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CAS No. : | 591-80-0 | MDL No. : | MFCD00004408 |
Formula : | C5H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HVAMZGADVCBITI-UHFFFAOYSA-N |
M.W : | 100.12 | Pubchem ID : | 61138 |
Synonyms : |
Allylacetic acid;3-vinylpropionic acid;4-penten-1-oic acid
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 27.45 |
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) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 1.23 |
Log Po/w (XLOGP3) : | 0.83 |
Log Po/w (WLOGP) : | 1.04 |
Log Po/w (MLOGP) : | 0.79 |
Log Po/w (SILICOS-IT) : | 0.51 |
Consensus Log Po/w : | 0.88 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -0.79 |
Solubility : | 16.4 mg/ml ; 0.164 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.2 |
Solubility : | 6.38 mg/ml ; 0.0637 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.43 |
Solubility : | 37.2 mg/ml ; 0.372 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.36 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 1760 |
Hazard Statements: | H227-H302-H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
85% | With hydroxy-substituted sulfonic acid-functionalized silica (HO-SAS) at 110℃; Flow reactor; | Typical Procedure for Flow Esterification (Table1,Entry 6) General procedure: Lauric acid (1a) (2.01 g, 10.0 mmol) was dissolved in methanol (10 mL) and then placed in a syringe, which wasthen attached to a syringe pump. The methanol solution was fedinto a stainless steel column (inner volume: 0.53 mL, 4.0 mm i.d. 50 mm) filled in HO-SAS (334 mg) with a flow rate of0.177 mL.min-1. The column was immersed into an oil bath(110°C). A back-pressure regulator (75 psi) was connected.The reaction mixture was collected from the outlet. The reaction mixture eluted during the first 10 min was discarded. Thereaction mixture was collected during 3 min and added n-decane as an internal standard for GC analysis. The followingportion was collected for a 30 min period in a glass flask, andsolvent was evaporated. The crude mixture was purified byflash column chromatography on SiO2 (hexane/ethyl acetate =5/1) to give 3a (1.13 g, 99%). |
72% | With sulfuric acid for 3h; Reflux; | |
72% | With sulfuric acid for 3h; Inert atmosphere; Reflux; |
72% | With sulfuric acid for 3h; Inert atmosphere; Schlenk technique; Reflux; | |
37% | With sulfuric acid at 70℃; for 24h; | 3 Example 3 Example 3 4-Pentenoic acid (50 mL, 51.0 g, 0.51 mol), methanol (400 mL) and 4 drops of concentrated H2S04 were heated at 70 °C for 24 hours. After this time the volatiles were removed in vacuo. The crude material was taken up in pentane (200 mL), washed with deionized water (100 mL x 2), followed by brine (100 mL), and then dried over MgS04. Filtration and evaporation of the volatiles gave a colourless liquid consisting of methyl pent-4-enoate. The yield of methyl pent- 4-enoate is 21.3 g which corresponds to 37%. |
With sulfuric acid | ||
With sulfuric acid | ||
With hydrogenchloride | ||
Stage #1: pent-4-enoic acid With oxalyl dichloride at 0 - 20℃; Stage #2: methanol at 0 - 20℃; | ||
With sulfuric acid for 3h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With toluene-4-sulfonic acid In benzene | |
78% | With sulfuric acid In benzene for 15h; Heating; | |
With sulfuric acid; benzene |
With hydrogenchloride for 16h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride; dihydrogen peroxide; In methanol; formic acid; | EXAMPLE 56 (+-)-Dihydro-5-Hydroxymethyl-2(3H) -Furanone STR89 To a stirring solution of 19% hydrogen peroxide (35 mL, 0.20 mol) in 85% aqueous formic acid (60 mL) at 50-55 C. was added over a 15 min period a solution of 4-pentenoic acid (15 g, 0.15 mol) in 85% aqueous formic acid (30 mL). The solution was maintained at this temperature for 2 h. Concentration gave an oil which comprised of a mixture of the desired compound and the corresponding formate ester. The oil was then stirred in methanol (50 mL) containing concentrated hydrochloric acid (1 mL) for 3 h. Concentration gave the desired compound as an oil (17.2 g, 99%). 1 H NMR (300 MHz, CDCl3) delta: 4.60 (m, 1H, H-5), 3.89 (dd, 1H, H-6, J=2.7 HZ and 12.6 Hz), 3.63 (dd, 1H, H-6', J=4.5 HZ and 12.3 Hz), 2.6 (m, 2H, H-3), 2.3 (m, 3H, H-4, OH). |
97% | With formic acid; dihydrogen peroxide; at 50℃; for 2.25h; | 4-pentenoic acid (2 g, 20 mmol) was dissolved in formic acid (5 mL), and added dropwise into formic acidsolution (20 mL) containing 35% of hydrogen peroxide (28 mmol) at 50 C over 15 min. At this temperature, the mixturewas stirred for 2 h, and distilled under reduced pressure to give the product 2-keto-5-hydroxymethyl-tetrahydrofuran (2g, yield 97%). |
88% | With dihydrogen peroxide; In tert-butyl alcohol; | EXAMPLE 5 A total of 2 ml of 30% by weight hydrogen peroxide aqueous solution was added dropwise to a stirred mixture of 1.00 g (10 mmol) of 4-pentenoic acid, 25 mg (0.1 mmol) of tungstic acid, and 15 ml of t-butyl alcohol at room temperature, followed by stirring at 70C for 10 hours. As a result, gamma-hydroxymethyl-gamma-butyrolactone was produced in a yield of 88%. |
With N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)ethane-1,2-diamineiron(II) bis(triflate); dihydrogen peroxide; In water; acetonitrile; for 0.166667h;Inert atmosphere; Schlenk technique; | General procedure: Epoxidations were performed in 25-mL Schlenk tubes under an inert atmosphere. In a typical run, the tube was charged with 1 equiv of catalyst (typically about 15mg), degassed acetonitrile (20mL) and 200 equiv of substrate. 600 equiv of the oxidant H2O2 (30% w/v in water) were added via syringe over a two-minute period, often resulting in an immediate color change to brown. This color faded to a pale orange for most substrates over a period of 30s. The reaction was allowed to stir for a total of 10min, and then was quenched by pouring the solution into an Erlenmeyer flask containing silica gel and anhydrous magnesium sulfate. The solution was passed through a short column of silica gel, and solvent evaporated under moderate vacuum. As a control, samples of substrates were taken through this workflow without use of catalyst, and analyzed gravimetrically and by 1H NMR. Pure substrate was recovered with no significant mass loss (typical recovery 98%). For other catalyst:substrate:oxidant ratios, the concentration of catalyst was kept constant, and amounts of substrate and oxidant varied. The products were analyzed by 1H NMR in CDCl3 with a relaxation delay of 10s. 1H NMR shifts of the epoxide products matched those reported in the literature [22,36-39]. For oleic acid and ethyl oleate, the shift of the CH3 group of C18 does not change between the starting materials and products. This signal was therefore used as an internal standard to measure conversions by comparing the integrations of the alkene signals relative to the methyl signals [36]. Similarly, epoxide selectivities were calculated from the integrations of the epoxide signals and the methyl signals. For undecylenic acid and methyl undecenoate, a similar approach utilized the methylene group next to the carboxylic acid group as an internal standard. For the epoxidation of 4-pentenoic acid and 5-hexenoic acid, conversions were determined by comparing the integrations of the alkene signals with those of the epoxide and lactone signals. GC-MS data was used to confirm the presence of two major products only, the epoxide and the lactone [38]. Owing to the limit of sensitivity of NMR, in experiments where epoxide or lactone was the only product clearly detected, selectivities of >95% are reported, as low concentrations of other products can not be ruled out. Selected spectra and GC-MS chromatograms are available in the Supplemental information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bromine In dichloromethane at -40℃; for 1.5h; | |
79% | With Oxalyl bromide; dimethyl sulfoxide In dichloromethane at -10 - 20℃; Inert atmosphere; | Bromination of Alkenoic Acids Using DMSO and (COBr)2; GeneralProcedure General procedure: To a solution of (COBr)2 (1.07 mL, 7.5 mmol, 1.5 equiv) in CH2Cl2 (10mL) at -10 °C was added dropwise a solution of DMSO (0.53 mL, 7.5mmol, 1.5 equiv) in CH2Cl2 (10 mL) under an atmosphere of nitrogen. After 10 min, a solution of alkenoic acid 1 (5 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added. The mixture was then allowed to warm to room temperature and stirred for 1 h. Distilled H2O (30 mL) was addeddropwise at 0 °C. After stirring for 10 min, the organic layer was separated and washed with brine (2 × 30 mL), dried (Na2SO4), filtered, and concentrated under vacuum. Purification by flash chromatography (silica gel, PE/EtOAc, 10:1) afforded the corresponding bromolactones 2a,d,g. The vicinal dibromo acids 3b,c,e,f,h-j can be obtained in high purity through simple pH adjustment as described above. |
With tetrachloromethane; bromine |
With carbon disulfide; bromine | ||
With bromine In dichloromethane at 20℃; for 0.0833333h; PTFE sealed tube; | ||
With bromine In dichloromethane at -40℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With poly-4-vinylpyridine In N,N-dimethyl-formamide for 0.0666667h; microwave irradiation; | |
85% | Stage #1: allylmalonic acid In N,N-dimethyl-formamide at 140℃; Stage #2: With hydrogenchloride In N,N-dimethyl-formamide | |
76% | In N,N-dimethyl-formamide at 140℃; Inductive heating; | 11 MagSilica 50/85 (PH 343-48), DMF, 25 kHz, 550 prom, 140C, 0.2 ml/min. single-pass |
beim Erhitzen; | ||
at 160℃; | ||
In N,N-dimethyl-formamide at 135℃; | Decarboxylation Reactions: A glass reactor (length 12 cm, internal diameter 8.5 mm) is filled with MagSilica and zinc (5.5 g) and both ends are closed with cotton wool. An HPLC pump is attached to one end of the reactor, while the other end is connected to a receiver. The reactor is inserted in the inductor and then rinsed with N,N-dimethylformamide (DMF). Then a flow rate of 0.2 ml/min is established and the reactor temperature is set to 135° C. (excitation frequency: 25 kHz, output setting: 550 per mil). Once a constant temperature has been reached a solution of dicarboxylic acid 1 (50 mg, 0.35 mmol) in DMF (5 ml) is pumped through the reactor at 0.2 ml/min. Then a further 15 ml of DMF are pumped through the reactor. The combined organic phases are acidulated with 4 M HCl and extracted repeatedly with ethyl acetate. The combined organic phases are concentrated to low volume over MgSO4 dried under vacuum. The title compound 2 is obtained with no further purification as a colorless oil (26.7 mg, 0.27 mmol, 76% yield). 1H-NMR (400 MHz, CDCl3, for main product): 5.83 (m, 1H, H-4), 5.08 (dd, 1H, J1=0.9 Hz, J2=17.1 Hz, H-5a), 5.02 (dd, J1=0.8 Hz, J2=9.7 Hz, H-5b), 2.46 (m, 2H, H-2), 2.38 (m, 2H, H-3); 13C-NMR (400 MHz, CDCl3): 178.6 (q, C-1), 136.5 (t, C-4), 115.8 (s, C-5), 33.4 (s, C:2), 28.7 (s, C-3). The data corresponds to the commercially available compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.9% | In diethyl ether | |
In diethyl ether Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With bis(tri-n-butyltin)oxide In toluene at 90℃; for 48h; | |
42% | With bis(tri-n-butyltin)oxide In toluene for 48h; Heating; | |
(alkaline hydrolysis); |
With potassium hydroxide Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With toluene-4-sulfonic acid In tetrachloromethane for 10h; Heating; | |
58% | With sulfuric acid In methanol for 3h; Reflux; | |
Multi-step reaction with 2 steps 1: (COCl)2 |
Multi-step reaction with 2 steps 1: oxalyl chloride / 0 - 40 °C 2: 20.9 g / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: (COCl)2 / 1) 0 deg C, 3 h, 2) room temperature, 17 h 2: 1) 0 deg C, 1.5 h, 2) room temperature, 4 h | ||
Multi-step reaction with 2 steps 1: chlorure de thionyle | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride / 20.3 h / 0 - 20 °C 2: 25.5 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / 1 h / 20 °C 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride / 20.3 h / 0 - 20 °C 2: 25.7 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 18-crown-6 ether; potassium carbonate In tetrahydrofuran for 6h; Heating / reflux; | 1.B Example 1: Chemical Synthesis of Fluorinated VPA Analogues. B) Synthesis of sodium 2-allyl-2-fluoropent-4-enoate (13). Preparation of ethyl pent-4-enoate (9) A mixture of 4-pentenoic acid (10. 01 g), ethyl iodide (31. 19 g), potassium carbonate (10.36 g) and 18-CROWN-6 (1.28 g) in dry THF (100 ml) was refluxed for 6 hours. After cooling the white solid formed was filtered, and the filtrate was fractionated under reduced pressure to give compound 9 in 80% as a colourless oil, bp 43-44°C/12 mmHg. |
With potassium hydroxide 1) EtOH, r.t. 2) reflux, 48h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In acetone | |
72% | With potassium carbonate In acetone at 60℃; for 6h; | |
57% | With potassium carbonate In acetone at 20 - 60℃; | Methyl pent-4-enoate: Pent-4-enoic acid (0.83 g, 8.29 mmol) and potassium carbonate (5.69 g,41.17 mmol) were dissolved in acetone (8.16 ml). To this suspension, iodomethane (2.55 ml,40.96 mmol) was added dropwise at room temperature. This suspension was refluxed at 60 oCovernight. The reaction mixture was cooled to room temperature, diluted with diethyl ether. The organic layer was washed with ammonium chloride solution, dried over Na2SO4, concentrated atreduced pressure to afford 0.54 g of methyl pent-4-enoate (57%) as a colorless oil. 1H NMR11(400 MHz, CDCl3) δ 5.86-5.76 (m, 1H), 5.08-4.95 (m, 2H), 3.67 (s, 3H), 2.43-2.36 (m, 4H); 13CNMR (100 MHz, CDCl3) δ 173.6, 136.8, 115.6, 51.6, 33.5, 28.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With manganese triacetate In dichloromethane; trifluoroacetic acid | |
91% | With manganese triacetate; trifluoroacetic acid In dichloromethane at 0℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 48h; | |
94% | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; | |
93.1% | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 36h; | 4-Pentenoic acid-N-hydroxysuccinimide ester (26) A mixture of 4-pentenoic acid (4.1 ML, 39.95 MMOL), N-HYDROXYSUCCINIMIDE (5.1 g, 43.95 mmol), DMAP (0.54 g, 4.4 mmol) and DCC (9.07 g, 43.95 mmol) were dissolved in THF (200 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed warming to room temperature and stirred for 36 h. The reaction mixture was kept in freezer overnight. After the precipitate was filtered out, the solvent was removed under reduced pressure. The residue was purified by chromatography on a column of silica gel (0.02% CH30H in CH2C12) to give 26 (7.33 g, 93.1%) as white solid: Rf = 0.50 (3.2% methanol in chloroform) ; IH NMR (400 MHz, CDC13) 8 2.47-2. 52 (M, 2H), 2.70-2. 74 (M, 2H), 2.84 (M, 2H), 5.07- 5.16 (M, 2H), 5.82-5. 89 (M, 1H); 13C NMR (100 MHz, CDC13) 8 25.81, 28.55, 30.52, 116.85, 135.38, 168.27, 169.34. |
91% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 23h; | |
89% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; for 16h; | V Example V Pent-4-enoic acid 2,5-dioxo-pyrrolidin-1-yl ester To a solution of 5 g (49.9 mmol) pent-4-enoic acid 25 in 250 mL dichloromethane were added 6.32 g N-hydroxy-succinimide, 10.48 g mg (3-Dimethylamino-propyl)-ethylcarbodiimide hydrochloride and the mixture was stirred for 16 hours at 23°C. After addition of water and extraction with dichloro-methane the combined organic extracts were dried over sodium sulfate. After filtration and solvent evaporation the crude product was purified by chromatography on silica gel to give 8.8 g (89%) of the title compound 26 as an oil. 1H-NMR (CDCl3): δ = 5.89 (1H), 5.17 (1H), 5.12 (1H), 2.87 (4H), 2.75 (2H), 2.53 (2H) ppm. |
89% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; for 16h; | V To a solution of 5 g (49.9 mmol) pent-4-enoic acid 25 in 250 mL dichloromethane were added 6.32 g N-hydroxy-succinimide, 10.48 g mg (3-Dimethylamino-propyl)-ethylcarbodiimide hydrochloride and the mixture was stirred for 16 hours at 23°C. After addition of water and extraction with dichloro-methane the combined organic extracts were dried over sodium sulfate. After filtration and solvent evaporation the crude product was purified by chromatography on silica gel to give 8.8 g (89%) of the title compound 26 as an oil. 1H-NMR (CDCl3): δ = 5.89 (1H), 5.17 (1H), 5.12 (1H), 2.87 (4H), 2.75 (2H), 2.53 (2H) ppm. |
79% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; | |
77% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 20h; | |
73% | With diisopropyl-carbodiimide In dichloromethane at 20℃; Molecular sieve; Cooling with ice; | |
68% | With dicyclohexyl-carbodiimide In dichloromethane at 21℃; for 1.5h; | 1 Chemical synthesis of N-pentenoyl succinimide N-pentenoyl succinimide is synthesized essentially as described with minor modifications (Lodder, Golovine, Laikhter, Karginov, & Hecht, 1998; Lodder et al., 2005). Briefly, 5.0 mL pentenoic acid and 5.6 g N-hydroxysuccinimide are dissolved in 95 mL dichloromethane (CH2Cl2), to which 10.3 g of N,N'-dicyclohexylcarbodiimide is added. The reaction mixture is stirred at 21 °C for 90 min, filtered to remove N,N'-dicyclohexylurea, and concentrated under reduced pressure (~ 380 mBar) at 40 °C using a rotary evaporator. The concentrated oily mixture is then loaded onto a silica gel column and eluted isocratically with 7:3 hexane-ethyl acetate (v/v) using an Isolera One purification system. The fractions containing N-pentenoyl succinimide are pooled, dried under reduced pressure (100 mBar), dissolved in ethyl acetate, and crystallized by gradual addition of hexanes and mixing by manual shaking. The product (6.6 g, 68% yield) is verified by mass spectrometry and NMR. |
61% | With dicyclohexyl-carbodiimide In dichloromethane for 2h; | |
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran | ||
With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 2h; Inert atmosphere; | ||
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | ||
In water | 10 EXAMPLE 10 EXAMPLE 10 114 g (1.0 mole) of methyl 4-pentenoate and 189 g (10 moles) of water were refluxed together with 20 g of an acidic ion exchanger (DOWEX 50 Wx8, commercial product from Aldrich-Chemie, Steinheim), and the methanol formed was distilled off continuously. After 12 hours, the mixture was cooled, the ion exchanger was filtered off and the filtrate was distilled. 96 g (96% of theory) of pure 4-pentenoic acid of boiling point 55° C./2 mbar were obtained. | |
With water; lithium hydroxide In methanol at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzoic acid anhydride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Title compound not separated from byproducts.; | ||
With (R)-(+)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole; 2,2-dimethylpropanoic anhydride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; optical yield given as %ee; enantioselective reaction; | ||
With (R)-9-methyl-2-phenyl-9-hydro-2-imidazolino[1,2-a]benzimidazole; 2,2-dimethylpropanoic anhydride In diethyl ether at 20℃; for 12h; Resolution of racemate; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane | 2.a A. (a) 3-(3-Cyclopropyl-2-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone A solution of mixed anhydride was prepared by adding under a N2 atmosphere pivaloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min. Meanwhile, a second solution was prepared by adding dropwise under a N2 atmosphere a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone [12.9 g, 100 mmol, described by L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989)] in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78°, the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4 Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2 O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3*). The combined organic phases were dried (Na2 SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone]. The latter oil was dissolved in 175 mL of a 0.4M Et2 O solution of diazomethane. The resulting solution was cooled to 0°. Palladium(II) acetate (112 mg, 0.5 mmol) was added to the cooled solution. The solution bubbled vigorously. After the bubbling subsided, additional palladium(II) acetate (112 mg, 0.5 mmol) and the Et2 O solution of diazomethane (175 mL) were added and the ensuing bubbling was allowed to subside. The latter addition was repeated two more times. (The total amount of diazomethane solution added was 700 mL.) The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2, eluent: EtOAc-hexane, 1:4) followed by distillation (100° at 0.05 mm Hg) to give the desired N-(3-cyclopropyl-1-oxopropyl)-2-oxazolidinone derivative (20.0 g, 89%); 1 H NMR (CDCl3) δ4.41 (complex m,1H), 4.28 (d, J=9.1 Hz, 1H), 4.20 (dd, J=3.4 Hz,8.8 Hz, 1H), 3.05 (m,2H), 2.36 (m, 1H), 1.55 (q, J=7.3 Hz, 2H), 0.91 (d, J=7.2 Hz, 3H), 0.87 (d, J=7.1 Hz, 3H), 0.89 (m, 1H), 0.43 (m,2H), 0.08 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; n-butyllithium In tetrahydrofuran; diethyl ether; hexane | 5.a Preparation of N4 -(Cyclohexylmethyl)-N4 -(2-morpholino-2-oxoethyl)-N1 -[1(S)-(cyclohexylmethyl)-(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide (a) 3-(3-Cyclopropyl-1-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone A solution of mixed anhydride was prepared by adding, under N2, pivoloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min. Meanwhile, a second solution was prepared by adding dropwise under N2 a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone (12.9 g, 100 mmol) in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78°, the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4 Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2 O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3*). The combined organic phases were dried (Na2 SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone]. The latter oil was dissolved in 175 mL of a 0.4M Et2 O solution of diazomethane. The resulting solution was cooled to 0°. Palladium(II) acetate (112 mg, 0.5 mmol) was added to the cooled solution. The solution bubbled vigorously. After the bubbling subsided, additional palladium(II) acetate (112 mg, 0.5 mmol) and the Et2 O solution of diazomethane (175 mL) were added and the ensuing bubbling was allowed to subside. The latter addition was repeated two more times. (The total amount of diazomethane solution added was 700 mL.) The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residual oil was purified by chromatography (SiO2, eluent: EtOAc-hexane, 1:4) followed by distillation (100° at 0.05 mm Hg) to give the desired 3-(3-cyclopropyl-1-oxopropyl)-2-oxazolidinone derivative (20.0 g, 89%); 1 H NMR(CDCl3) δ4.41 (complex m,1H), 4.28 (d, J=9.1 Hz,1H), 4.20 (dd, J=3.4 Hz,8.8 Hz,1H), 3.05 (m,2H), 2.36 (m,1H), 1.55 (q, J=7.3 Hz,2H), 0.91 (d, J=7.2 Hz,3H), 0.87 (d, J=7.1 Hz,3H), 0.89 (m,1H), 0.43 (m,2H), 0.08 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | PREPARATION 77 N-Methoxy-N-methyl-4-pentenoic amide (Formula S-2) Refer to Chart S To a suspension of 4-pentenoic acid (Formula S-1) (2.00 g) and N,O-dimethylhydroxylamine hydrochloride (2.15 g) in dichloromethane (50 mL) at 0 C. is added diisopropylethylamine (11.5 mL) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.60 g). After stirring overnight, the reaction mixture is concentrated under reduced pressure. The residue is partioned between dilute aqueous potassium hydrogen sulfate and diethyl ether. The aqueous phase is extracted with two additional portions of diethyl ether. The organic extracts are combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel eluding with 50% to 80% diethyl ether in hexane to provide 2.58 g of the title compound as a tan oil. Physical characteristics are as follows: 1 H NMR delta2.3-2.6, 3.20, 3.70, 4.9-5.1, 5.75-5.95 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 40℃; for 72h; | 20 Example 20; 6-(Triisopropylsilyl)-hex-4-enoic-acid; A flame dried round-bottomed flask was charged with allyltriisopropylsilane (0.722 mL, 3 mmol, 3 eq), 4-pentenoic acid (0.102 mL, 1 mmol, 1 eq) and dichloromethane (3 nmL). Hoveyda-Grubbs' catalyst (5 mol %, 31 mg) was subsequently added as a solid and the reaction was heated to reflux (40° C.) and left to stir under an atmosphere of argon. After 3 days the reaction was concentrated under reduced pressure to give a dark brown oil. Column chromatography (100% hexane to remove remaining silane, then hexane:ether, 75:25) gave 6-(triisopropylsilyl)-hex-4-enoic acid as a colourless oil (258 mg, 95% yield). For major isomer E: 1H NMR (400 MHz, CDCl3) δ 1.04-1.06 (m, 21H, Si(i-Pr)3), 1.54-1.56 (d, 2H, CH2Si(i-Pr)3, J=8.0 Hz), 2.29-2.35 (m, 2H, HOOCCH2CH2), 2.37-2.42 (m, 2H, HOOCCH2), 5.28-5.35 (m, 1H, CH2CHCH), 5.52-5.60 (m, 1H, CH2CHCH); 13C NMR (100 MHz, CDCl3) δ 11.0 (Si(CH(CH3)2)3), 15.3 (CH2Si(i-Pr)3), 18.7 (Si(CH(CH3)2)3), 27.8 (HOOCCH2CH2), 34.3 (HOOCCH2CH2), 125.9 (CH2CHCH), 129.0 (CH2CHCH), 179.5 (HOOC). For minor isomer Z: 1H NMR (400 MHz, CDCl3) δ 1.04-1.06 (m, 21H, Si(i-Pr)3), 1.62-1.64 (d, 2H, CH2Si(i-Pr)3, J=8.0 Hz), 2.29-2.35 (m, 2H, HOOCCH2CH2), 2.37-2.42 (m, 2H, HOOCCC2), 5.38-5.50 (m, 1H, CH2CHCH), 5.63-5.75 (m, 1H, CH2CHCH); 13C NMR (100 MHz, CDCl3) δ 10.9 (CH2Si(i-Pr)3), 11.1 (Si(CH(CH3)2)3), 18.7 (Si(CH(CH3)2)3), 24.7 (HOOCCH2CH2), 30.9 (HOOCCH2CH2), 124.6 (CH2CHCH), 128.2 (CH2CHCH), 176.9 (HOOC); IR (v, cm-1) 2867 (COO-H), 1713 (HOCO), 660 (C-Si); HRMS required for C15H30O2Si [M-H]-: 269.1937, found 269.1937. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; dicyclohexyl-carbodiimide In 1,1-dichloroethane at 20℃; Inert atmosphere; Cooling with ice; | |
Stage #1: pent-4-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: 1.3-butanediol In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 20h; Inert atmosphere; Sealed tube; | C General procedure: Example C (3R,11R,E)-11-methyl-3-phenyl-1-oxa-4-azacyclododec-8-ene-5,12-dione (R)-N-(2-hydroxy-1-phenylethyl)pent-4-enamide: Using general procedure B for amide bond formation with DMF as solvent (R)-N-(2-hydroxy-1-phenylethyl)pent-4-enamide was prepared from (R)-2-amino-2-phenylethanol (4.5 g, 33 mmol) and pent-4-enoic acid (2.6 mL, 25 mmol). Product (5.3 g) was obtained as a colorless oil in 97% yield after column chromatography (MeOH/DCM gradient). LRMS (ESI+) (M+H): 220.14. |
77% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; Sealed tube; Cooling with ice; | AV (R)-N-(2-hydroxy-1-phenylethyl)pent-4-enamide 10878] To a flask containing the carboxylic acid (1 eq.) sealed under nitrogen was added THF, to give a concentration of 0.2 molar. The solution was cooled on ice and then the amino alcohol (1.1 eq.) and EDCI (1.2 eq.) were quickly added as solids. The mixture was stirred for 20 mm., then the ice bath was removed and the reaction was stirred at room temperature until complete (typically 4-6 h). It was then poured slowly onto water (five times the volume of THF used) in an Erlenmeyer flask, and stirred well for 2 h. If the producthad precipitated, it was filtered and dried, otherwise the product was diluted with an appropriate organic solvent (e.g. ethyl acetate) and washed twice with aqueous HC1, then aqueous sodium bicarbonate (if there was carboxylic acid remaining), then brine. The resulting solution was dried over magnesium sulfate, filtered, and concentrated (R)-N-(2-hydroxy-1-phenylethyl)pent-4-enamide: Using general procedure D for amide bond formation, the desired product was prepared from pent-4-enoic acid (1.037 g, 10.36 mmol) and (R)-2-amino-2-phenylethanol. The product (1.76 g, 77%) was obtained as a white solid after the crude oil obtained after work-up was concentrated with hexanes. LRMS (ESI+) (M+H): 220.11 |
64% | Stage #1: pent-4-enoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: D-2-phenylglycinol With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 16h; | 4 To a solution of 4-pentenoic acid (2.55 mL, 25.0 mmol) in DMF (312 mL) cooled in an ice/water bath was added HOBt (3.37 g, 25.0 mmol) and EDC (4.79 g, 25.0 mmol) and the resulting solution was stirred for 30 min. (i?)-(-)-2-phenylglycinol (3.43 g, 25.0 mmol), /Pr2NEt (17.8 mL, 100 mmol), and DMAP (0.305 g, 2.50 mmol) were subsequently added and the reaction mixture was stirred 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4CI and EtOAc and the layers separated. The aqueous layer was extracted 2x with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO^ filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOHZCH2Cl2 gradient) to yield 3.5 g of product as a colorless oil in 64% yield. LRMS (M + H)+: 220.1. |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dmap; N1,N2-Diisopropylformamidine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With (R)-(+)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole; nicotinic anhydride In dichloromethane at 0℃; for 12h; Resolution of racemate; optical yield given as %ee; enantioselective reaction; | |
43% | With (R)-(+)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole; nicotinic anhydride In dichloromethane at 0℃; for 12h; Inert atmosphere; Resolution of racemate; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [bis(acetoxy)iodo]benzene In acetonitrile at 20℃; for 2h; | |
71% | With ammonium iodide; 3-chloro-benzenecarboperoxoic acid In [(2)H6]acetone at 20℃; for 8h; | NH4I catalytic phosphoryloxylactonisation of alkenoic acids; typicalprocedure General procedure: To CH3CN (5 mL), pent-4-enoic acid (0.030 g, 0.3 mmol), diphenylphosphate (0.090 g, 0.36 mmol), mCPBA (75%, 0.138 g, 0.60 mmol)and NH4I (0.0043 g, 0.030 mmol) were added. The mixture wasstirred at room temperature for 8 h. Then H2O (5 mL), sat.aq Na2S2O3(2 mL) and sat. aq Na2CO3 (2 mL) were added. The mixture wasextracted with CH2Cl2 (3 × 5 mL) and the combined organic extractwas dried over anhydrous Na2SO4, filtered, and concentrated underreduced pressure. The residue was purified on silica gel plate using(3 : 2 hexane-ethyl acetate) as eluent to afford 5-(bis(phenyloxy)phosphoryl)oxy-4-pentanolactone in 71% yield. |
70% | With iodobenzene; 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47%Spectr. | With ammonium iodide; 3-chloro-benzenecarboperoxoic acid; In acetonitrile; at 20℃; for 8h; | General procedure: To CH3CN (5 mL), pent-4-enoic acid (0.030 g, 0.3 mmol), diphenylphosphate (0.090 g, 0.36 mmol), mCPBA (75%, 0.138 g, 0.60 mmol)and NH4I (0.0043 g, 0.030 mmol) were added. The mixture wasstirred at room temperature for 8 h. Then H2O (5 mL), sat.aq Na2S2O3(2 mL) and sat. aq Na2CO3 (2 mL) were added. The mixture wasextracted with CH2Cl2 (3 × 5 mL) and the combined organic extractwas dried over anhydrous Na2SO4, filtered, and concentrated underreduced pressure. The residue was purified on silica gel plate using(3 : 2 hexane-ethyl acetate) as eluent to afford 5-(bis(phenyloxy)phosphoryl)oxy-4-pentanolactone in 71% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | To a solution of pent-4-enoic acid (740 muL, 7.3 mmol) in DMF (4.5 mL) was added HOBt (990 mg, 7.3 mmol) and EDC (1.4 g, 7.3 mmol) and the resulting solution was stirred 30 min. (R)-2-amino-phenylethanol (500 mg, 3.64 mmol), iPr2NEt (1.3 mL, 7.3 mmol), and DMAP (89 mg, 0.73 mmol) were subsequently added and the reaction mixture was stirred 16 h. The reaction mixture was then diluted with EtOAc and sat. NH4Cl and the layers separated. The aqueous was extracted 2* with EtOAc and the combined organic extracts were washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/DCM gradient) to yield 160 mg of product as a white solid in 15% yield. LRMS (ESI+) (M+Na): 324.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: pent-4-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 1.3-butanediol In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; chemoselective reaction; | Compound S1: A solution of DCC (8.65 g, 42 mmol) and DMAP (1.21 g, 0.0098 mmol) in DCM (125mL) was cooled to 0 0C, to this solution 4-pentenoic acid (4.1 mL, 40 mmol) was added, after stirring itfor 0.5 h at 0 0C, then 1,3-butanediol (3.6 mL, 40 mmol) in DCM (10 mL) was added at sametemperature. The resulting suspension was allowed to stir at rt for 12 h. and filtered through ceilite,solvents were removed under reduced pressure. The resulting residue was purified by columnchromatography using 85: 15 Hex: EtOAc as an eluent to give S1 (6.14 g, 88%) as colorless oil. Rf 0.6(3:1 Hex: EtOAc); 1HNMR (400 MHz, CDCl3) δ 5.82-5.75 (m, 1H), 5.05-4.96 (m, 2H), 4.30-4.27 (q, J= 8.0 Hz, 1H), 4.14-4.08 (m, 1H), 3.89- 3.84 (m, 1H), 2.41-2.33 (m, 5H), 1.76-1.65 (m, 2H), 1.20 (d,J=8.0 Hz, 3H); 13CNMR (100 MHz, CDCl3) δ 173.6, 136.7, 115.7, 64.9, 61.8, 38.2, 33.7, 28.9, 23.6;TOF HRMS (DART) m/z calcd for C9H16O3 (M+H)+ 173.1099, found 173.1191. |
88% | Stage #1: pent-4-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 1.3-butanediol In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | A solution of DCC (8.65 g, 42 mmol) and DMAP (1.21 g, 0.0098 mmol) in DCM (125mL) was cooled to 0 °C, to this solution 4-pentenoic acid (4.1 mL, 40 mmol) was added, after stirring itfor 0.5 h at 0 °C, then 1,3-butanediol (3.6 mL, 40 mmol) in DCM (10 mL) was added at same temperature. The resulting suspension was allowed to stir at rt for 12 h. and filtered through ceilite, solvents were removed under reduced pressure. The resulting residue was purified by column chromatography using 85: 15 Hex: EtOAc as an eluent to give S1 (6.14 g, 88%) as colorless oil. |
84% | Stage #1: pent-4-enoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: 1.3-butanediol In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 23℃; for 19h; | To a solution of Hunig's Base (10.48 ml, 60.0 mmol) in DMF (22 mL) cooled in an ice-water bath was added pent-4-enoic acid (2.041 ml, 20.00 mmol), HOBT (3.06 g, 20.00 mmol), and EDC (4.22 g, 22.00 mmol) sequentially. The solution was stirred at 0 C for 5 minutes, and remains a light orange slurry throughout this time. <strong>[1081548-91-5](R,R)-pseudoephenamine</strong> (5g, 22.00 mmol) (freshly crushed) was added in one portion, and the vessel was allowed to warm to 23 C. After 5 minutes, some product was visible by TLC (10% MeOH/DCM, +1% NH40H). After 20 minutes, the solution was completely homogeneous. After 1 h, conversion was >50%. At 19 h, progress had not changed. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 75 mL). The organic layers were combined and the resulting light yellow solution was washed with water (2 x 100 mL), sat aq NaCl (1 x 75 mL), dried through a pad of sodium sulfate, and concentrated. The product was purified by flash chromatography (30% to 50% ethyl acetate to hexane) affording N-((lR,2R)-2-hydroxy-l,2- diphenylethyl)-N-methylpent-4-enamide (5.32g, 17.19 mmol, 86 % yield). |
86% | To a solution of Hunig's Base (10.48 ml, 60.0 mmol) in DMF (22 mL) cooled in an ice-water bath was added pent-4-enoic acid (2.041 ml, 20.00 mmol), HOBT (3.06 g, 20.00 mmol), and EDC (4.22 g, 22.00 mmol) sequentially. The solution was stirred at 0 C for 5 minutes, and remains a light orange slurry throughout this time. <strong>[1081548-91-5](R,R)-pseudoephenamine</strong> (5g, 22.00 mmol) (freshly crushed) was added in one portion, and the vessel was allowed to warm to 23 C. After 5 minutes, some product was visible by TLC (10% MeOH/DCM, +1% NH4OH). After 20 minutes, the solution was completely homogeneous. After 1 h, conversion was >50%. At 19 h, progress had not changed. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 75 mL). The organic layers were combined and the resulting light yellow solution was washed with water (2 x 100 mL), sat aq NaCl (1 x 75 mL), dried through a pad of sodium sulfate, and concentrated. The product was purified by flash chromatography (30% to 50% ethyl acetate to hexane) affording N-((1R,2R)-2-hydroxy-1,2- diphenylethyl)-N-methylpent-4-enamide (5.32g, 17.19 mmol, 86 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0) In neat (no solvent) at 20℃; | Initially, we carried out the reaction of 2,2-difluoro-2-iodo-1-phenylethanone 1a with 4-pentenoic acid 2a in the presence of Pd(PPh3)4 at room temperature under solvent-free condition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In 1,4-dioxane; at 160℃; for 1h;Microwave irradiation; Sealed tube; | General procedure: Phenyphosphinic acid (0.2 mmol), alkene (0.4 mmol) and dioxane (4 mL) were added into a 10 mL microwavevial containing a Teflon-coated stirrer bar and a septum. The vial was sealed and was heated under microwaveirradiation at 160 C for 1 hour. After cooling to room temperature the reaction mixture was purified by columnchromatography on silica gel using CH2Cl2-MeOH-CH3COOH: 9-0.5-0.5 as eluent to give the corresponding<strong>[1779-48-2]phenyl phosphinic acid</strong>s 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With ammonium iodide; 3-chloro-benzenecarboperoxoic acid In 2,2,2-trifluoroethanol at 20℃; for 5h; | Selenolactonization; General Procedure General procedure: Alkenoic acid 1 (0.4 mmol), diselenide 2 (0.24 mmol), NH4I (0.04mmol) and mCPBA (0.22 mmol) were added successively to a reaction vessel containing CF3CH2OH (1.5 mL). The resulting suspension was stirred vigorously at r.t. for 5 h. Upon completion, the reaction mixture was quenched by the addition of sat. aq Na2S2O3 (2 mL) solution, and made basic by the addition of sat. aq Na2CO3(8 mL) solution and then H2O (5 mL). The mixture was extracted with CH2Cl2(3 × 5 mL) and the combined organic phase dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel plate (PE-EtOAc, 2:1) to furnish the corresponding selenolactone 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonium iodide; 3-chloro-benzenecarboperoxoic acid; In 2,2,2-trifluoroethanol; at 20℃; for 5h; | General procedure: Alkenoic acid 1 (0.4 mmol), diselenide 2 (0.24 mmol), NH4I (0.04mmol) and mCPBA (0.22 mmol) were added successively to a reaction vessel containing CF3CH2OH (1.5 mL). The resulting suspension was stirred vigorously at r.t. for 5 h. Upon completion, the reaction mixture was quenched by the addition of sat. aq Na2S2O3 (2 mL) solution, and made basic by the addition of sat. aq Na2CO3(8 mL) solution and then H2O (5 mL). The mixture was extracted with CH2Cl2(3 × 5 mL) and the combined organic phase dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel plate (PE-EtOAc, 2:1) to furnish the corresponding selenolactone 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With Cyclohexanethiol; 10-phenyl-10H-phenothiazine; sodium formate In water; dimethyl sulfoxide at 23℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; Schlenk technique; | |
68% | With Cyclohexanethiol; sodium formate In water; dimethyl sulfoxide at 60℃; Irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In methanol at 25℃; for 48h; | Synthesis of peptidomimetics 1a-l by three-component Ugi reaction (General method). General procedure: The carboxylic acid (4.27 mmol) and the isocyanide (4.27 mmol) were added to a stirred solution of compound 2 (0.560 g, 4.27 mmol) in methanol (10 ml). The reaction mixture was stirred at room temperature for 2 days and concentrated in vacuo. A crude oil was obtained. After purification by silica gel column chromatography (eluent varied from n-hexane-EtOAc, 7:3, to pure EtOAc), the desired product was obtained as oil or foamy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In methanol at 25℃; for 48h; | Synthesis of peptidomimetics 1a-l by three-component Ugi reaction (General method). General procedure: The carboxylic acid (4.27 mmol) and the isocyanide (4.27 mmol) were added to a stirred solution of compound 2 (0.560 g, 4.27 mmol) in methanol (10 ml). The reaction mixture was stirred at room temperature for 2 days and concentrated in vacuo. A crude oil was obtained. After purification by silica gel column chromatography (eluent varied from n-hexane-EtOAc, 7:3, to pure EtOAc), the desired product was obtained as oil or foamy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In methanol at 25℃; for 48h; | Synthesis of peptidomimetics 1a-l by three-component Ugi reaction (General method). General procedure: The carboxylic acid (4.27 mmol) and the isocyanide (4.27 mmol) were added to a stirred solution of compound 2 (0.560 g, 4.27 mmol) in methanol (10 ml). The reaction mixture was stirred at room temperature for 2 days and concentrated in vacuo. A crude oil was obtained. After purification by silica gel column chromatography (eluent varied from n-hexane-EtOAc, 7:3, to pure EtOAc), the desired product was obtained as oil or foamy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper(I) thiophene-2-carboxylate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(5-methyl-2-(4-fluorophenyl)pyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N?,N?-tetramethyl-N?-tert-butylguanidine; bathophenanthroline; iodomesitylene diacetate; In 1,4-dioxane; at 20℃; for 1h;Inert atmosphere; Irradiation; | General procedure: To a 20 ml or 40 ml viale quipped with a stir bar was added photocatalyst, nitrogen nucleophile, iodomesitylene dicarboxylate, copper salt, and ligand. Dioxane was added followed by addition of the base. The solution was sonicated for 1-3 min until it became homogeneous. Next, the solution was degassed by sparging with nitrogen for 5-10 min before sealing with Parafilm. The reaction was stirred and irradiated using two 34-W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 h. The reaction mixture was removed from the light, cooled to ambient temperature, diluted with water (15 ml) and ethyl acetate (25 ml), and the aqueous layer was extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel to afford the desired decarboxylative C-N coupling product. For aniline substrates, a solution of these nitrogen nucleophiles in dioxane was used; additionally, if the iodomesitylene dicarboxylate is a liquid, its solution in dioxane was used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; dicyclohexyl-carbodiimide In dichloromethane; acetonitrile at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | General procedure: Under an inert atmosphere, CDI (1.0 equiv) was added to a solution of the corresponding carboxylic acid (1.0 equiv) in dry THF (1.0 M) (Caution CO 2 is released violently). Upon stirring at rt for 1 h, the corresponding aniline derivative (1.0 equiv) was added. The reaction was stirred at rt overnight. Then, it was taken to dryness under reduced pressure and purified using an automated system (silica gel, hexanes/EtOAc gradient), obtaining the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Pent-4-enoic acid (1, 2.04 mL, 20 mmol) was dissolved in a DCM (dichloromethane) solvent (66 mL) and oxalyl chloride (2.03 mL, 24 mmol) was then added dropwise thereto. Subsequently, DMF (dimethylformamide) (200 muL) was added thereto, and the reaction was carried out at 40 C. for 1 hr. The reaction solution was cooled to room temperature and the solvent was removed therefrom using an evaporator. Subsequently, the resulting product was diluted with DCM (66 mL) and was then added dropwise to a solution of (S)-4-phenyloxazolidin-2-one (2, 3590 mg, 22 mmol), DIPEA (diisopropylethylamine) (6968 muL, 40 mmol), and DMAP (dimethylaminopyridine) (122.17 mg, 1 mmol) dissolved in DCM (36.6 mL). The resulting reaction solution was stirred at room temperature for 2 hr. After completion of the reaction, the reaction was terminated with 0.5 M HCl (50 mL), followed by extraction with DCM (60 mL, 20 mL×3). The DCM layer was dried with anhydrous MgSO4 and then filtered. Further, column chromatography (ethyl acetate:hexane=1:2) was performed, thus yielding a desired compound (S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3, 4219 mg, 86%). (S)-3-(pent-4-enoyl)-4-phenyloxazolidin-2-one (3) 4219 mg, 86%, White solid; Rf=0.5 (ethyl acetate:hexane=1:2); 1H NMR (400 MHz, CDCl3) delta 7.41-7.29 (m, 5H), 5.85-5.75 (m, 1H), 5.43 (dd, J=8.7 Hz, 3.6 Hz, 1H), 5.06-4.95 (m, 2H), 4.69 (t, J=8.8 Hz, 1H), 4.29 (dd, J=8.9 Hz, 3.64 Hz, 1H), 3.07-3.03 (m, 2H), 2.39-2.34 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) delta 172.2, 153.9, 139.2, 136.7, 129.3, 128.9, 126.1, 115.8, 70.2, 57.7, 35.0, 28.2; IR (KBr) 3069, 2979, 1780, 1706, 1385, 1326, 1200, 1060 cm-1; HRMS (EI) m/z: [M]+ Calcd for C14H15NO3 245.1052; Found 245.1051. | |
With dmap; pivaloyl chloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 30℃; | 4-Pentenoic acid (compound X), 4-dimethylammoniumpyridine (DMAP) was added to a mixture of methylene dichloride and DMF at about 20C to about 30C and the reaction mass was cooled to about 15C to about 20C. Triethylamine and (S)-(+)-4-Phenyl-2-oxazolidinone (compound GammaChi') was added to the reaction mass and the reaction mass was stirred for about 5-10 minutes. The reaction mass was then cooled to about 0C to about 5C. A solution of pivaloyl chloride in methylene dichloride was added to the reaction mass. The temperature of reaction mass was then raised to about 25C to about 30C and stirred for about 10-15 hours. After completion of reaction, the reaction mass was quenched in dilute sulfuric acid at about 0C to about 5C. The temperature of the reaction mass was raised to about 20C to about 30C and layers were separated. The aqueous layer was extracted with methylene dichloride. After washing with 5% potassium carbonate solution followed by brine, the organic layer was distilled off completely under reduced pressure to obtain oily residue. To this oily mass, cyclohexane was added at about 50C to about 55C and the reaction mass was cooled gradually to about 20C to about 30C and stirred for 2 hours, the reaction mass was filtered, the residue obtained was dried to get (4S)-3-(pent-4-enoyl)- 4-phenyl-l,3-oxazolidin-2-one (compound Vffl') as off-white to pale yellow solid. HPLC Purity more than 98.0%. |
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Code | Phrase |
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Code | Phrase |
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
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P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
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Code | Phrase |
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P306 | IF ON CLOTHING: |
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P322 | |
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P372 | Explosion risk in case of fire. |
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P378 | |
P380 | Evacuate area. |
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P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
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P370 + P376 | In case of fire: Stop leak if safe to Do so. |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
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Disposal | |
Code | Phrase |
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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 |
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H221 | Flammable gas |
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H228 | Flammable solid |
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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 |
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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 |
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H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
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H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
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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 |
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H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
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H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
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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 |
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