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CAS No. : | 1615-02-7 | MDL No. : | MFCD00004396 |
Formula : | C9H7ClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GXLIFJYFGMHYDY-ZZXKWVIFSA-N |
M.W : | 182.60 | Pubchem ID : | 637797 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.12 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.68 cm/s |
Log Po/w (iLOGP) : | 1.81 |
Log Po/w (XLOGP3) : | 2.44 |
Log Po/w (WLOGP) : | 2.33 |
Log Po/w (MLOGP) : | 2.47 |
Log Po/w (SILICOS-IT) : | 2.34 |
Consensus Log Po/w : | 2.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.75 |
Solubility : | 0.327 mg/ml ; 0.00179 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.87 |
Solubility : | 0.248 mg/ml ; 0.00136 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.48 |
Solubility : | 0.609 mg/ml ; 0.00333 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.78 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
98% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran for 12 h; Inert atmosphere; Cooling with ice; Reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0 - 20℃; for 0.5 h; |
9.1 3-(4-Chloro-phenyl)-propan-1-olTo a suspension of lithium aluminium hydride (20.26 g, 37.95 mmol) in THF (tetrahy- drofuran) (300 mL) under nitrogen atmosphere was slowly added a solution of 3-(4- chloro-phenyl)-acrylic acid (65.00 g, 355.96 mmol) in THF (500 mL) under cooling with an ice bath. The resulting mixture was stirred until it reached room temperature and then refluxed for 12 h. After cooling to room temperature, a 10percent HCI solution was added at 0° C and the resultant solution was stirred for 0.5 h. The mixture was then extracted with MTBE (methyl tert-butyl ether) and the organic layers were washed with water, dried and evaporated. The title compound was obtained as a brown oil (70.0 g, 98percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.7% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice Stage #2: for 4 h; Reflux; Inert atmosphere |
Yield: 23.3-88.0percent .Take 3-(4-chlorophenyl)propan-1-ol (3c) for example. To a suspension of lithium aluminum hydride (1.71 g, 45 mmol) in THF (30 mL), under nitrogen atmosphere and ice bath, the solution of 2.74 g (15 mmol) 3-(4-chlorophenyl)acrylic acid (2c) in THF was gently added in 30 min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15 ml methanol and 15 ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10percent hydrochloric acid, The crude mixture was extracted with ethyl acetate (3 × 30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product, yellow oil, yield 54.7percent. 1H NMR (300 MHz, CDCl3) δ: 7.27-7.22(m, 2H), 7.15-7.10 (m, 2H), 3.66(t, J=6.4Hz, 2H), 2.68(t, J=7.44Hz, 2H), 1.91-1.81(m, 2H). |
54.7% | With lithium aluminium tetrahydride In tetrahydrofuran for 4.5 h; Inert atmosphere; Reflux; Cooling with ice | General procedure: To a suspension of lithium aluminum hydride (1.71g, 45mmol) in THF (30mL), under nitrogen atmosphere and ice bath, the solution of 15mmol 3-(4-substituted phenyl)acrylic acid (2a-h) in THF was gently added in 30min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15ml methanol and 15ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10percent hydrochloric acid, The crude mixture was extracted with ethyl acetate (3×30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: With triethylamine In benzene for 2 h; Stage #2: at 90℃; for 3.5 h; Reflux |
Step 1To a solution of (is)-3-(4-chlorophenyl)acrylic acid (18.3 g, 0.1 mol) and Et3 (20.2 g, 0.2 mol) in benzene (100 mL) was added dropwise DPPA (27.5 g, 0.1 mol). After stirring for 2 h, the solution was concentrated and purified by chromatography (Biotage, mobile phase 20/80 EtOAc/hexanes) to give 16 g of an intermediate azide as a solid. This intermediate was dissolved in 100 mL of PI12CH2 and the resulting mixture was slowly heated to 90 °C over a 30 min time period. The reaction mixture was heated to reflux and maintained at this temperature for 3h. After cooling to RT, a solid precipitated which was collected by filtration and washed with toluene to provide 9.5 g of 7-chloroisoquinolin-l(2H)-one (53percent). XH NMR (400 MHz, CD3OD) δ ppm 6.66 (d, J=7.05 Hz, 1 H), 7.18 (d, J=7.05 Hz, 1 H), 7.66 (s, 1 H) 7.67 (d, J=2.01 Hz, 1 H), 8.24 (d, J=2.27 Hz, 1 H); 13C NMR (101 MHz, DMSO-D6) δ ppm 104.05, 125.62, 127.21, 128.54, 129.52, 130.77, 132.43, 136.55, 160.72; LC/MS, MS m/z (M+H)+ 180. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrazine hydrate In ethanol for 5.5h; Reflux; | |
92% | With sodium tetrahydroborate; sodium hydroxide In water at 20 - 60℃; | |
90% | With sodium hypophosphite In sodium hydroxide; ethanol; water at 50℃; for 1.5h; |
86% | With palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In ethyl acetate at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction; | |
With sodium hypophosphite different conditions; | ||
With phosphorus; hydrogen iodide | ||
With sodium amalgam | ||
With hydrogen | ||
With sodium amalgam Yield given; | ||
With samarium diiodide; <i>tert</i>-butyl alcohol In tetrahydrofuran at 30℃; | ||
With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; for 12h; | ||
With hydrogen In tetrahydrofuran for 14h; | 3-(4-Chloro-phenyl)-acrylic acid (25.00 g, 0.14 mol) in THF was mixed with Rh/Al2O3 (1.00 g) and hydrogenated for 14 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(4-chloro-phenyl)-propionic acid. | |
With palladium on activated charcoal; hydrogen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Austausch von NH2 gegen Cl; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrogen In tetrahydrofuran for 4h; Ambient temperature; | |
78% | With 10% Pd/C; cyclohexa-1,4-diene In ethyl acetate at 100℃; for 0.5h; Microwave irradiation; | |
With hydrogenchloride; ethanol; platinum Hydrogenation.anschliessend Hydrolyse; |
With hydrogen In methanol | ||
Multi-step reaction with 2 steps 1: H2 / PtO2 / ethyl acetate 2: 3.3 g / aq. NaOH / methanol / 4 h / Heating | ||
1.82 g (9.8 mmol, 98%) | In tetrahydrofuran | 25 3-(4-Chlorophenyl)propanoic Acid (4-Chlorohydrocinnamic Acid) EXAMPLE 25 3-(4-Chlorophenyl)propanoic Acid (4-Chlorohydrocinnamic Acid) To a solution of 1.80 g (10 mmol) of 4-chlorocinnamic acid in 50 mL of THF was added Pd/C (1.04 g, 5% w/w) and the solution was stirred under a hydrogen atmosphere until no further H2 take-up was observed (~1 h). The solution was filtered through Celite and the solvent removed under reduced pressure to yield 1.82 g (9.8 mmol, 98%) of a white solid: mp. 103°-105° C.; 1 H NMR (DMSO-d6) δ2.51 (t, 2H, β--CH2), 2.79 (t, 2H, (α--CH2), 7.28 (dd, 4H, aromatic CH's), 12.12 (s, 1H, COOH); MS (EI, calculated for C9 H9 ClO2, 184.0291) m/e 184.0288 (M+). |
In tetrahydrofuran | 9 4-[Bis[3-(p-chlorophenyl)propyl]amino]benzoic acid EXAMPLE 9 4-[Bis[3-(p-chlorophenyl)propyl]amino]benzoic acid A suspension of 50 g. of p-chlorocinnamic acid and 1 g. of 10% palladium on carbon in 200 ml. of tetrahydrofuran is hydrogenated in a Parr apparatus until the uptake of hydrogen is complete. The mixture is then filtered and evaporated, giving 50.42 g. of 3-(p-chlorophenyl)propionic acid. | |
1.82 g (9.8 mmol, 98%) | In tetrahydrofuran | 25 3-(4-Chlorophenyl)propanoic Acid (4-Chlorohydrocinnamic Acid) EXAMPLE 25 3-(4-Chlorophenyl)propanoic Acid (4-Chlorohydrocinnamic Acid) To a solution of 1.80 g (10 mmol) of 4-chlorocinnamic acid in 50 mL of THF was added Pd/C (1.04 g, 5% w/w) and the solution was stirred under a hydrogen atmosphere until no further H2 take-up was observed (~1 h). The solution was filtered through Celite and the solvent removed under reduced pressure to yield 1.82 g (9.8 mmol, 98%) of a white solid: mp. 103-105° C.; 1H NMR (DMSO-d6) δ2.51 (t, 2H, β-CH2), 2.79 (t, 2H, α-CH2), 7.28 (dd, 4H, aromatic CH's), 12.12 (s, 1H, COOH); MS (EI, calculated for C9H9ClO2, 184.0291) m/e 184.0288 (M+). |
With palladium on activated charcoal; hydrogen In ethyl acetate at 20℃; for 10h; | 62 Preparation example 62 : 6-chloro-2,3-dihydro-1H-inden-1-one To a stirred solution of 4-chlorocinnamic acid (1.0g, 5.46mmol) in EtOAc (20mL) was added Pd on carbon (0.12g, 0.11mmol) at room temperature under H2atmosphere. The mixture was stirred for 10h. The resulting mixture was filtered through celite and the solvent of the filtrate was removed in vacuo. The concentrated product was employed without further purification in the next reaction. Oxalyl chloride (0.96mL, 10.92mmol) was cautiously added to a solution of the 3-(4-chlorophenyl)propanoic acid in CH2Cl2(20mL). The mixture was stirred for 8h and then the solvent was removed vacuo. The appropriate acid chloride was employed without further workup in the next reaction step. To a stirred solution of acid chloride in CH2Cl2(20mL) was added portionwise AlCl3(0.82g, 6.22mmol) at room temperature and heated under reflux for 6h. The resulting mixture was poured into ice-water and the aq. phase was extracted with CH2Cl2,washed with 1N aq. NaOH and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to produce the title compound (0.59 g, 66 %).1H NMR (400 MHz, CDCl3) δ 2.64-2.78 (m, 2H), 3.04-3.17 (m, 2H), 7.41 (d,J=7.9, 1H), 7.55 (dd,J=8.2, 1H), 7.65-7.75 (m, 1H). | |
With tetralin; palladium(0) for 1.5h; Heating; | To synthesize the compound, in a flask, 5 g solution of 4-chlorocinnamic acid was mixed with 180 ml tetraline comprising 1 g of palladium black was heated at high temperature for 1.5 hours. The catalyst was drained out upon completion of the reaction, the 3-(4-chlorophenyl)propanoicacid and unreacted 4-chlorocinnamic acid were separated from the sodium carbonate filtrate solution, the adhesive tetraline was extracted from ether using the alkaline solution, hydrochloric acid was used to acidify alkaline solution and 3-(4-chlorophenyl)propanoic acid was taken up in ether. The complete 3-(4-chlorophenyl)propanoic acid having a melting point of 123 °C was collected on evaporation. The tetraline was treated with dilute hydrochloric acid, cleaned and dried with calcium chloride, and then diluted at boiling point temperature 207 °C. | |
With tetralin; palladium(0) for 1.5h; Heating; | To synthesize the compound, in a flask, 5 g solution of 4-chlorocinnamic acid was mixed with 180 ml tetraline comprising 1 g of palladium black was heated at high temperature for 1.5 hours. The catalyst was drained out upon completion of the reaction, the 3-(4-chlorophenyl)propanoicacid and unreacted 4-chlorocinnamic acid were separated from the sodium carbonate filtrate solution, the adhesive tetraline was extracted from ether using the alkaline solution, hydrochloric acid was used to acidify alkaline solution and 3-(4-chlorophenyl)propanoic acid was taken up in ether. The complete 3-(4-chlorophenyl)propanoic acid having a melting point of 123 °C was collected on evaporation. The tetraline was treated with dilute hydrochloric acid, cleaned and dried with calcium chloride, and then diluted at boiling point temperature 207 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With copper(II) nitrate trihydrate; trimethylsilyl bromide; In acetonitrile; at 50℃; for 2h; | General procedure: In a pressure tube, to a solution of alpha,beta-unsaturated carboxylic acid (0.5 mmol, 1 equiv) and copper(II) nitrate trihydrate (60.4 mg, 0.25 mmol, 0.5 equiv) in 3 mL dry acetonitrile, bromotrimethylsilane (306.18 mg, 2 mmol, 4 equiv) was added. The reaction mixture was stirred vigorously at 50C for 2 h (in case of ortho substituted compounds, the reaction mixture was stirred for 3 h). After neutral aqueous work-up, organics were extracted by dichloromethane. Organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. Upon recrystallization from hexane, the corresponding products were obtained in pure form in good yields. |
With bromine; In chloroform; at 0℃; for 0.333333h; | General procedure: Aldehyde (1 equiv), malonic acid (1 equiv), pyridine (3 equiv) and afew drops of piperidine were taken into a 50-mL three-neck flaskequipped with a reflux condenser, and the reaction mixture wasstirred at 100 C for 8 h and 120 C for 2 h. It was then transferred to abeaker containing concentrated hydrochloric acid (10 mL) and ice-water (30 mL). The resultant precipitate was filtered, washed withice-water (3 ×) and recrystallized (EtOH) to give the pure trans-cinnamicacid.The trans-cinnamic acid (1 equiv) was dissolved in CHCl3 and thesolution was cooled to 0 C. Bromine (3 equiv) was added dropwiseand the resulting solution was stirred at this temperature for 20 min.The solution was stored in a refrigerator overnight, then filtered andwashed with cold CHCl3 (2 ×) to give the crude 2,3-dibromohydrocinnamicacid 4 which was used in the next step without further purification.To a mixture of 2,3-dibromohydrocinnamic acid 4 (1 equiv) and anhydDMF at 0 C, triethylamine (2 equiv) was added dropwise. Thesolution was stirred at 0 C for 30 min and then at room temperaturefor 6 h. Water (20 mL) was added and the mixture was extracted withEt2O. The organic layers were combined, washed with saturated potassiumcarbonate and brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude reaction mixture was purifiedby silica gel column chromatography (EtOAc/hexane) to afford respective(Z)-beta-bromostyrene 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With piperidine; pyridine;Reflux; | General procedure: A solution of suitably substituted carbaldehyde (200mmol), propenedioic acid (20.8g, 200mmol) in pyridine (10mL, 120mmol) and piperidine (1mL) was warmed at reflux for 2h. The resultant solution was poured into 2M HCl aq. and cooled to room temperature. The solid was filtered, washed with water and recrystallized in ethanol/water |
90% | With piperidine; In pyridine; at 85℃; for 6h; | Yield: 86.5-97.5%. Take (E)-3-(4-chlorophenyl)acrylic acid (2c) for example. To a stirred solution of 6.76 g (65 mmol) malonic acid in pyridine (5 mL) and piperidine (0.5 mL), the corresponding aldehyde (50 mmol) was added slowly under 85 C. The resulting mixture was stirred for 6 h, when TLC analyses indicated the disappearance of the starting material. After cooling to ambient temperature, the reaction mixture was neutralized with 10% hydrochloric acid under ice bath, observing crystallization of a white solid, which was filtered and washed three times with cooled waster. Recrystallization from aqueous ethanol (1:1) afforded 2c in 90.0% yield, m.p.= 244-246 C: 1H NMR (300 MHz, DMSO) delta: 12.45 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 16.1 Hz, 1H), 7.46(d, J = 8.5 Hz, 2H), 6.54 (d, J = 16.0 Hz, 1H). |
90% | With piperidine; pyridine; at 85℃; for 6h; | General procedure: To a stirred solution of 6.76 g (65 mmol) malonic acid in pyridine (5 mL) and piperidine (0.5 mL), the corresponding aldehyde (50 mmol) was added slowly under 85 oC. The resulting mixture was stirred for 6 h, when TLC analyses indicated the disappearance of the starting material. After cooling to ambient temperature, the reaction mixture was neutralized with 10% hydrochloric acid under ice bath, observing crystallization of a white solid, which was filtered and washed three times with cooled waster. Recrystallization from aqueous ethanol (1:1) afforded 2a-h. |
88% | With piperidine; pyridine; at 110℃; | General procedure: To a solution of pyridine (3 vol), was added aldehyde (1 mmol) malonic acid (2 mmol)followed by catalytic amount of piperidine (0.1 mmol). The reaction mass was slowly heatedto 110 0C and maintained for 10 - 12 hr at 110 0C. Reaction was monitored by TLC. Reactionmass was cooled to room temperature and quenched into 10 vol of water of pyridine. To thequenched mass was added, NaOH (2 mmol). Reaction mixture was stirred to obtain clearsolution. Then reaction mixture was washed with ethyl acetate (20 vol X 2). Aqueous layerwas then acidified with 50 % sulfuric acid till pH 2.The precipitated solid was filtered andwashed with water (5 vol X 2) followed by pet ether wash 2 vol. The product was suck driedon buchner funnel for 15 min to 60 min. The solid product was dried in oven at 50 to 60 Covernight. Cinnamic acids were obtained in 80 - 90 % yield. |
82% | With lithium perchlorate; In pyridine; for 5h;Reflux; | General procedure: To a stirred solution of benzaldehyde (1a, 1.7 ml, 16.04mmol, 1 equiv) and malonic acid (2, 2 g, 24.06 mmol, 1.5equiv) in pyridine (5 mL) was added LiClO4 (0.34 g, 3.2mmol, 0.2 equiv) and refluxed for 5 hrs. The progress ofreaction was monitored by TLC using eluent EtOAc: nhexane(4:6). After completion of reaction, the solution wasacidified with concentrated HCl to afford a white precipitate.The precipitate was filtered and washed with water (10 ml)twice, further dried to afford 2.2 g (93%) of 3a as the finalproduct. All synthesized compounds were characterized byIR, NMR and mass with satisfactory spectral data. |
77% | With piperidine; pyridine; for 0.333333h;Microwave irradiation; | General procedure: A 25mL round-bottom flask was charged with 1.37 g (13.2 mmol) of malonic acid, an aldehyde (6.60 mmol, compounds 3a-3f, Scheme 1), pyridine (5.00 mL), and piperidine (1.00 mL, 13.0 mmol). The resulting mixture was submitted to microwave irradiation (20 min at 150 W), similar to compounds 1 and 2. Then, the mixture was poured into an ice bath and 10.0 mL of HCl 16 M. The resulting mixture was vacuum filtered on sintered funnel. The residue was washed with portions of cold water (4 x 5.00 mL). All the cinnamic acid derivatives 4ae4f were purified by silica gel column chromatography. The structures of the compounds are supported by the following data. |
70.2% | With 1,4-diaza-bicyclo[2.2.2]octane; In N,N-dimethyl-formamide; at 110℃; for 2h; | General procedure: The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted benzaldehydes (1.0g, 1.0eq) in 100.0ml round bottom flask containing 15.0ml dimethylformide and malanoic acid (1.1eq). Diaza bicyclooctane (DABCO 1.0eq) was added as a catalyst and the temperature was raised to 110.0C and maintained for 2.0h. The reaction was monitored by thin layer chromatography. After the completion of the reaction the reaction mass was quenched into cold water 40.0ml and extracted with ethyl acetate 2×25ml. The organic layer was dried with anhydrous sodium sulfate and concentrated under high vacuum, the resulted solid was washed with hexane (5.0ml), suck dry for 15.0min and then dried under vacuum at 45C for 5.0h to yield the solid compound. |
With piperidine; pyridine; at 80 - 90℃; for 24h; | General procedure: A mixture of aromatic aldehydes (3.2 mmol), malonic acid (3.87 mmol), piperidine (0.387 mmol) was dissolved in pyridine and stirred on 80-90 C for 24 h. The pyridine was removed at the vacuum. The reaction mixture was poured into water and washed with HCl. And the precipitate was filtered and washed with hexane for three times, and dried under vacuum to afford the cinnamic acids (Scheme 1). | |
With piperidine; pyridine; at 80℃; for 24h; | General procedure: The starting materials (acids 7-19) for the synthesis of amides should be activated in the first procedure: the compounds 7-19 (1.0 mM) and SOCl2 (6-10 mL) were mixed and stirred at reflux 80Cfor 4 h. The reaction mixture was cooled and evaporated to give reactive acyl chloride obtained as an oil, which would be dissolved in ethyl acetate (5-6 mL) in the next step.A solution of acyl chloride (1.0 mM) in ethyl acetate was added dropwise to compounds 5 or 6 (0.5 mM) in ethyl acetate containing potassium carbonate (600 mg) at 0 C with constant stirring overnight. The reaction mixture was then poured in excess of diluted NaOH and extracted with EtOAc .The extraction liquid was purified by a flash chromatography with EtOAc/petroleum ether (3:1, v/v) to give these cinnamamides as follows: the yields were between 40% and 60%. | |
General procedure: To a solution of malonic acid (200 mmol) in pyridine (60 mL) was added aldehyde (150 mmol), the heterogeneous mixture was stirred at room temperature for several minutes. Piperidine (2.0 mL) was then added, and the mixture was heated to 80 C slowly (about 30 min should be allowed for this period). After the reaction mixture was refluxed at 80 deg;C for 4-5 h, it was finally heated under reflux (110-115 C) for additional 8 h. The reaction mixture was allowed to cool to room temperature, and then it was acidified by slowly pouring into hydrochloric acid (1.5 N, 90 mL) with stirring. The solid was separated by suction filtration and washed with cold water (3 times). The solid was then dried at 60 C. It could be purified by recrystallization from methyl ethyl ketone (12 mL/1 g). The hot solution was then filtered rapidly through a steam-heated Buechner funnel and chilled for several hours. The pure product could be obtained after filtration and drying. | ||
With piperidine; pyridine; at 85℃; for 24h; | General procedure: A mixture of aromatic aldehydes (3.2 mmol), malonic acid (3.87 mmol), piperidine (0.387 mmol) was dissolved in pyridine and stirred on 85 for 24 h. The pyridine was removed at the vacuum. The reaction mixture was poured into water and washed with HCl. And the precipitate was filtered and washed with hexane for three times, and dried under vacuum to afford the cinnamic acids. | |
With piperidine; pyridine; at 85℃; for 24h; | General procedure: A mixture of aromatic aldehydes (3.2 mmol), malonic acid (3.87 mmol), piperidine (0.387 mmol) was dissolved in pyridine and stirred on 85 C for 24 h. The pyridine was removed at the vacuum. The reaction mixture was poured into water and washed with HCl. And the precipitate was filtered and washed with hexane for three times, and dried under vacuum to afford the cinnamic acids. | |
With pyridine; In N,N-dimethyl-formamide; at 90℃; | General procedure: To a solution of the substituted benzaldehyde (50 mmol) and malonic acid (150 mmol) in DMF (30 mL) was added pyridine (50 mmol) and stirred for 3-5 h at 90 C. After adding water (60 mL), the reaction solution was acidified (pH 1) with concentrated hydrochloric acid and then was cooled to 0 C. Then the residue was filtered, washed with cold water (2×10mL) and dried in vacuum for 12 h to afford corresponding crude product 2 in yields ranging from 30.2 to 100.0%, which was used directly without further purification. | |
With piperidine; pyridine; at 90℃;Inert atmosphere; | General procedure: To a stirred solution of malonic acid (10 mmol) in pyridine(5 mL) and piperidine (3-5 drops) the corresponding aldehydes1a-p (8 mmol) were added. The resulting mixture was stirred at 90C for 8-12 h. The progress of the reaction was monitored byTLC analyses which indicated the disappearance of the starting material. After the completion of the reactions the reaction mixture were cooled to ambient temperature and the reaction mixture was neutralized with 1N HCl in ice bath resulting a white solid.This soled was filtered and washed three times with cold water.The recrystallization were done from aqueous ethanol (1:1)afforded the product 2a-p. | |
With piperidine; pyridine; at 100 - 120℃; for 10h; | General procedure: Aldehyde (1 equiv), malonic acid (1 equiv), pyridine (3 equiv) and afew drops of piperidine were taken into a 50-mL three-neck flaskequipped with a reflux condenser, and the reaction mixture wasstirred at 100 C for 8 h and 120 C for 2 h. It was then transferred to abeaker containing concentrated hydrochloric acid (10 mL) and ice-water (30 mL). The resultant precipitate was filtered, washed withice-water (3 ×) and recrystallized (EtOH) to give the pure trans-cinnamicacid.The trans-cinnamic acid (1 equiv) was dissolved in CHCl3 and thesolution was cooled to 0 C. Bromine (3 equiv) was added dropwiseand the resulting solution was stirred at this temperature for 20 min.The solution was stored in a refrigerator overnight, then filtered andwashed with cold CHCl3 (2 ×) to give the crude 2,3-dibromohydrocinnamicacid 4 which was used in the next step without further purification.To a mixture of 2,3-dibromohydrocinnamic acid 4 (1 equiv) and anhydDMF at 0 C, triethylamine (2 equiv) was added dropwise. Thesolution was stirred at 0 C for 30 min and then at room temperaturefor 6 h. Water (20 mL) was added and the mixture was extracted withEt2O. The organic layers were combined, washed with saturated potassiumcarbonate and brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude reaction mixture was purifiedby silica gel column chromatography (EtOAc/hexane) to afford respective(Z)-beta-bromostyrene 2. | |
With piperidine; pyridine; for 2h;Reflux; | General procedure: A mixture of corresponding substituted benzaldehydes 1(50 mmol), malonic acid (75 mmol), and piperidine (1 mL)in 35 mL pyridine was refluxed for 2 h. The solvent wasevaporated under reduced pressure. The residue was addedto a mixture of 35 mL HCl and 70 g ice. The solid productwas filtered and recrystallized in ethanol to obtain corresponding(E)-substitutedacrylic acids 2. | |
With pyridine; In N,N-dimethyl-formamide; at 150℃; | In a 100 mL single-necked round bottom flask, 10 mmol of para-substituted benzaldehyde, 20 mmol of malonic acid, 10 mmol of pyridine, and 20 mL of N, N-dimethylformamide were sequentially added. Heat at 150 C for 6-7h under reflux; add 20mL of water to the reaction system, and then adjust to pH = 1 with 5% dilute HCl. During the adjustment, a large amount of solids are precipitated and filtered to obtain compound c2. |
Yield | Reaction Conditions | Operation in experiment |
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28% | at 180℃; for 6h;Molecular sieve; Inert atmosphere; | General procedure: A mixture of 3-substituted-acrylic acid (106 mmol), 2-aminobenzenetiol (13.3 g, 106 mmol) and 4 ? molecular sieve was heated at 180 C under nitrogen atmosphere for 6 h, then acetonitrile (80 ml) was added and the solution was cooled to room temperature. The resultant solid was collected by filtration and washed with acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
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93% | General procedure: Under a N2 atmosphere, LiOtBu or KOtBu (3.0 mmol), H2O (2.0 mL) and acrylic acid (1.2 mmol) were added into a Schlenk reaction tube and the mixture was stirred at room temperature for 10 minutes. Then an aryl halide 2 (1.0 mmol) and Pd(II)-Im complex 1 (1.0 mol%) were added. The mixture was stirred at 100 C for 12 h. After cooling to room temperature, the reaction mixture was acidified by HCl (4 M) to pH 1 and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to afford the pure product 5. | |
92% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h; | General procedure: In a typical experiment, a mixture of aryl halide (1.0 mmol), acrylic acid (1.5 mmol), K2CO3 (3.0 mmol), DMF (5.0 mL), and Fe3O4/SiO2/HPG-OPPh2-PNP catalyst (0.025 g, 0.95 mol % Pd) was charged in a 25 mL round-bottom flask and stirred at 100 C. The end of reaction was monitored by TLC. After completion of the reaction, the mixture was cooled down to room temperature and the catalyst was separated with a magnet and washed with diethyl ether (2×10 mL), deionized water (2×10 mL), and dried under vacuum for the next run. The resultant residual mixture diluted with H2O (20 mL) and aqueous layer was acidified using diluted aqueous HCl. The organic material was then extracted twice (2×15 mL) with diethyl ether. The organic fraction was dried over MgSO4, and removing the solvent leaving the crude product. The pure product was obtained by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With ammonium bromide; In water; acetonitrile; at 75℃; for 1h;Electrochemical reaction; | General procedure: Substrate 1 (0.5mmol), NH4Br (3mmol) were added to an undivided cell which equipped with platinum anode and cathode. Followed by addition of MeCN (7mL) and H2O (3mL). The mixture was electrolyzed under continuous stirring at 75C under a constant current of 40mA for 1h. The solution was cooled to r.t., condensed under vacuum, extracted with DCM (3×10mL), washed with saturated sodium chloride solution. And the organic layers were dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=50:1-30:1) to afford the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
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71% | With tetrabutyl ammonium fluoride; In neat (no solvent); at 80℃; for 24h;Green chemistry; | General procedure: a mixture of 2-aminothiophenol 7 (4 mmol), unsaturated acid 8 (2 mmol), and TBAF (0.2 mmol, 10 mol %) was heated to 80 C under stirring for 24 h. After cooling, 30 mL of dichloromethane was added. The mixture was washed with aq HCl (2 N), aq Na2CO3 (saturated), and brine. Then, the organic layer was dried over MgSO4 and concentrated. The crude product residue was purified by chromatography on silica to give pure product 9. |
71% | With tetrabutyl ammonium fluoride; at 80℃; for 24h; | General procedure: A mixture of 2-aminothiophenol (4mmol), unsaturated acid 2 (2mmol), and TBAF (0.2mmol, 10mol %) was heated to 80C under stirring for 24h. After cooling, 30mL of dichloromethane (DCM) was added. The mixture was washed with aq HCl (2N), aq Na2CO3 (saturated), and brine. Then, the organic layer was dried over MgSO4 and then concentrated. The crude product residue was purified by chromatography on silica to give pure product |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogen In ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
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97% | With chloro-trimethyl-silane; copper(II) nitrate trihydrate; In acetonitrile; at 100℃; for 2h; | General procedure: In a pressure tube, to a solution of alpha,beta-unsaturated carboxylic acid (0.5 mmol, 1 equiv) and copper(II) nitrate trihydrate (423 mg, 1.75 mmol, 3.5 equiv) in dry acetonitrile (3 mL), chlorotrimethylsilane (65 mg, 0.6 mmol, 1.2 equiv) was added. The reaction mixture was stirred vigorously at 100 C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution and organics were extracted using dichloromethane. Organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, giving the corresponding products in pure form in excellent yields. |
86% | With ferric nitrate; for 1h;Milling; | General procedure: Known amounts of unsaturated acid (0.1 mol), PEG (0.02 mol) and Fe(III) or Mn(II) nitrate (0.12 mol) were taken in a mortar and ground with a pestle till the reaction mixture became homogeneous. After completion of the reaction, as confirmed by TLC, about 2 % Na2CO3 solution was added to the reaction mixture till it is neutralized. Reaction product was extracted by dichloromethane (DCM) or dichloroethane (DCE), dried with sodium sulfate and purified by column chromatography. Binary solvent mixture of ethyl acetate and hexane (3:7) was used as eluent to obtain pure product. |
65% | With copper(II) nitrate; In acetonitrile; at 110℃; for 8h;Sealed tube; Green chemistry; | General procedure: A 25-mL Schlenk tube was charged with alpha,beta-unsaturated acid (0.4 mmol), Cu(NO3)2 (0.48 mmol), and CH3CN (2 mL). The tube was sealed, then the mixture was stirred under air at 110 C for 8 h. After completion of the reaction as monitored by thin-layer chromatography (TLC), H2O (5 mL) was added. The mixture was extracted with dichloromethane (3 X 4 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (10 mL) and water (10 mL), dried over anhydrous Na2SO4, then concentrated by rotary evaporator. Finally, the residue was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 6:1) to provide the desired products (3). (E)-(2-Nitrovinyl)benzene (3a) [18, 19, 21] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4,5-Diamino-1,3-dimethyluracil; 3-(4-chlorophenyl)prop-2-enoic acid With hydrogenchloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane; water for 2h; Stage #2: With sodium hydroxide In 1,4-dioxane; water for 0.75h; Heating; | ||
With hydrogenchloride; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In 1,4-dioxane; water at 20℃; for 2h; | 4.2. General procedure for the synthesis of xanthine analogues (4-9) General procedure: Synthesis of intermediary 1,3-dialkyl-7H-xanthine analogues (14):1,3-Dimethyl- (10a) or 1,3-diethyl-5,6-diaminouracil (10b)(10 mmol) was dissolved in a minimum amount of dioxane/H2O(1:1). EDAC (13.4 mmol) and the appropriate carboxylic acid(10 mmol) was added and the pH was adjusted to 5 with 4 NHCl. The reaction was stirred for 2 h at room temperature. Exceptfor the synthesis of compounds 8c, 8d and 9b-d, the reactionwas subsequently neutralized (pH 7) with the addition of 1 NNaOH. The precipitate was collected via filtration and suspendedin 100 mL of dioxane/H2O (1:1). The reaction was then heated atreflux for 2 h at room temperature. After cooling to 0 C, the precipitatethat formed was collected by filtration and washed with50 mL H2O. In the case of compounds 8c and 8d, H2O (30 mL)was added to the reaction and the reaction was subsequently extractedto CHCl3 (9 25 mL). The combined organic phases werewashed with H2O (4 80 mL) followed with brine (4 80 mL),dried over anhydrous MgSO4 and finally concentrated under reducedpressure. The crude residue was dissolved in a mixture of30 mL aqueous NaOH (1 M)/dioxane (1:1) and heated under refluxfor 45 min. After cooling to 0 C, the reaction was acidified with 4 N HCl and the resulting precipitate was collected by filtration andwashed with 50 mL water. For the synthesis of 9b-d, 1 g of sodiumhydroxide was dissolved in H2O (1 mL) and added to the reaction.The reaction was heated under reflux for 2 h, cooled to 0 C andacidified with 4 N HCl. The resulting precipitate, the 7H-xanthineanalogues (yields 29-75%), were collected via filtration andwashed with 50 mL H2O. |
Yield | Reaction Conditions | Operation in experiment |
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81%Chromat. | With 1-butyl-3-methylimidazolium hydroxide; CuCr2O4; In tetrahydrofuran; at 20 - 50℃; for 4h; | General procedure: A mixture of trans-cinnamic acid (0.3 g, 2 mmol) and 1.18 g iodoform (3 mmol) in dried THF (5 mL) was stirred at room temperature. The ionic liquid prepared in the previous step (1 mL), was added to the stirring mixture and the resultant liquid-liquid biphasic system was vigorously stirred at 50 C for 4 h. Then, the reaction mixture was poured into an aqueous hydrochloric acid (1 M, 10 mL) and stirred for 60 min at room temperature. The mixture was extracted with dried THF (3 9 10 mL). The aqueous phase was stored in order to recycle the IL catalyst for subsequent reactions. The combined organic phases were then evaporated under reduced pressures. The residue was added to sodium hydroxide (33 %, 5 mL) and then acidified with concentrated hydrochloric acid to pH = 2. The precipitate was filtered, recrystallizedin boiling water and dried to yield 0.3 g (93 %) (±)-trans-2-phenylcyclopropanecarboxylic acid A. 1H NMR, 13C NMR and IR spectra of A as a key intermediate in the tranylcypromine synthesis are indicated in the supplementary material. |
Yield | Reaction Conditions | Operation in experiment |
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54.7% | Yield: 23.3-88.0% .Take 3-(4-chlorophenyl)propan-1-ol (3c) for example. To a suspension of lithium aluminum hydride (1.71 g, 45 mmol) in THF (30 mL), under nitrogen atmosphere and ice bath, the solution of 2.74 g (15 mmol) 3-(4-chlorophenyl)acrylic acid (2c) in THF was gently added in 30 min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15 ml methanol and 15 ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10% hydrochloric acid, The crude mixture was extracted with ethyl acetate (3 × 30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product, yellow oil, yield 54.7%. 1H NMR (300 MHz, CDCl3) delta: 7.27-7.22(m, 2H), 7.15-7.10 (m, 2H), 3.66(t, J=6.4Hz, 2H), 2.68(t, J=7.44Hz, 2H), 1.91-1.81(m, 2H). | |
54.7% | With lithium aluminium tetrahydride; In tetrahydrofuran; for 4.5h;Inert atmosphere; Reflux; Cooling with ice; | General procedure: To a suspension of lithium aluminum hydride (1.71g, 45mmol) in THF (30mL), under nitrogen atmosphere and ice bath, the solution of 15mmol 3-(4-substituted phenyl)acrylic acid (2a-h) in THF was gently added in 30min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15ml methanol and 15ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10% hydrochloric acid, The crude mixture was extracted with ethyl acetate (3×30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H+ / Heating 2: H2 / Pd/C |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1: HCl / diethyl ether / Heating 2: H2 / PtO2 / ethanol |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; LiAlH4; hydrazine; In tetrahydrofuran; thionyl chloride; diethyl ether; ethanol; dichloromethane; water; | PREPARATION EXAMPLE 6 Synthesis of 3-(4-chlorophenyl)propylamine A mixture of 6.75 g of 4-chlorocinnamic acid and 0.3 g of CuSO4.5H2 O dispersed in 50 ml of ethyl alcohol was stirred at room temperature for 10 minutes; and 23 ml of 95% hydrazine was added thereto. This reactant was stirred for 18 hours with air bubbling at the speed of 1 L/min. The reaction mixture was filtered through a Celite layer and 30 ml of 1N NaOH was added thereto. The solution was washed twice with 30 ml of dichloromethane, acidified with concentrated hydrochloric acid, extracted with 100 ml of ethyl acetate four times and dried over magnesium sulfate. The solvent was evaporated to give 6.05 g(yield 89%) of 3-(4-chlorophenyl)propanoic acid as a yellow solid. 5.90 g of 3-(4-chlorophenyl) propanoic acid obtained above was dissolved in 6 ml of thionyl chloride, heated to reflux for 2 hours and concentrated under reduced pressure. The residues thus obtained were dissolved in 100 ml of dry ethyl ether and the solution was added dropwise to 150 ml of NH4 OH in an ice bath. The resultant solution was stirred at room temperature for 1 hour and extracted twice with 200 ml of dichloromethane. The organic phase was washed with 100 ml of a saturated sodium hydrogen carbonate aqueous solution and dried over magnesium sulfate. The solvent was evaporated to provide 4.62 g(yield 78%) of 3-(4-chlorophenyl)propanamide. 4.62 g of amide obtained above was dissolved in 50 ml of dry tetrahydrofuran; and the solution was slowly added to a dispersion of 2.4 f of LiAlH4 in 150 ml of dry tetrahydrofuran with reflux for 2 hours. The reaction mixture was cooled to room temperature, treated with 10 ml of 1N NaOH and filtered through a Celite layer to give solids, which were dissolved in 150 ml of distilled water and then filtered through a Celite layer. The filtrate so obtained was extracted with ethyl ether(100 ml*3). The combined organic layer was dried over magnesium sulfate, concentrated and distilled under reduced pressure to provide 3.12 g(yield 73%) of the title compound as a colorless liquid: b.p. 140 C./3.4 mmHg. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; bromine; acetic acid In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate | S.2 Preparation of base precursor (4) SYNTHESIS EXAMPLE 2 Preparation of base precursor (4) After a mixture of p-chlorocinnamic acid (36.5 g) and acetic acid (100 ml) was heated at 50° C., bromine (35 g) was added dropwise. After stirring at 50° C. for 1 hour, the resulting mixture was allowed to cool and ice water (100 ml) was added. The white crystals formed were filtered, washed with water and dried (yield: 58 g). The crystals (34.3 g) were gradually added to methanol (200 ml) containing sodium hydroxide (42 g) and the methanol was evaporated to dryness by stirring with heating over a water bath. The resulting residue was recrystallized from water to afford potassium p-chlorophenylpropionate as white crystals. These crystals were dissolved into 100 ml of water and neutralized with a diluted sulfuric acid to afford white crystals, which give 14.1 g of p-chlorophenylpropiolic acid after filtration, washing with water and drying. |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; In pyridine; benzene; | EXAMPLE IV 1-(4-Chlorocinnamamido)hydantoin To 4-chlorocinnamic acid (46 g, 0.25 mole) was added dropwise SOCl2 (140 ml). The mixture was heated under reflux for 45 minutes after the addition was complete. After stirring at room temperature for 1 hour the SOCl2 was removed in vacuo. Dry benzene was added and then removed in vacuo. The acid chloride residue was treated with <strong>[2827-56-7]1-aminohydantoin hydrochloride</strong> (42 g, 0.275 mole) in 350 ml of pyridine, then heated under reflux for 2 hrs. After cooling slightly, the reaction mixture was poured into a mixture of 200 ml of con HCl and 1500 ml of ice. After standing overnight the product was removed by filtration and washed with H2 O. Recrystallization from NaOH/dimethylformamide (H2 O) provided analytical material which melted at 230-235 (25 g, 36%). Anal. Calcd. for C12 H10 ClN3 O3: C, 51.53; H, 3.60; N, 15.03 Found: C, 51.49; H, 3.58; N, 14.89. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; LiAlH4; hydrazine; In tetrahydrofuran; thionyl chloride; diethyl ether; ethanol; water; | Preparation Example 6: Synthesis of 3-(4-chlorophenyl)propylamine A mixture of 6.75g of 4-chlorocinnamic acid and 0.3g of CuSO4 · 5H2O dispersed in 50ml of ethyl alcohol was stirred at room temperature for 10 minutes; and 23ml of 95% hydrazine was added thereto. This reactant was stirred for 18 hours with air bubbling at the speed of 1L/min. The reaction mixture was filtered through a Celite layer and 30ml of 1N NaOH was added thereto. The solution was washed twice with 30ml of dichloromethane, acidified with concentrated hydrochloric acid, extracted with 100ml of ethyl acetate four times and dried over magnesium sulfate. The solvent was evaporated to give 6.05g(yield 89%) of 3-(4-chlorophenyl)propanoic acid as a yellow solid. 5.90g of 3-(4-chlorophenyl) propanoic acid obtained above was dissolved in 6ml of thionyl chloride, heated to reflux for 2 hours and concentrated under reduced pressure. The residues thus obtained were dissolved in 100ml of dry ethyl ether and the solution was added dropwise to 150ml of NH4OH in an ice bath. The resultant solution was stirred at room temperature for 1 hour and extracted twice with 200ml of dichloromethane. The organic phase was washed with 100ml of a saturated sodium hydrogen carbonate aqueous solution and dried over magnesium sulfate. The solvent was evaporated to provide 4.62g(yield 78%) of 3-(4-chlorophenyl)propanamide. 4.62g of amide obtained above was dissolved in 50ml of dry tetrahydrofuran; and the solution was slowly added to a dispersion of 2.4g of LiAlH4 in 150ml of dry tetrahydrofuran with reflux for 2 hours. The reaction mixture was cooled to room temperature, treated with 10ml of 1N NaOH and filtered through a Celite layer to give solids, which were dissolved in 150ml of distilled water and then filtered through a Celite layer. The filtrate so obtained was extracted with ethyl ether(100ml x 3). The combined organic layer was dried over magnesium sulfate; concentrated and distilled under reduced pressure to provide 3.12g(yield 73%) of the title compound as a colorless liquid: b.p. 140C/3.4mmHg. |
Yield | Reaction Conditions | Operation in experiment |
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86% | With 1-ethyl-3-(3-aminopropyl)carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | General Procedure: Ethyl-3-aminopropyl carbodiimide hydrochloride (EDCI) Couplings of piperazines with cinnamic acids Cinnamic acid (1.3 mmol), EDCI (1.3 mmol), dimethylaminopyridine (0.1 mmol) and substituted piperazine (1 mmol) were combined in a screw cap vial and dissolved in dimethylformamide (6 mL). The reaction was stirred overnight at room temperature. The solution was then diluted with dichloromethane and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo, then chromatographed in 0?50% ethyl acetate in hexanes to yield the desired product.; The following compounds were made in this manner: Example Structure Name Yield 11.1 ethyl 4-[(2E)-3-(4-chloro- phenyl prop-2-enoyl]piperazine-1-carboxylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 70℃; | General procedure: A mixture of alpha,beta-unsaturated aromatic or aliphatic acid (10 mmol), CH3SO2Bt (10 mmol) and Et3N (15 mmol) were refluxed in dry THF (50 mL) overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2 (100 mL). The organic phase was washed with brine (3 times) and dried over anhydrous Na2SO4. The organic phase was concentrated under vacuum to give a crude product, which could be further purified by recrystallization from a proper solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | 9.1 3-(4-Chloro-phenyl)-propan-1-olTo a suspension of lithium aluminium hydride (20.26 g, 37.95 mmol) in THF (tetrahy- drofuran) (300 mL) under nitrogen atmosphere was slowly added a solution of 3-(4- chloro-phenyl)-acrylic acid (65.00 g, 355.96 mmol) in THF (500 mL) under cooling with an ice bath. The resulting mixture was stirred until it reached room temperature and then refluxed for 12 h. After cooling to room temperature, a 10% HCI solution was added at 0 C and the resultant solution was stirred for 0.5 h. The mixture was then extracted with MTBE (methyl tert-butyl ether) and the organic layers were washed with water, dried and evaporated. The title compound was obtained as a brown oil (70.0 g, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.1% | 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 |
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21% | Stage #1: 3-(4-chlorophenyl)prop-2-enoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.333333h; Stage #2: 4-amino-7-chloroquinoline In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; | 4.16. General procedure for the synthesis of compounds 9a-k General procedure: The relevant cinnamic acid (1.1 eq), PyBOP (1.1 eq), DIEA (2 eq.) and DCM (2 mL) were mixed in a round bottom flask and put under stirring for 20 min. Then, a solution of 3 (0.250 g, 1.40 mmol) in DMF (2 mL) was added and the reaction allowed to proceed for one day at room temperature. Following, the reaction mixture was diluted with 14 mL of DCM and sequentially washed with 1% aq. HCl (3 × 18 mL) and 5% aq. Na2CO3 (3 × 18 mL). Finally, the organic layer was dried with anhydrous Na2SO4, filtered, and evaporated to dryness In all cases, the crude product had to be purified by column liquid chromatography on silica, using DCM/Me2CO 6:1 v/v as eluent. Target compounds were isolated as solids, with analytical and spectral data given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Step 1To a solution of (is)-3-(4-chlorophenyl)acrylic acid (18.3 g, 0.1 mol) and Et3 (20.2 g, 0.2 mol) in benzene (100 mL) was added dropwise DPPA (27.5 g, 0.1 mol). After stirring for 2 h, the solution was concentrated and purified by chromatography (Biotage, mobile phase 20/80 EtOAc/hexanes) to give 16 g of an intermediate azide as a solid. This intermediate was dissolved in 100 mL of PI12CH2 and the resulting mixture was slowly heated to 90 C over a 30 min time period. The reaction mixture was heated to reflux and maintained at this temperature for 3h. After cooling to RT, a solid precipitated which was collected by filtration and washed with toluene to provide 9.5 g of 7-chloroisoquinolin-l(2H)-one (53%). XH NMR (400 MHz, CD3OD) delta ppm 6.66 (d, J=7.05 Hz, 1 H), 7.18 (d, J=7.05 Hz, 1 H), 7.66 (s, 1 H) 7.67 (d, J=2.01 Hz, 1 H), 8.24 (d, J=2.27 Hz, 1 H); 13C NMR (101 MHz, DMSO-D6) delta ppm 104.05, 125.62, 127.21, 128.54, 129.52, 130.77, 132.43, 136.55, 160.72; LC/MS, MS m/z (M+H)+ 180. |
Yield | Reaction Conditions | Operation in experiment |
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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 |
---|---|---|
1: 10% 2: 90% | With palladium 10% on activated carbon; hydrogen at 40℃; for 2h; Autoclave; | General procedure for the esterification General procedure: benzoic acid (Table 3, entry 1) (1.0 g,0.0081 mol), bromobenzene (0.125 g, 0.0081 mol), 10% palladium on carbon(50% wet) (0.2 g) and methanol (3 mL) were placed in autoclave vessel. Autoclave was pressurized with 1-2 bar of nitrogen followed by 1-2 bar of hydrogen gas and then put under the desired pressure of hydrogen (5-6 bar).The reaction mixtures are then warmed to 55-60 C temperature and stirredfor 4 h at 300 rpm. After reaction, the catalyst was filtered through celite bed.Filtrate was added with water (30 mL). The reaction mixture was extracted with isopropyl acetate (2 15 mL). The combined organic layers were washedwith 5% aqueous sodium bicarbonate solution (2 15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum togive of methyl benzoate product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | 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 |
---|---|---|
81% | In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tetrabutylammonium perchlorate; acetic acid In water; acetonitrile at 20℃; for 2h; Electrolysis; regioselective reaction; | |
69% | 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 potassium iodide; copper(II) oxide In dimethyl sulfoxide at 100℃; for 24h; Sealed tube; Green chemistry; stereospecific reaction; |
64% | With palladium diacetate; silver carbonate; 1,4-di(diphenylphosphino)-butane In N,N-dimethyl-formamide at 75℃; for 6h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 1h; Reflux; | 11 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 |
---|---|---|
60% | With 1,10-Phenanthroline; palladium diacetate; silver carbonate In dimethyl sulfoxide at 130℃; for 72h; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water for 0.666667h; Sonication; Green chemistry; | 2.3. Ultrasound-promoted synthesis of propanamide derivatives(4 and 5) General procedure: The carboxylic acid derivative (2) (1.0 mmol), 2-oxopropyl benzoate (3) (1 mmol), isocyanide (1) (1 mmol) and water (7 mL) were added into a 25 mL round bottomed flask. The reaction mixture was sonicated under 100 W for the period of time (the reaction was monitored by TLC). The solvent was eliminated under decreased pressure, and the products were generated without any purification (4 and 5). The authenticity of the samples (4a-4i and 5a-5i) was established by their 1H NMR, 13C NMR, FT-IR, elemental analyses and MS. The characterization data of the compounds are given below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34%; 15% | In a sealed tube, (E)-3-(4-chlorophenyl)acrylic acid (0.25 g, 1.37 mmol), anisole (0.163 g, 1.51 mmol) and 4-methylbenzenesulfonic acid hydrate (0.26 g, 1.37 mmol) were mixed and heated to 125C for 5h. After cooling, the red solid was dissolved in EtOAc, poured into water (10 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). Combined organics were washedwith brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 40% EtOAc-heptane gradient to give a 2/1 mixture of 3-(4-chlorophenyl)-3- (4-methoxyphenoxy)propanoic acid and 3-(4-chlorophenyl)-3-(2-methoxyphenoxy)propanoic acid. This material was then re-purified by HPLC chromatography (Reprosil Chiral NR column, gradient: 0-30% ethanol-heptane) to give the title compound (0.137 g, 34%) as a colorless solid. MS: 289.3 (M-Ff) and its isomer (0.06, 15%) as a yellow solid. MS:289.3 (M-Ff). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 3-(4-chlorophenyl)propanoic acid With Zn(2,2,6,6-tetramethylpiperidine)2*2LiCl In tetrahydrofuran at -40℃; for 1.5h; Inert atmosphere; Sealed tube; Stage #2: With bis(η3-allyl-μ-chloropalladium(II)); Allyl acetate In tetrahydrofuran at -40 - 60℃; for 3h; Inert atmosphere; Sealed tube; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.8 g | 100.0 g Rink-amide-AM resin (loading 0.88mmol/g, 1.0 eq) was put into a solid-phase reactor and vacuumedunder reduced pressure for 1h. Anhydrous DCM (500 mL) was added to swell the resin for 45 min and then removed.The Fmoc group of resin was removed by using of 20%(Volume percentage) piperidine/DMF for 1 h at r.t, followed bythorough washing with DMF (500 mL36) and DCM (500 mL36) respectively. Fmoc-Lys(Boc)-COOH (61.8 g, 1.5 eq),HOBt (17.8 g, 1.5 eq), and DIC (20.8 mL, 1.5 eq) were dissolved in DMF (500 mL), then added into the reactor, the firstamino acid was bonded to the resin after reacting for 8 h at r.t. When it was negative by the ninhydrin method, thecoupling reaction was completed followed by thorough washing with DMF (500 mL36) and DCM (500 mL36) respectively.Then the Fmoc was removed by using 20% (Volume percentage) piperidine/DMF. <strong>[292150-20-0]Fmoc-D-iso-Gln-OH</strong> (48.5 g, 1.5 eq),Fmoc-Ala-OH (41.0 g, 1.5 eq), and 4-chlorocinnamic acid (24.1 g, 1.5 eq) were successfully added to introduce thesecond amino acid to the solid phase. The reaction was lasted 12 h and was monitored by ninhydrin method. Clearedthe liquid phase, 500 mL 20% (Volume percentage) piperidine/DMF was added to remove Fmoc, cleared liquid againafter 1h, the resin was washed with DMF (500 mL*6) and DCM (500 mL*6) respectively. Fmoc-Ala-COOH (41g, 1.5eq),HOBt (17.8 g, 1.5 eq), DIC (20.8 mL, 1.5 eq) and 500mL DMF were added to introduce the third amino acid. The reactionwas lasted 12 h and was monitored by ninhydrin method. Cleared the liquid phase, 500 mL 20% (Volume percentage)piperidine/DMF was added to remove Fmoc, cleared liquid again after 1h, the resin was washed with DMF (500 mL36)and DCM (500 mL36) respectively. Chlorocinnamic acid (24.1g, 1.5eq), HOBt (17.8 g, 1.5 eq), DIC (20.8 mL, 1.5 eq) and 500mL DMF were added to introduce the organic acid. The reaction was lasted 8 h and was monitored by ninhydrinmethod. Cleared the liquid phase, the resin was washed with DMF (500 mL36) and DCM (500 mL36) respectively.TFA water solution 90% (Volume percentage) was added to the reactor, the reaction was lasted for 2 h. Removed theliquid, TFA water solution 90% (Volume percentage) was added to the reactor, the reaction was lasted for 2 h, removedthe liquid, the resin was washed with 200 mL DCM. TFA water solution and DCM was combined and evaporated undervacuum. In ice bath, to the residue was added abundant Error Hyperlink reference not valid. ether, white solidprecipitated, remove the supernatant. To the white solid was grinded with diethyl ether for several times to obtain crudeproduct (39.8) with the yield 89%. The crude product was purified by ODS column chromatography with gradient elution,methanol/water to produce 35.8g target product in 98.5% purity. m.p.=215?217C, [alpha]=+37.7(C=11.05mg/mL,DMF). 1H-NMR(600MHz, DMSO-d6): 7.47(2H, d, J=8.4Hz, 2 and 6-H), 7.57(2H, d, J=8.4Hz, 3 and 5-H), 7.39(1H, d,J=15.9Hz, 7-H), 6.75(1H, d, J=15.9Hz, 8-H), 8.39(1H, d, J=6.6Hz, 10-H), 4.38(1H, m, 11-H), 1.26(3H, m, 12-H), 8.21(1H, d, J=8.4Hz, 14-H), 4.14(1H, m, 15-H), 6.98(1H, s, 17-Ha), 7.41(1H, s, 17-Hb), 1.71(1H, m, 18-Ha), 1.97(1H, m, 18-Hb),2.15(2H, t, J=7.2Hz, 19-H), 7.90(1H, d, J=8.4Hz, 21-H), 4.11(1H, m, 22-H), 7.10(1H, s, 24-Ha), 7.30(1H, s, 24-Hb),1.46(1H, m, 25-Ha), 1.63(1H, m, 25-Hb), 1.27(2H, m, 26-H), 1.53(2H, m, 27-H), 2.73(2H, m, 28-H), 7.75(2H, br.s, 29-H). 13C-NMR(150MHz,DMSO-d6): 134.0(1-C), 129.0(2 and 6-C), 129.2(3 and 5-C), 133.8(4-C), 137.6(7-C),122.7(8-C), 164.7(9-C), 48.8(11-C), 18.1(12-C), 172.4(13-C), 52.2(15-C), 173.8(16-C), 27.7(18-C), 31.7(19-C),171.6(20-C), 52.1(22-C), 173.3(23-C), 31.3(25-C), 22.4(26-C), 26.8(27-C), 38.7(28-C). IR: 3282.3, 3202.2((nuOH and (nuNH), 3067.3((nu=CH), 2938.0((nu-CH), 1609.5((nu-C=O), 1537.5, 1450.2((nuC=C),1199.0, 1180.2, 1130.6(delta-CH), 972.4, 820.4, 799.4, 720.0(delta=CH and (nuC-Cl).ESI-MS: 509.60 [M+H]+, 1017.24 [2M+H]+.HR-MS(TOF): 509.2292 [M+H]+, C23H33ClN6O5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With urea; at 140℃; for 2h;Green chemistry; | General procedure: A 10-mL test-tube was equipped with magnetic stirring bar and charged with 1 mmol cinnamic acid and 6 mL DES, heated at 140 C in a preheated oil bath for 2 hours, then the mixture was cooled to room temperature, extracted with ethyl acetate (3*15 mL), combined and evaporated under vacuum. Pure product was obtained by silica gel column chromatography with petroleum ether and ethyl acetate. All the compounds, after purification, were weighted and characterized by MS, 1H NMR, 13C NMR, and then compared them with the spectral data of authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1H-imidazole at 140℃; for 2h; Green chemistry; | Typical Procedure for the esterification of carboxylic acid in DES General procedure: A 10-mL test-tube was equipped with magnetic stirring bar and charged with 1 mmol cinnamic acid and 6 mL DES, heated at 140 °C in a preheated oil bath for 2 hours, then the mixture was cooled to room temperature, extracted with ethyl acetate (3*15 mL), combined and evaporated under vacuum. Pure product was obtained by silica gel column chromatography with petroleum ether and ethyl acetate. All the compounds, after purification, were weighted and characterized by MS, 1H NMR, 13C NMR, and then compared them with the spectral data of authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere; | General Procedure for Synthesis of FTY720 Derivatives 2-10 General procedure: EDCI (3 eq), N,N-dimethyl-4-aminopyridine (DMAP) (0.5 eq), and the acid intermediates (1.5 eq) were added to a stirred solution of 4-n-octylaniline (100 mg, 0.49 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred under nitrogen for 12 h. The solvent was removed in vacuo and the resulting residue was purified by flash column chromatography to afford the desired products 2-10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: p-chlorocinnamic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Schlenk technique; Inert atmosphere; Stage #2: (E,Z)-2-benzoyl-3-phenylbut-2-enenitrile With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 12h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76 % de | Stage #1: (4-chlorophenyl)propiolic acid With 18-crown-6 ether; caesium carbonate In toluene at 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: With bis(pinacol)diborane In toluene at 65℃; for 24h; Inert atmosphere; Schlenk technique; Overall yield = 46 %; regioselective reaction; | 4.1.13 General procedure for the synthesis of acrylic acid derivatives General procedure: To a solution of alkynoic acid (1 equiv) in toluene at room temperature was added Cs2CO3 (1.2 equiv) and 18-crown-6 (1.2 equiv), and the resulting reaction mixture was stirred for 30min. Subsequently, B2pin2 (1.5 equiv) was added to the solution and the reaction mixture was stirred for additional 16-29hat the indicated temperature. The reaction was quenched with 0.33M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a 2:98 ethyl acetate in hexane with 1% acetic acid isocratic method to yield the desired product. Only the trans (major) product are reported, which match the literature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With copper(II) acetate monohydrate; silver carbonate; CyJohnPhos In 1,2-dichloro-ethane at 130℃; for 24h; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24h; | 2.1. Synthesis of Amide Derivatives 3a-e and 5a-e General procedure: The title amide derivatives have been synthesized by following the previously reported method with slight modification. Briefly, 4-isopropyl aniline (0.01 mol), triethylamine (0.01 mol) were mixed in anhydrous dichloromethane (20 ml) at 0 to -5°C. This mixture was treated with chloroacetyl chloride (0.01 mol) in dry dichloromethane with constant stirring over a period of 1 hr, maintaining the temperature constant. After the addition is complete, the reaction mixture was further stirred at room temperature for 4hr, washed with dilute hydrochloric acid and 5% sodium hydroxide solution. The organic layer was removed under reduced pressure to afford the intermediate 1 as solid melting point 138-140°C; FTIR νmax cm-1: 3157 (-NH), 2933 (sp2C-H), 2868 (sp3 C-H), 1665 (C=O amide) and 1592 (C=Caromatic). The intermediate 1 was treated with hydroxy substituted benzoic acids 2a-e (0.01mole), triethyl amine(0.01 mol) and potassium iodide (0.01 mol) in dimethylformamide (20 ml) were stirred overnight at room temperature (Fig. 1a). After the completion of reaction, the mixture was poured into ice cold water with stirring and extracted with ethyl acetate (4x20 ml). The combined organic layer was washed with dilute hydrochloric acid (5%), sodium hydroxide solution (5%) and finally with aqueous NaCl solution.The organic layer was dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the crude products 3a-e. The amide derivatives 3a-e were purified by silica gel column chromatography. The same procedure was used to synthesize compounds 5a-e (Fig. 1b). The structures of the final products 3a-e and 5a-e were confirmed by FTIR, 1H NMR and 13C NMR spectral data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h; | General procedure: Compounds 9e-35e were obtained by using one-pot reaction. A mixture of aromatic acid (6.30 mmol), EDCI (7.50 mmol), DMAP (0.60 mmol), and anhydrous dichloromethane (20 mL) was stirred to dissolve, then decane-diamine (3 mmol) was added and stirred at room temperature for 12 h. The mixture solution was filtered under reduced pressure. After that, the residue was washed with little amount of CH2Cl2and water successively, and dried to give the solid. Then, the residue was purified on preparative TLC eluted with chloroform/methanol = 40:1-7:1 to yield compounds 26e, 28e, 30e, and 31e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phenylalanine ammonia-lyase from Pseudozyma antarctica yeast; In aq. buffer; at 30℃; for 168h;pH 8.5;Resolution of racemate; | General procedure: The ammonia elimination reaction mixtures containing 5mM of theracemic phenylalanines (rac-1a-s) in 100mM TRIS buffer (pH 8.5) andpurified PzaPAL or PcPAL (50 Xg, either) in 1 mL reaction volume wereincubated at 30 C. Samples (50 XL) taken at different time points (17,40, 64, and 168 h) from the reaction mixtures were analyzed by HPLCfor conversion and ee values, using previously developed methods [44].The ammonia addition and elimination reactions were followed byHPLC measurements. Conversions were determined on Agilent 1200HPLC instrument using Phenomenex Gemini NX-C-18 column and amixture of NH4OH buffer (0.1 M, pH 8.5) and MeOH at a flow rate of1 mL min-1. Conversions were calculated from peak area integrationswith use of appropriate response factor (Table S2). Enantiomer separationswere carried out on Agilent 1100 HPLC instrument usingCrownpak CR-I (+) column and a mixture of aqueous HClO4, pH 1.5and acetonitrile as eluent at a flow rate of 0.4 mL min-1. (Table S3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h; Inert atmosphere; | 7 In a 50mL round-bottom flask, add chrysin (compound represented by structural formula (1)) (1mmol, 1eq), cinnamic acid (compound represented by structural formula (2g)) (1.5mmol, 1.5eq.), EDCI (1.5mmol , 1.5eq) and DMAP (0.5mmol, 0.5eq), and then under the protection of N2, add dichloromethane (10.0mL), react at room temperature for about 6h (TLC detection), after the reaction is completed, filter with suction and remove the filter cake After washing with petroleum ether, ethyl acetate and acetone in sequence, it is dried to obtain 3 g of compound.Obtained compound 3g: pale yellow solid, yield 88.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tert.-butylhydroperoxide; 6-(quinolin-2-yl)pyridin-2(1H)-one; sodium acetate; palladium diacetate; lithium carbonate In 1,4-dioxane; tert-Amyl alcohol; water at 80℃; for 16h; Inert atmosphere; |
Tags: 1615-02-7 synthesis path| 1615-02-7 SDS| 1615-02-7 COA| 1615-02-7 purity| 1615-02-7 application| 1615-02-7 NMR| 1615-02-7 COA| 1615-02-7 structure
[ 1866-38-2 ]
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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