 4 0.45 g (2.5 mmol) of 4-methoxycinnamic acid, 27 g of acetic acid and 3.0 g of water were charged in a 100 mL four-necked flask equipped with a thermometer, a condenser, a stirrer, and an introduction line of an ozone / oxygen mixed gas , While stirring at 0 to 10 ° C., oxygen gas having an ozone concentration of 4 to 5% was blown at a rate of about 40 mL / min for about 1 hour and 10 minutes.After completion of the reaction, only oxygen was bubbled for 15 minutes or more to remove residual ozone in the system.Thereafter, 1.9 g of 30 to 35% hydrogen peroxide water was added at 15 to 25 ° C., and the solution was heated at a liquid temperature of 60 to 70 ° C. for 0.5 hours, and then heated at a liquid temperature of 85 to 95 ° C. for 2.5 hours did. After completion of the reaction, the reaction solution was cooled to room temperature and quantitatively analyzed by HPLC to calculate the yield, the yield of 4-methoxybenzoic acid was 40% |
With potassium peroxomonosulfate In water monomer; acetonitrile for 24h; Reflux; | 1 5.2 General procedure for the oxidative cleavage of olefins General procedure: To a solution of the olefin (0.5-1.2 mmol) in 16 mL of acetonitrile-water (1:1) mixture at reflux was introduced oxone incrementally over the entire duration of the reaction. Progress of the reaction in each case was monitored by TLC analysis. After completion of the reaction as judged by TLC analysis, the reaction mixture was cooled to rt, and the organic matter was extracted with ethyl acetate. The combined organic extract was dried over anhyd Na2SO4 and concentrated in vacuo. The residue was subjected to a short-pad silica gel column chromatography to isolate pure product/s. All the products were characterized by their 1H NMR spectral data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With iodine In neat (no solvent) at 120 - 130℃; for 4h; | 4.2.1 General procedure for the synthesis of dihydrocoumarins General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
68% | With iodine In neat (no solvent) at 120 - 130℃; for 4h; | 4.2.1. General procedure for the synthesis of dihydrocoumarins. General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With iodine In neat (no solvent) at 120 - 130℃; for 3h; | 4.2.1 General procedure for the synthesis of dihydrocoumarins General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
82% | With iodine In neat (no solvent) at 120 - 130℃; for 3h; | 4.2.1. General procedure for the synthesis of dihydrocoumarins. General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With iodine In neat (no solvent) at 120 - 130℃; for 4h; | 4.2.1 General procedure for the synthesis of dihydrocoumarins General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
85% | With iodine In neat (no solvent) at 120 - 130℃; for 4h; | 4.2.1. General procedure for the synthesis of dihydrocoumarins. General procedure: Iodine (0.13 mmol) was added into a mixture of phenol (0.69 mmol) and cinnamic acid (0.69 mmol) under an air atmosphere and the mixture was neat heated at 120-130 °C for a period of time (1-4 h). Following completion of the reaction as monitored by TLC, the reaction mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium thiosulphate solution and dried over sodium sulfate. The solvent was removed under vacuum to provide the crude products. Further purification was done by column chromatography on silica gel with hexanes/ethyl acetate (4:1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrabutylammonium perchlorate; acetic acid In water; acetonitrile at 20℃; for 2h; Electrolysis; regioselective reaction; | |
72% | 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 |
68% | With palladium diacetate; silver carbonate; 1,4-di(diphenylphosphino)-butane In N,N-dimethyl-formamide at 75℃; for 6h; Inert atmosphere; Sealed tube; |
42% | 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 |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | Synthesis of target compound Compound 1 (72 mg, 0.2 mmol) was mixed with 4-methoxycinnamic acid (0.22 mmol), EDCI (0.25 mmol) and DMAP (0.01 mmol) in 15 mL of dry dichloromethane and stirred at room temperature for 18 h. The mixture was poured into 15 mL of 10% HCl, and extracted with dichloromethane (10 mL * 3). The organic layer was combined, washed with water and saturated NaCl solutions sequentially, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (MeOH/CH2Cl2 1:150 v/v) to give the compound 2. ent-1alpha,6beta,7beta-trihydroxy-(14beta-O-p-methoxycinnamoyl)-15-oxo-7,20-epoxy-16-kaurene (Compound 2) 75% as white solid, mp. 175-177 C; 1H NMR (CDCl3, 300 MHz): delta (ppm) 7.59, 6.20 (dd, JA = JB = 15.9 Hz, each 1H), 7.44 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.21 (m, 2H), 5.93 (s, 1H), 5.49 (s, 1H), 4.42 (s, 1H), 4.09, 4.35 (dd, JA = JB = 9.6 Hz, each 1H), 3.86 (s, 3H), 3.79 (m, 1H), 3.53 (m, 1H), 3.27 (m, 1H), 2.63 (m, 1H), 2.38 (m, 1H), 2.04 (m, 1H), 1.80 (m, 2H), 1.71 (m, 5H), 1.54 (m, 1H), 1.11 (s, 6H); 13C NMR (CDCl3, 75 MHz): delta (ppm) 206.3, 165.0, 161.4, 149.4, 145.8, 129.6, 126.0, 119.7, 113.9, 113.5, 95.8, 76.1, 72.9, 62.9, 61.4, 59.4, 54.9, 54.1, 40.9, 40.8, 38.2, 33.3, 32.0, 30.0, 29.5, 21.1, 19.2; MS (ESI) m/z: 525.3 [M + H]+; HR-MS (ESI) m/z: calcd for C30H37O8 [M + H]+ 525.2483, found 525.2493. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 72h; | General procedure for the Steglich esterification protocol General procedure: To a solution of 7, epi-7 or 9 (1 equiv) in anhydrous CH2Cl2 (0.01 M) were successively added 4-substituted cinnamic acid (2 equiv for 5a-c, 8b-d; 4 equiv for epi-8b, epi-8c and epi-8d), DCC (2.2 equiv for 5a-c, 8b-d; 4.4 equiv for epi-8b, epi-8c and epi-8d)and DMAP (4 equiv for 5a-c, 8b-d; 8 equiv for epi-8b, epi-8c and epi-8d). The mixture was stirred at room temperature until the starting materials were consumed (TLC, 22 h for 5a-c; 48 h for 8b-d; 72 h for epi-8b, epi-8c and epi-8d). The mixture was poured to water (80 mL) and extracted with CH2Cl2. The combined organic phases were washed with 10% NaCl, dried and evaporated, and the residue was purified by flash column chromatography (CH2Cl2 for 8b and 8d, 17:3 light petroleum/EtOAc for 8c, 3:2 hexane/Et2O for epi-8b and epi-8d, 1:1 hexane/Et2O for epi-8c, 47:3 toluene/EtOAc for 5b, CH2Cl2 for 5c, 19:1 toluene/EtOAc for 5d) and in few cases by additional preparative TLC (iPr2O, 3 successive developments, for 5b and 5c). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 48h; | General procedure for the Steglich esterification protocol General procedure: To a solution of 7, epi-7 or 9 (1 equiv) in anhydrous CH2Cl2 (0.01 M) were successively added 4-substituted cinnamic acid (2 equiv for 5a-c, 8b-d; 4 equiv for epi-8b, epi-8c and epi-8d), DCC (2.2 equiv for 5a-c, 8b-d; 4.4 equiv for epi-8b, epi-8c and epi-8d)and DMAP (4 equiv for 5a-c, 8b-d; 8 equiv for epi-8b, epi-8c and epi-8d). The mixture was stirred at room temperature until the starting materials were consumed (TLC, 22 h for 5a-c; 48 h for 8b-d; 72 h for epi-8b, epi-8c and epi-8d). The mixture was poured to water (80 mL) and extracted with CH2Cl2. The combined organic phases were washed with 10% NaCl, dried and evaporated, and the residue was purified by flash column chromatography (CH2Cl2 for 8b and 8d, 17:3 light petroleum/EtOAc for 8c, 3:2 hexane/Et2O for epi-8b and epi-8d, 1:1 hexane/Et2O for epi-8c, 47:3 toluene/EtOAc for 5b, CH2Cl2 for 5c, 19:1 toluene/EtOAc for 5d) and in few cases by additional preparative TLC (iPr2O, 3 successive developments, for 5b and 5c). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 1h; Reflux; | 13 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 |
---|---|---|
94% | With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; | General procedure for the preparation of compounds 8a-s General procedure: To a solution of 7 (200 mg, 0.43 mmol) in DMF, corresponding 3-arylacrylic acids (0.47 mmol, 1.1 equiv), HATU (179 mg, 0.47 mmol, 1.1 equiv) and TEA (131 mg, 1.29 mmol, 3.0 equiv)were added, respectively. The solution was stirred at room temperature overnight, then excess water was added and the precipitate formed. The solids were filtrated, washed with water and dried under infrared lamp to obtain the target compounds 8a-s. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tert.-butylhydroperoxide; sodium iodide In N,N-dimethyl-formamide at 60℃; for 12h; | General procedure for preparation of α-oxybenzoylative products through the reaction between dimethyl malonate and carboxylic acids at 60 °C General procedure: To a reaction tube equipped with a magnetic stir bar cinnamic acid (0.3 mmol), dimethyl malonate (0.9 mmol), NaI (20 mol%) TBHP (1.5 equiv.) in DMF (2 mL). The resulting reaction mixture was kept stirring at 60 °C for 12 h. At the end of the reaction, the reaction mixture was cooled to room temperature. After the removal of the solvent, the residue was subjected to column chromatography on silica gel using ethyl acetate and petroleum ether mixtures to afford the desired product in high purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tert.-butylhydroperoxide; sodium iodide In N,N-dimethyl-formamide at 120℃; for 12h; | General procedure for preparation of oxyacylation-decarboxylation products through the addition reaction between dimethyl malonate and carboxylic acids at 120 °C General procedure: To a reaction tube equipped with a magnetic stir bar cinnamic acid (0.3 mmol), dimethyl malonate (0.9 mmol), NaI (20 mol%), TBHP (1.5 equiv.) and DMF (2 mL) was added under air. The resulting reaction mixture was kept stirring at 120 °C for 12 h. At the end of the reaction, the reaction mixture was cooled to room temperature. After the removal of the solvent, the residue was subjected to column chromatography on silica gel using ethyl acetate and petroleum ether mixtures to afford the desired product in high purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tert.-butylhydroperoxide In water at 110℃; for 4h; Sealed tube; | Activity test General procedure: The typical experimental procedure for the decarboxylative coupling reaction was as follows: Cu-X catalyst (5mg), CA 1 (0.5mmol), TBHP (1.0mmol, 70% aqueous solution), and ethanol 2 (2.0mL) were placed in a sealed tube (10mL). The reaction was heated at 110°C for 4h. After the reaction finished, the catalyst was separated by centrifugation and filtration to obtain the liquid phase. The liquid products were analyzed by an Agilent 1260 Infinity Liquid Chromatogram. The pure product was obtained by flash column chromatography on silica gel using petroleum ether (60-90°C) and ethyl acetate as eluents. Compounds described in the literature were characterized by comparing their 1H and 13C NMR spectra and MS data with the reported data. The 1H NMR (500 and 400MHz) and 13C NMR (125 and 100MHz) were recorded with spectrometers at 20°C using CDCl3 as the solvent. Chemical shifts are given in parts per million relative to TMS as the internal standard at room temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Amberlyst 15 In neat (no solvent, gas phase) at 130℃; for 0.116667h; Microwave irradiation; | The tandem reaction of cinnamic acid with phenol catalyzed by amberlyst-15 undermicrowave irradiation (method A) General procedure: Suitable amounts of cinnamic acid (1.5mmol, 0.222 g), phenol (2.0mmol, 0.188 g) andAmberlyst 15 (0.2 g) were added successively into the test tube (U10mm, h100mm)placed into CEM oven. The irradiation program set up at 130 C for 7minutes wasapplied to the reaction mixture. After cooling, the product mixture was extracted withdiethyl ether (415mL) and filtrated by porous filter funnel to separate and collect theacidic catalyst A-15 for recycling. Subsequently, the filtrate was stirred magnetically with10mL of aqueous sodium hydroxide 5% (to remove all excess or unreacted cinnamic acidand phenol) and then washed with water until neutralization. Organic layer was dried byanhydrous sodium sulfate and removed solvent by rotary evaporation. The remainingcrude product was analyzed by GC/MS to check the composition of crude product. Thedesired product was purified by silica gel column chromatography, and then was identifiedtheir structure by HRMS, 1H and 13C NMR spectroscopy |
84% | With 1-methyl-2-oxopyrrolidinium hydrogen sulfate In neat liquid at 120℃; for 4h; | Synthesis dihydrocoumarins: general procedure General procedure: Synthesis dihydrocoumarins: general procedure To a 25 mL round bottomed ask equipped with a reux condenser, phenol(1 mmol), cinnamic acid (1 mmol), and acidic ionic liquid N-methyl-2-pyrroli-donum hydrosulfate ([H-NMP]HSO4) (3 mmol) were placed. The reaction mixturewas heated at 120 °C for a period of time as indicated in Table 1 (2-5 h). Aftercompletion of the reaction (monitored by TLC), the reaction mixture was cooledand poured in water. The mixture was extracted with ethyl acetate (2 9 10 mL).The organic layer was separated, washed with water and brine and separated again,dried over anhydrous Na2SO4, and concentrated under reduced pressure to give thecrude product. This crude product was column chromatographed over silica gel(230-400 mesh) using ethyl acetate and petroleum ether as eluent to give the highlypure products in satisfactory yield (Table 1). |
62% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With boron trifluoride diethyl etherate; trichlorophosphate at 0℃; for 0.25h; Stage #2: phenol at 25 - 28℃; | 3.4. General Procedures III: Synthesis of Compounds 22-28 General procedure: To a mixture of POCl3 (10 mmol) and BF3-Et2O (20 mmol) at 0 °C, appropriated cinnamic acid(5 mmol) was added and the reaction mixture stirred for 15 min at 0 °C. Phenol (5 mmol) was added tothe above reaction mixture in small portions and stirring continued at 25-28 °C for 4-12 h. The reactionmixture was poured on to ice-water; sodium acetate (1 g) was added and the mixture was warmedon a water bath for 2 min. It was cooled, extracted with ethyl acetate (2 x 150 mL), washed withwater (150 mL), dried, and the solvent removed under reduced pressure to obtain the crude product,which was purified by column chromatography using acetone-chloroform as eluent to afford pure4-phenyldihydro-coumarins 22-28 in 60%-75% yields. 4-(4-Methoxyphenyl)chroman-2-one (22). This was prepared from p-methoxycinnamic acid and phenolusing the general procedure III. Yield 62%; A white solid; m.p. 160-162 °C (CH2Cl2/MeOH); IR (KBr): ν= 2943, 2927, 2907, 2833, 1832, 1717, 1701, 1608 cm-1; 1H-NMR (CDCl3) δ 7.31 (br d, J = 8.1 Hz,1H), 7.12 (d, J = 8.2 Hz, 2H), 7.07 (br d, J = 8.2 Hz, 1H), 6.97 (m, 2H), 6.87 (d, J = 8.2 Hz, 3H), 4.30 (t,J = 7.3 Hz, 1H), 3.79 (s, 3H), 3.08 (dd, J = 7.3 Hz, 15.7 Hz, 1H), 2.96 (dd, J = 7.3, 15.7 Hz, 2H); 13C-NMR(CDCl3) δ 37.2, 40.0, 55.3, 114.5 (2C), 117.1, 124.7, 126.3, 128.3, 128.6 (3C), 132.2, 151.7, 159.0, 167.8. (EI)m/z: 254 (M+ C16H14O3, 65), 226 (14), 212 (15), 211 (72), 197 (22), 182 (15), 181 (100), 168 (13), 139 (12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.8% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h; | 7 Example 7: preparaton of L4 (Compound No. 4) Round-bottomed flask were added sequentially 235.84mg (1.32mmol) 4- methoxy cinnamic acid, 4.30mL (1.33mmol) TMP-NH2The CH2Cl2Solution, 253mg (1.32mmol) EDCI, 528 μL (3.97mmol) of triethylamine; 20mL of dichloromethane was added, the reaction mixture was stirred at room temperature 12h.TLC [V (petroleum ether) :V (acetone) = 2] Detection reaction is essentially complete, the reaction was successively washed with water (2 × 20 mL) and saturated brine (20 mL) wash, dried over anhydrous sodium sulfate, filtered, and reduced pressure evaporated to dryness.The residue was separated by silica gel column white solid, yield: 85.8%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; 2,6-di-tert-butyl-4-methyl-phenol; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 3 3. synthesis of polymerizable compound (M3) The intermediate compound (Q2) 3.4g (10mmol), 4-methoxy cinnamic acid 1.8g (10mmol), DMAP 0.08 g and a small amount of BHT to stir at room temperature under the suspended dichloromethane 30 ml in, adding by DCC2.6g (13mmol) dissolved in the dichloromethane 15 ml solution in which a, stirring overnight. Filtering precipitation of urea of DCC, the filtrate for the sequentially 0.5mol/L hydrochloric acid 50 ml, saturated sodium bicarbonate aqueous solution 50 ml, saturated salt water 50 ml various washing 2 times, after drying with magnesium sulfate, solvent is removed by distillation, recrystallization with ethanol refined, polymerizable compound to obtain a target of (M3) 4.3g (yield 86%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | General procedure for the synthesis of cinnamoyl-, haro-cinnamoyl-, NO2-cinnamoyl- and (OCH3)ncinnamoyl-decursin derivatives (5a-e, 6a-i) General procedure: The mixture of cinnamic acid (1.2 equiv), EDC (2 equiv) and 4-DMAP (0.4 equiv) was dissolved inanhydrous dichloromethane. After (+)-Decursinol (1 equiv) was added, the reaction mixture stirred to roomtemperature for 5-12 hours. The completion of reaction was juged by TLC. When a spot of (+)-decursinolwas disappeared on TLC, the reaction was finished. The mixture was concentrated in vacuo and the residuewas purified by flash silica gel column chromatography using EtOAc/Hexane system as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 0.5h; | General procedure for the preparation of compounds 7a-7o General procedure: A solution of the appropriate caffic acid derivitives (1mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafl-uorophosphate (HATU) (1.2mmol) and N,N-diisopropylethylamine (2mmol) in dichloromethane was stirred at ambient temperature for 30min. Compound 4 (1mmol) was added to the solution, and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with diluted hydrochloric acid, saturated sodium bicarbonate solution and brine. And dried with anhydrous magnesium sulfate, and the solvent was evaporated in vacuum to give the crude product, which was purified by chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3.5h; | 4.1.6. General procedure for the preparation of 4-methoxycinnamoates 1c-4c General procedure: To a solution of 1-4 (1 equiv)2 in dry CH2Cl2 (0.03e0.04 M) wereadded 4-methoxycinnamic acid (2.1 equiv), DMAP (4.2 equiv) and DCC (2.5 equiv). The mixture was stirred at room temperature for 3-5 h, then poured into water and extracted with CH2Cl2. The combined extracts were dried and evaporated. The residue was purified by flash column chromatography (7:3 light petroleum/EtOAc for 1c and 2c; 3:2 light petroleum/EtOAc for 3c; 3:2 lightpetroleum/EtOAc for 4c) and then by preparative TLC (7:3 lightpetroleum/EtOAc for 1c and 2c, two successive developments; 3:2light petroleum/EtOAc for 3c; 4:1 light petroleum/EtOAc threesuccessive developments for 4c). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With [2,2]bipyridinyl; copper(I) trifluoromethanesolfonate toluene complex; Dimethyl phosphite In acetonitrile at 80℃; for 72h; Schlenk technique; Inert atmosphere; Sealed tube; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.2% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; Inert atmosphere; | 6 4.1.9. General procedure for the preparation of 5a-5d and 6a-6d General procedure: An anhydrous DCM (10mL) solution of kidjoranin (5, 50mg, 0.098mmol) and 17β-O-cinnamoyl-3β,8β,14β-trihydroxypregn-12,20-ether (6, 50mg, 0.098mmol) and DCC (2.0equiv), DMAP (0.4equiv) and appropriate carboxylic acid or chloride (1.13equiv) in flask (25mL) was stirred for 24h at r.t., in the present nitrogen. When the starting material was exhausted, the mixture was filtered, and the residue was washed with DCM (2×10mL), poured into H2O and extracted with DCM (3×30mL).8 The organic layer was successively washed with saturated aqueous tartaricacid (3×30mL) and NaHCO3 (3×30mL), and saturated NaCl (2×10mL), respectively. Subsequently, the organic layer was dried over anhydrous MgSO4 and the solution was evaporated under reduced pressure. At last, the residue was loaded onto a silica gel column, and eluted with petroleum ether/acetone to afford 5a-5d and 6a-6d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With [2,2]bipyridinyl; palladium diacetate; acetic acid In tetrahydrofuran; water at 80℃; for 24h; Schlenk technique; | |
90% | With dichloro(2,2'-bipyridine)palladium(II); silver nitrate In water at 60℃; for 12h; Green chemistry; | Procedure of synthesis of 3,3-diphenylpropanoic acid (3aa) General procedure: A screw-top vial was charged with a magnetic stirrer, PdCl2-bpy (16.6 mg, 0.05 mmol, 5 mol%), AgNO3 (16.9 mg, 0.1 mmol, 10 mol%), PhB(OH)2 (244.0 mg, 2.0 mmol), cinnamic acid (148.2 mg, 1.0 mmol). The mixture was suspended in H2O (2.0 mL) and stirred for 10 h at 60 °C. Then the solvent was removed by syringe at 60 °C. Water was added to the vial again to remove the excessive PhB(OH)2. The process was repeated three times. The residue was dissolved in chloroform (10 mL), filtered and concentrated in vacuum, 216.8 mg pure product (Yield: 96%) was obtained. |
83% | With silver nitrate In water; acetone at 90℃; |
With palladium diacetate; acetic acid In tetrahydrofuran; water at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1,4-diaza-bicyclo[2.2.2]octane; tris(bipyridine)ruthenium(II) dichloride hexahydrate In N,N-dimethyl acetamide at 20℃; for 12h; Schlenk technique; Inert atmosphere; Irradiation; stereoselective reaction; | |
72% | With 1,4-diaza-bicyclo[2.2.2]octane; tetrakis(actonitrile)copper(I) hexafluorophosphate; 2.9-dimethyl-1,10-phenanthroline; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran at 20℃; for 48h; Schlenk technique; Inert atmosphere; Irradiation; | 4.1. General procedure General procedure: In air, Cu(MeCN)4PF6 (10 mol%), L1 (15 mol%), xantphos (15 mol %), DABCO (50 mol%), a,b-unsaturated carboxylic acids (0.2 mmol)and redox active ester (0.6 mmol) were added to a schlenk tubeequipped with a stir bar. The vessel was evacuated and lled withargon (three cycles). Anhydrous THF (1 mL) were added by syringe.The resulting reaction mixture was stirred under the irradiation of a20 W blue LEDs (465 nm) at room temperature for 48 h under Ar.The resulting solution was puried by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid; (2S,4S)-4-hydroxy-4-((3aR,7S,8aS)-7-methyl-3-methylene-2-oxo-3,3a,4,7,8,8a-hexahydro-2H-cyclohepta[b]furan-6-yl)butan-2-yl acetate With dmap In dichloromethane at 0℃; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 3.08333h; | General procedures for preparation of aryl esters (7-10) General procedure: In a two-necked round bottom flask equipped with a calciumchloride drying tube was charged aryl carboxylic acid(1 equiv.), isoxanthanol (1) (1 equiv.), and DMAP (10 mol%) in dry dichloromethane. The resulting reaction mixturecooled in an ice bath to 0 °C and stirred for a while followedby addition of DCC (1.1 equiv.) at 0 °C over a period of 5min. The ice bath was removed, and the dark-brown reactionmixture stirred for 3 h at room temperature. Aftercompletion of the reaction, the precipitate of dicyclohexylureawas removed by filtration through a fritted Buchnerfunnel, and the filtrate washed with water and extracted withdichloromethane. The organic layer was dried over anhydroussodium sulfate and concentrated on a rotavapor. The crude product obtained was purified by CC on silica gelcolumn using hexane-ethyl acetate as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With copper(l) iodide; 1,10-Phenanthroline In N,N-dimethyl-formamide at 100℃; for 12h; Inert atmosphere; | 5 Example 1Preparation of compound (1), the specific reaction equation is as follows: General procedure: The specific preparation process: To a magnetic stirrer with 10mLA round bottom flask with a beaker was charged with acetonitrile (2 mL) as a solvent,4-methylphenylacetic acid (0.46 g, 1 mmol),N-fluorodibenzenesulfonimide (0.097 g, 1.2 mmol),Copper iodide (0.026 ml, 0.3 mmol) and1,10-o-phenanthroline (0.026 ml, 0.3 mmol),After mixing,Put it in a 80 ° C oil bath and continue stirring.TLC detection of substrate disappeared,The reaction is over. The reaction was poured into saturated aqueous sodium chloride (5 mL)Extract with dichloromethane (3 x 6 mL), combine the organic phases, dry over anhydrous magnesium sulfate,After depressurization, the organic solvent was distilled off under reduced pressure,The liquid mixture was obtained and finally subjected to silica gel column chromatography(Eluent V petroleum ether: V ethyl acetate = 10: 1) to give 0.41 g of a light yellow solid which was confirmed as compound (1) by NMR after MS,Based on 4-methylphenylacetic acid, the yield was calculated to be 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hypochlorite In water; acetonitrile at 20℃; for 8h; | 1.2 General procedure for the synthesis of vinyl chloride General procedure: A 100 mL Round Bottom Flask was charged with α,β-unsaturated acid 1(10 mmol), NaOCl(50 mmol), and CH3CN (15 mL), and then the mixture was stirred at room temperature for 8 h. After completion of the reaction as monitored by thin-layer chromatography (TLC), H2O (10 mL) was added. The mixture was extracted with Chloroform (3x10 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (10 mL) and water (10 mL), dried over anhydrous Na2SO4, and then concentrated by rotary evaporator. Finally, the residue was purified by column chromatography on silica gel with petroleum ether as mobile phase to provide the desired product 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dipotassium peroxodisulfate; oxygen; In N,N-dimethyl-formamide; at 100℃; for 12h; | General procedure: A mixture of cinnamic acid 1 (1.0 mmol), K2S2O8 (1.5 mmol) and sodium sulfinate 2 (1.5 mmol) in DMF (5 mL) was stirred at 100 oC under ambient air for 12 h. Upon completion of the reaction (monitored by TLC), the mixture was extracted with EtOAc (3 x 15 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (EtOAc/n-hexane, 1:4) to afford an analytically pure sample of beta-keto sulfones 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With palladium(II) trifluoroacetate; silver carbonate In dimethyl sulfoxide; N,N-dimethyl-formamide at 130℃; for 24h; Schlenk technique; Inert atmosphere; | |
75% | With silver (II) carbonate; palladium diacetate In dimethyl sulfoxide; N,N-dimethyl-formamide at 120℃; for 12h; | 2 Example 2 In a 50mL thick-walled high-pressure resistant reaction tube, add a stir bar, a mixed solvent of dimethyl sulfoxide and N, N-dimethylformamide (5.0mL, volume ratio: 1/20), and 4-methoxycinnamic acid in order. (89.1 mg, 0.5 mmol), diphenylacetylene (267.4 mg, 1.5 mmol), catalyst palladium (II) acetate (11.2 mg, 0.05 mmol), oxidant silver carbonate (413.6 mg, 1.5 mmol), and the reaction system was placed at 120 ° C. Reaction in oil bath for 12h. After cooling to room temperature and diluting with ethyl acetate (25 mL),Filter through diatomaceous earth and wash with ethyl acetate (10mL * 3). The combined organic phases are first washed with water (30mL * 5) and then with saturated brine (30mL * 1), dried with desiccants such as magnesium sulfate,Concentrated on a rotary evaporator, and the crude product was separated by silica gel column chromatographyA red solid was obtained (183.2 mg, yield: 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With 1,1'-carbonyldiimidazole In dichloromethane Stage #2: L-arginine With dmap In N,N-dimethyl-formamide at 80℃; | Method B (3b, 3d and 3h) General procedure: To a solution of the correspondent carboxylic acid (1.2 equiv.) in dry DCM (volume to make a0.5 M solution of substrate) CDI (1.5 equiv.) was added, and the reaction was stirred until completeconsumption of the starting material (TLC, DCM/MeOH 19:1). Then, the reaction mixture wasconcentrated under vacuum and to the attained residue a solution of the arginine derivative (1equiv.) in DMF (volume to make a 0.5 M solution of substrate) and DMAP (0.1 equiv.) were addedand the reaction was stirred at 80 °C until complete consumption of the starting material (TLC,DCM/MeOH/H2O 13:7:1). After the consumption of the starting material, the solvent was removedunder reduced pressured and the reaction mixture was purified by RP-18 column chromatography.The collected fractions were analyzed by UV-vis and combined according to the obtainedUV-spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 82% 2: 7% | Stage #1: methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride With triethylamine In dichloromethane at 40℃; for 2h; Stage #2: 3-(4'-methoxyphenyl)propenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; | General procedure for the synthesis of 6a-d. General procedure: In a 250 mL flat bottom ballflask with magnetic stirrer (Flask 1) 0.3051 g (2.0 Eq) of compound 5and 0.2743 mL (2.0 Eq) of Et3N in 20 mL of dichloromethane (CH2Cl2)were added. The solution was allowedto stir and reflux at 40 °C for 2 h. After an hour and a half, in a 100 ml ballflask with magnetic stirrer (Flask 2) 0.200 g (1.0 Eq) of compound 4a-d,and 0.2315 g (1.0 Eq) of N,N'-dicyclohexylcarbodiimide (DCC) wereadded followed by 0.0274 g (0.2 Eq) of dimethylaminopyridine (DMAP) in 20 mL ofCH2Cl2, leaving under stirring for 30 min. After twohours Flask 1 was removed from reflux and the contents of Flask 2 werepoured into it, and the solution left under stirring for 24 h at roomtemperature. After this time, the flask was refrigerated at 5 °C for 1 h andsubsequently filtered under vacuum. The solvent was evaporated under vacuum and20 mL of EtOAc and water were added to perform a liquid-liquid extraction. Theorganic phase was dried with anhydrous Na2SO4 and the EtOAc evaporated under vacuum. Finally, the product was purified by column chromatography using a Hex: EtOAc elution system (1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 4.1.4. General procedure for preparation of 5,3′,4′,5′-tetramethoxyflavan-7-caroxylates (A1-A17) General procedure: To a mixture of intermediate GTF-2 (10.0 mg, 27.5 μmoL), EDCI(10.5 mg, 55.0 μmoL) and DMAP (3.4 mg, 27.5 μmoL) in 6 mL anhydrousCH2Cl2, the appropriate carboxylic acid (55.0 μmoL) was added.After stirring overnight at room temperature, water (4 mL) was addedto the reaction mixture, and the content was extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed by brinewater, dried over anhydrous sodium sulfate and concentrated. The residualoil was purified by semi-preparative reversed-phase C18 HPLCwith acetonitrile and water to give A1-A17 as white powder or oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With rose bengal; caesium carbonate In acetonitrile at 20℃; for 12h; Irradiation; | 3 General Experimental Procedure In a flame-dried round bottom flask was equipped with a magnetic stirrer bar, cinnamic acid 1 (0.5mmol, 1 equiv), KSCN 2 (1.5mmol, 3 equiv), Rose Bengal (1mol%, 0.005equiv) and Cs2CO3 (1.5mmol, 3 equiv) were added in 5mL acetonitrile. The resulting mixture was stirred under irradiation with 23W CFL at room temperature. Upon completion of the reaction (monitored by TLC) after 12h, the reaction mixture was quenched with water and extracted with EtOAc (3 × 5mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo and the crude product was purified by silica gel chromatography (EtOAc/n-hexane,1:6) to afford an analytically pure sample of (E)-vinyl thiocyanates 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.51% | With silicomolybdic heteropolyacid; 1-butyl-3-methylimidazolium Tetrafluoroborate at 30℃; for 8h; Inert atmosphere; | 1-8 Example 7: Preparation of Compound (E)-3,4-dihydroxyphenethyl 3-(4-methoxyphenyl)acrylate In a 100 mL three-necked flask, 100.1 mg (0.65 mmol) of hydroxytyrosol, 126.5 mg (0.71 mmol) of 4-methoxycinnamic acid and 12.0 mg (0.007 mmol) silicomolybdic acid were dissolved in 50 mL of 1-butyl-3-methylimidazolium tetrafluoroborate under nitrogen atmosphere. After full dissolution, the temperature was raised to 30° C. and the reaction was carried out for 8 hours. Thin layer chromatography was used to track the reaction to completion, heating was stopped, and the protective device was removed. The reaction mixture system was allowed to separate into layers to give a crude product. The crude product was recrystallized with 50 mL methanol and dried to obtain the title compound, 174.6 mg, a yield of 85.51%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0 - 20℃; for 5h; Molecular sieve; | 3.2 Preparation of compounds 3a-3l General procedure: General glycosylation procedure: A solution of the glycosyl donor 1 (0.12mmol, 1.2 equiv) and acceptor 2 (0.1mmol, 1.0 equiv) in dry CH2Cl2 (2.0mL) in the presence of 4ÅMS (100wt%) was stirred for 15min at 0°C. After addition of TMSOTf (0.01mmol, 0.1 equiv), the mixture was slowly warmed to room temperature and stirred for 5h. Molecular sieves were removed by filtration and the solution was purified by silica gel chromatography to give the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 3-(4'-methoxyphenyl)propenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.25h; Stage #2: 3β-hydroxypregna-4,16-diene-6,20-dione In dichloromethane at 20℃; | General procedure for the synthesis of 3β-cinnamoyloxypregn-4,16-diene-6,20-diones 6a-g General procedure: The corresponding cinnamic acid derivative (3 mmol) wasstirred at room temperature with N,N0-dicyclohexylcarbodiimide(DCC, 2.3 mmol), and 4-dimethylaminopyridine (DMAP,2.7 mmol) in dichloromethane (20 mL) for 15 min. Then, steroid5 (1 mmol) was added, and the reaction mixture wasstirred between 60-90 min. Upon termination of the esterification,ethyl acetate (20 mL) was added, and the precipitatedicyclohexylurea was filtered. The solvent was removed atreduced pressure, and the solid obtained was stirred with a1:1 hexane: methanol solution using ethyl acetate as cosolventfor 30 min. The crude product was recrystallizedfrom methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 24h; | 4.2.11. 3,6-Anhydro-7-C-(4′ -(carbamoyl)thiazol-2′ -yl)-2,7-dideoxy-5-O-(4′′′ -methoxycinnamoyl)-D-gluco-heptono-1,4-lactone (7) To a solution of compound 4 (0.022 g, 0.08 mmol) in anhydrousacetonitrile (6 mL) stirred vigorously at room temperature, were added4-methoxycinnamic acid (0.027 g, 0.15 mmol), DCC (0.020 g, 0.17mmol) and DMAP (0.033 g, 0.16 mmol). The mixture was stirred atroom temperature for 24 h, then filtered and evaporated. The remainingcrude compound 7 was purified by preparative thin-layer chromatography(9 plates, 30:1 EtOAc/MeOH, eluted with 6:1 CH2Cl2/MeOH),whereby pure product 7 (0.023 g, 66%) was obtained in the form ofwhite amorphous powder, [α]D = +11.0 (c 0.2, CHCl3); Rf. = 0.70 (29:1EtOAc/MeOH). IR (film): νmax 3463 and 3348 (NH, amide), 1790 (C- -O,lactone), 1718 (C- -O, ester), 1632 (C- -C, vinyl), 1602 (Ph), 1148(C-O, ester). 1H NMR (400 MHz, CDCl3): δ 2.74 (d, 1H, J2a,2b = 17.8 Hz,H-2a), 2.83 (dd, 1H, J2a,2b = 18.9, J2b,3 = 6.1 Hz, H-2b), 3.36 (dd, 1H,J6,7a = 6.9, J7a,7b = 15.1 Hz, H-7a), 3.41 (dd, 1H, J6,7b = 6.9, J7a,7b =15.1 Hz, H-7b), 3.87 (s, 3H, OMe), 4.62 (td, 1H, J6,7 = 6.8, J5,6 = 3.2 Hz,H-6), 5.01 (d, 1H, J3,4 = 4.5 Hz, H-4), 5.10 (dd, 1H, J3,4 = 4.5, J2b,3 =4.9 Hz, H-3), 5.80 (d, 2H, J5,6 = 3.0 Hz, H-5 and NH), 6.33 (d, 1H, J2′′ ,3′′= 15.9 Hz, H-2′′ ), 6.92 (d, 2H, J = 8.8 Hz, H-3′′′ and H-5′′′ ), 7.22 (br s,1H, CONH2), 7.51 (d, 2H, J = 8.8 Hz, H-2′′′ and H-6′′′ ), 7.73 (d, 1H, J2′′ ,3′′= 15.9 Hz, H-3′′ ), 8.04 (s, 1H, H-5′ ). 13C NMR (100 MHz, CDCl3): δ 32.4(C-7), 35.8 (C-2), 55.4 (OMe), 75.1 (C-5), 77.0 (C-3), 78.5 (C-6), 85.6 (C-4), 113.5 (C-2′′ ), 114.5 (C-3′′′ and C-5′′′ ), 124.4 (C-5′ ), 126.5 (C-1′′′ ),130.1 (C-2′′′ and C-6′′′ ), 146.8 (C-3′′ ), 149.5 (C-2′ ), 162.0 (C-4′′′ ), 162.8(C-4′ ), 165.1 (CONH2), 165.9 (C-1′′ ), 174.61 (C-1). HRMS (ESI): m/z467.0906 (M++Na), calcd for C21H20N2NaO7S: 467.0883. |
66% | With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 24h; | 4.2.11. 3,6-Anhydro-7-C-(4′ -(carbamoyl)thiazol-2′ -yl)-2,7-dideoxy-5-O-(4′′′ -methoxycinnamoyl)-D-gluco-heptono-1,4-lactone (7) To a solution of compound 4 (0.022 g, 0.08 mmol) in anhydrousacetonitrile (6 mL) stirred vigorously at room temperature, were added4-methoxycinnamic acid (0.027 g, 0.15 mmol), DCC (0.020 g, 0.17mmol) and DMAP (0.033 g, 0.16 mmol). The mixture was stirred atroom temperature for 24 h, then filtered and evaporated. The remainingcrude compound 7 was purified by preparative thin-layer chromatography(9 plates, 30:1 EtOAc/MeOH, eluted with 6:1 CH2Cl2/MeOH),whereby pure product 7 (0.023 g, 66%) was obtained in the form ofwhite amorphous powder, [α]D = +11.0 (c 0.2, CHCl3); Rf. = 0.70 (29:1EtOAc/MeOH). IR (film): νmax 3463 and 3348 (NH, amide), 1790 (C- -O,lactone), 1718 (C- -O, ester), 1632 (C- -C, vinyl), 1602 (Ph), 1148(C-O, ester). 1H NMR (400 MHz, CDCl3): δ 2.74 (d, 1H, J2a,2b = 17.8 Hz,H-2a), 2.83 (dd, 1H, J2a,2b = 18.9, J2b,3 = 6.1 Hz, H-2b), 3.36 (dd, 1H,J6,7a = 6.9, J7a,7b = 15.1 Hz, H-7a), 3.41 (dd, 1H, J6,7b = 6.9, J7a,7b =15.1 Hz, H-7b), 3.87 (s, 3H, OMe), 4.62 (td, 1H, J6,7 = 6.8, J5,6 = 3.2 Hz,H-6), 5.01 (d, 1H, J3,4 = 4.5 Hz, H-4), 5.10 (dd, 1H, J3,4 = 4.5, J2b,3 =4.9 Hz, H-3), 5.80 (d, 2H, J5,6 = 3.0 Hz, H-5 and NH), 6.33 (d, 1H, J2′′ ,3′′= 15.9 Hz, H-2′′ ), 6.92 (d, 2H, J = 8.8 Hz, H-3′′′ and H-5′′′ ), 7.22 (br s,1H, CONH2), 7.51 (d, 2H, J = 8.8 Hz, H-2′′′ and H-6′′′ ), 7.73 (d, 1H, J2′′ ,3′′= 15.9 Hz, H-3′′ ), 8.04 (s, 1H, H-5′ ). 13C NMR (100 MHz, CDCl3): δ 32.4(C-7), 35.8 (C-2), 55.4 (OMe), 75.1 (C-5), 77.0 (C-3), 78.5 (C-6), 85.6 (C-4), 113.5 (C-2′′ ), 114.5 (C-3′′′ and C-5′′′ ), 124.4 (C-5′ ), 126.5 (C-1′′′ ),130.1 (C-2′′′ and C-6′′′ ), 146.8 (C-3′′ ), 149.5 (C-2′ ), 162.0 (C-4′′′ ), 162.8(C-4′ ), 165.1 (CONH2), 165.9 (C-1′′ ), 174.61 (C-1). HRMS (ESI): m/z467.0906 (M++Na), calcd for C21H20N2NaO7S: 467.0883. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | 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 |
---|---|---|
89% | With 4-dimethylaminopyridine; diisopropyl-carbodiimide In dichloromethane at 0℃; for 0.5h; | 2.1.2. General procedure for the synthesis of compound XJS-1 ~ XJS-18 General procedure: Compound 10 (2.0 mmol) and the substituted cinnamic acids CA-1~ CA-18 (2.4 mmol) in anhydrous CH2Cl2 (10 mL) was added withDMAP (2.4 mmol) and DIPC (4.8 mmol) at 0 C. After stirring for 30 min,the reaction mixture was allowed to warm to room temperature. Afterthe reaction was completed, as monitored by TLC, the reaction mixturewas washed with 10% NaHCO3 (2 × 20 mL), and 1 N HCl (2 × 20 mL).The combined organic layers, dried over Na2SO4, filtered, and concentratedin vacuo. The crude residue was purified by chromatography onsilica gel with DCM/MeOH to give compounds XJS-1 ~ XJS-18.2.1.2.1. 7-ethyl-10-fiiluoro-20-O-(4-methoxyphenyl)a crylate-camptothecin(XJS-1). Yield: 89%, white solid. 1H NMR (DMSO-d6, 400 MHz) : 8.21(dd, 1H, J = 9.3, 5.6 Hz, C9-H), 8.05 (d, 1H, J = 10.4 Hz, C12-H),7.83-7.69 (m, 4H, C11-H, -COCH = CH-, Ar-H), 7.01 (d, 3H, J = 8.9Hz, C14-H, Ar-H), 6.71 (d, 1H, J = 16.0 Hz, -COCH = CH-), 5.54 (s, 2H,C17-H), 5.33 (s, 2H, C5-H), 3.81 (s, 3H, Ar-OCH3), 3.19 (d, 2H, J = 7.7Hz, C7-CH2-CH3), 2.22 (d, 2H, J = 7.7 Hz, C19-H), 1.27 (t, 3H, J = 7.5Hz, C7-CH2-CH3), 0.99 (t, 3H, J = 7.4 Hz, C18-H); 13C NMR (100 MHz,DMSO-d6) : 167.84, 165.67, 162.10, 160.08, 157.04, 151.91, 147.18,146.76, 146.08, 145.87, 145.82, 133.10 (d, J = 8.5 Hz), 131.18, 129.28,128.13 (d, J = 9.7 Hz), 126.77, 120.52 (d, J = 25.8 Hz), 119.33, 114.95,114.19, 108.38 (d, J = 23.0 Hz), 94.99, 76.06, 66.78, 55.87, 50.02,30.78, 22.70, 14.17, 8.11. MS-ESI m/z: 577.2 [M + Na]+. |
89% | With 4-dimethylaminopyridine; diisopropyl-carbodiimide In dichloromethane at 0℃; for 0.5h; | 2.1.2. General procedure for the synthesis of compound XJS-1 ~ XJS-18 General procedure: Compound 10 (2.0 mmol) and the substituted cinnamic acids CA-1~ CA-18 (2.4 mmol) in anhydrous CH2Cl2 (10 mL) was added withDMAP (2.4 mmol) and DIPC (4.8 mmol) at 0 C. After stirring for 30 min,the reaction mixture was allowed to warm to room temperature. Afterthe reaction was completed, as monitored by TLC, the reaction mixturewas washed with 10% NaHCO3 (2 × 20 mL), and 1 N HCl (2 × 20 mL).The combined organic layers, dried over Na2SO4, filtered, and concentratedin vacuo. The crude residue was purified by chromatography onsilica gel with DCM/MeOH to give compounds XJS-1 ~ XJS-18.2.1.2.1. 7-ethyl-10-fiiluoro-20-O-(4-methoxyphenyl)a crylate-camptothecin(XJS-1). Yield: 89%, white solid. 1H NMR (DMSO-d6, 400 MHz) : 8.21(dd, 1H, J = 9.3, 5.6 Hz, C9-H), 8.05 (d, 1H, J = 10.4 Hz, C12-H),7.83-7.69 (m, 4H, C11-H, -COCH = CH-, Ar-H), 7.01 (d, 3H, J = 8.9Hz, C14-H, Ar-H), 6.71 (d, 1H, J = 16.0 Hz, -COCH = CH-), 5.54 (s, 2H,C17-H), 5.33 (s, 2H, C5-H), 3.81 (s, 3H, Ar-OCH3), 3.19 (d, 2H, J = 7.7Hz, C7-CH2-CH3), 2.22 (d, 2H, J = 7.7 Hz, C19-H), 1.27 (t, 3H, J = 7.5Hz, C7-CH2-CH3), 0.99 (t, 3H, J = 7.4 Hz, C18-H); 13C NMR (100 MHz,DMSO-d6) : 167.84, 165.67, 162.10, 160.08, 157.04, 151.91, 147.18,146.76, 146.08, 145.87, 145.82, 133.10 (d, J = 8.5 Hz), 131.18, 129.28,128.13 (d, J = 9.7 Hz), 126.77, 120.52 (d, J = 25.8 Hz), 119.33, 114.95,114.19, 108.38 (d, J = 23.0 Hz), 94.99, 76.06, 66.78, 55.87, 50.02,30.78, 22.70, 14.17, 8.11. MS-ESI m/z: 577.2 [M + Na]+. |
Tags: 830-09-1 synthesis path| 830-09-1 SDS| 830-09-1 COA| 830-09-1 purity| 830-09-1 application| 830-09-1 NMR| 830-09-1 COA| 830-09-1 structure
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