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Ethyl 2-(diethoxyphosphoryl)acetate is reactant involved in Horner-Wadsworth-Emmons reactions and intramolecular Heck-type cyclization and isomerizations etc.
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CAS No. : | 867-13-0 |
Formula : | C8H17O5P |
M.W : | 224.19 |
SMILES Code : | O=C(OCC)CP(OCC)(OCC)=O |
MDL No. : | MFCD00009177 |
InChI Key : | GGUBFICZYGKNTD-UHFFFAOYSA-N |
Pubchem ID : | 13345 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H315-H318-H335-H411 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501 |
Class: | 9 |
UN#: | 3082 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
79% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Inert atmosphere Stage #2: at 0 - 10℃; for 2.5 h; Inert atmosphere |
To a slurry of NaH (8.0 g, 60percent in oil) in THF (150mL), was added triethyl phosphonoacetate (44.8 g)in 25 mL of THF dropwise at 0-10 oC over 40 min. The reactionmixture was stirred at 0-10 oC for another 0.5 h. Then cyclobutanone(5, 14.0 g) in 25 mL of THF was added dropwise at 0-10 oCover 30 min. The reaction mixture was stirred at 0-10 oC for 2 h. Atotal of 50 mL of water was then added slowly at 20-30 oC. Theorganic solvent was removed under reduced pressure followed by addition of 150mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL). Thecombined organic phase was washed with water (100 mL). It was then dried overanhydrous MgSO4. Filtration followed by evaporation gave the crudeproduct, which was purified by fractional distillation at 81-82 oC/19mbar to give 22.2 g (79percent yield) of Compound 9 as a colorless liquid. 1HNMR (500 MHz,CDCl3) δ 5.58 (m, 1H), 4.13(q, 2H, J = 7.1 Hz), 3.15-3.12 (m, 2H),2.85-2.82 (m, 2H),2.12-2.06 (m, 2H),1.26 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 167.60, 166.60, 112.38, 59.53, 33.75, 32.32, 17.66, 14.36; MS (m/z)140.1; ESI-HRMS m/zcalcd for C8H12O2 [M + H]+ 141.0910, found 141.0911. |
79% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Stage #2: at 0 - 10℃; for 2.5 h; |
To a slurry of NaH (8.0 g, 60 in oil) in THF (150 mL) , was added triethyl phosphonoactate (44.8 g) in 25mL of THF dropwise at 0-10 over 40 min. The reaction mixture was stirred at 0-10 for another 0.5 h. Then cyclobutanone (14.0 g) in 25 mL of THF was added dropwise at 0-10 over 30 min. The reaction mixture was stirred at 0-10 for 2 h. A total of 50 mL of water was then added slowly at 20-30 . The organic solvent was removed under reduced pressure followed by addition of 150 mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL) . The combined organic phase was washed with water (100 mL) . It was then dried over anhydrous MgSO4. Filtration followed by evaporation gave the crude product, which was purified by fractional distillation at 81-82 /19 mbar to give 22.2 g (79 yield, 99 purity) of Compound 12 as a colorless liquid.1HNMR(400 MHz, CDCl3) δ 5.56 (m, 1H) , 4.13 (q, 2H, J 7.2 Hz) , 3.12 (m, 2H) , 2.81 (m, 2H) , 2.08 (m, 2H) , 1.25 (t, 3H, J 7.2 Hz) 13CNMR(100 MHz, DMSO-d6) δ167.2, 165.3, 111.8, 58.9, 33.3, 31.8, 17.1, 14.0 MS (m/z) 140.1. |
75% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h; Stage #2: at 20℃; for 4 h; |
(0203) Triethyl phosphonoacetate (3.32 g, 1.0 equiv) was dissolved in abs. tetrahydrofuran and added to a suspension, cooled down to 0° C., of sodium hydride (0.58 g, 1.02 equiv, 60percent dispersion) in abs. tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at a temperature of 0° C. for 10 minutes and then admixed with a solution of cyclobutanone (1.0 g, 1.0 equiv) in abs. tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for a further 4 h. After the cautious addition of water, the reaction mixture was concentrated under reduced pressure and admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl cyclobutylideneacetate (1.5 g, 75percent of theory) was isolated. Ethyl cyclobutylideneacetate (1.0 g, 1.0 equiv) was dissolved in methanol and admixed with a 1 M solution of KOH in aq. methanol. The resulting reaction mixture was stirred at room temperature for 16 h, then neutralized with dil. HCl, admixed with water, concentrated under reduced pressure and then admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), cyclobutylideneacetic acid (0.40 g, 51percent of theory) was isolated. Aniline (0.26 g, 1 equiv.) was dissolved in dichloromethane (5 mL) and cooled down to a temperature of 0° C., and diisopropylethylamine (1.98 mL, 4.0 equiv.), cyclopentylideneacetic acid (0.30 g, 1.0 equiv.) and N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (0.97 g, 1.1 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 3 h, and water and dichloromethane were then added. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 2-cyclobutylidene-N-phenylacetamide (0.27 g, 54percent of theory) was isolated. In the next step, aluminum trichloride (0.42 g, 3.0 equiv.) was initially charged in abs. dichloroethane (5 mL) under argon in a baked-out round-bottom flask and then, while cooling with ice, a solution of 2-cyclobutylidene-N-phenylacetamide (0.20 g, 1.0 equiv.) in abs. dichloroethane (5 mL) was added. The resulting reaction mixture was stirred at room temperature for a further 4 h and then added cautiously to ice-water. After adding aqueous HCl and dichloromethane, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated cautiously under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one was isolated as a colorless solid. 1′H-Spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (0.2 g, 1 equiv.) was added to conc. acetic acid (1.5 mL) and then cautiously admixed at 0° C. with fuming nitric acid (0.5 mL). The resulting reaction mixture was then stirred at 90° C. for 2 h and, after cooling to room temperature, cautiously diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 78percent of theory) was isolated as a colorless solid. 6′-Nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved under argon in abs. dioxane (2 mL) and admixed with fine cesium carbonate powder (400 mg, 3.0 equiv.). After stirring at room temperature for 5 min, cyclobutylmethyl bromide (110 mg, 2.0 equiv.) and potassium iodide (35 mg, 0.1 equiv.) were added at room temperature. The resulting reaction mixture was stirred at 150° C. under microwave conditions for 1 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (70 mg, 60percent of theory) was isolated as a colorless solid. In the next step, 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (50 g, 1 equiv.) was added together with zinc dust (55 mg, 5 equiv.) and ammonium chloride (90 mg, 10 equiv.) to methanol/water (5:1) and the mixture was stirred under argon at a temperature of 70° C. for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water and then adjusted to pH 12 with 6 N NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (35 mg, 70percent of theory) was isolated as a colorless solid. 6′-Amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved together with 4-methylphenylsulfonyl chloride (81 mg, 1.1 equiv) in abs. dichloromethane (5 mL) in a baked-out round-bottom flask under argon, then pyridine (0.15 mL, 5 equiv.) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HCl and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 4-methyl-N-[1′-(cyclopropylmethyl)-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutyl-1,4′-quinolin]-6′-yl]phenylsulfonamide (70 mg, 43percent of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 10.05 (s, 1H, NH), 7.62 (d, 2H), 7.36 (d, 2H), 7.12 (m, 2H), 6.96 (m, 1H), 3.76 (m, 2H), 2.61 (s, 2H), 2.33 (s, 3H), 2.03-1.92 (m, 5H), 1.79 (m, 1H), 0.97 (m, 1H), 0.36 (m, 2H), 0.22 (m, 2H). |
16% | Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333 h; Stage #2: at 27℃; for 2 h; |
To a stirred suspension of 60percent NaH (1.23 g, 51.35 mmol) in THF (50 mL), ethyl 2-(diethoxyphosphoryl)acetate (6.23 mL, 31.38 mmol) in 10 mL THF was added at 0°C and stirred for 5 mm at same temperature. Then cyclobutanone 75 (2 g, 28.53 mmol) in THF (10 mL) was added to it and allowed to stir at room temperature for 2h. Then the reaction mixture was quenched with cold water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain ethyl 2-cyclobutylideneacetate 76 as colorless liquid (0.65 g, 16percent yield). 1HNMR (400 MHz, CDC13): ö 5.57 (s, 1H), 4.13 (q, 2H), 3.12 (t, 2H), 2.82 (t, 2H), 2.12-2.04 (m, 2H), 1.26 (t, 3H). |
96% | With NaH In tetrahydrofuran | Synthesis of Cyclobutylidene-acetic acid ethyl ester (2) NaH (60percent dispersion in oil, 1.80 g, 44.94 mmol) was suspended in dry tetrahydrofuran (80 mL) and cooled to 0° C. Triethylphosphonoacetate (9.33 mL, 47.08 mmol) was added and the mixture stirred at 0° C. for 15 minutes. Cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was then added and the mixture allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 mL) and water (150 mL). The organic phase was separated, washed with brine, dried (MgSO4), and the solvent removed in vacuo at 600 mm Hg. The residue was purified by flash chromatography (silica, ethyl acetate:pentane 1:19) to give 5.81 g (96percent) of (2) as a colorless oil. 1H NMR, 400 MHz (CDCl3): δ1.27 (3H, t, J=6 Hz), 2.09 (2H, m), 2.82 (2H, m,) 3.15 (2H, m), 4.14 (2H, q, J=6 Hz), 5.58 (1H, s). MS (ES+) m/e: 141 ([MH+], 100percent). IR (film) ν cm-1: 1088, 1189, 1336, 1673, 1716, 2926. |
80% | With ammonium chloride; sodium hexamethyldisilazane In tetrahydrofuran | Step A Ethyl 3,3-trimethylene acrylate A solution of triethylphosphonoacetate (17 mL, 85.6 mmol), in 150 mL dry THF was cooled to -78° C. A solution of sodium hexamethyldisilazide (86 mL, 1.0M in THF, 86 mmol) was added. The mixture was warmed to 0 C for 30 min and cyclobutanone (5 grams, 71.3 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Sat'd ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic was dried over sodium sulfate and concentrated. Flash chromatography (30/1 hexane/ether) afforded 8.0 grams (80percent) of the desired compound. 1H NMR (300 MHz, CDCl3). δ1.25 (t, 3H), 2.0-2.2 (p, 2H), 2.8-2.9 (t, 2H), 3.1-3.2 (t, 2H), 4.1-4.2 (q, 2H), 5.58 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; ice-water; mineral oil; | EXAMPLE 1 Preparation of N-acetyl-4-piperidineacetaldehyde A 55 percent dispersion of sodium hydride in mineral oil containing 3.24 g. of a 55percent dispersion of sodium hydride in mineral oil was washed with three 50 ml portions of dry pentane and then the sodium hydride was suspended in 100 ml of anhydrous 1,2-dimethoxyethane (to be referred to hereinafter as DME). 16.58 g. of triethylphosphonoacetate in 50 ml of anhydrous DME were added to the sodium hydride suspension under a nitrogen atmosphere slowly with stirring and cooling to about 0° C. After the addition had been completed, the ice bath was removed and the mixture stirred for an additional hour at ambient temperature. The ice bath was then replaced and a solution of 10 g. of N-benzoyl-4-piperidone in 25 ml of anhydrous DME was added in dropwise fashion with stirring. After this addition had been completed, the ice bath was again removed and stirring continued for about three hours. Excess solvents were removed in vacuo from the reaction mixture. About 100 ml of an ice-water mixture were added. The resulting aqueous mixture was extracted with three 100 ml portions of ether, and the ether extracts separated, combined and dried. Removal of the ether therefrom in vacuo yielded a residue comprising N-benzoyl-4-(carbethoxymethylene) piperidine formed in the above reaction. Recrystallization of the residue from hexane yielded about 11.7 g. of colorless prisms of N-benzoyl-4-(carbethoxymethylene) piperidine melting at about 102°-103° C. N-benzoyl-4-(carbethoxymethylene) piperidine thus prepared had the following physical characteristics. Boiling point = 178°-180° C. at 0.03 mm Hg. nmr (CDCL3): delta1.28 (5, 3), 2.38 (broad m, 2), 3.05 (broad m, 2), 3.67 (broad m, 4), 4.18 (q, 2), 5.78 (broad s, 1), 7.41 (s,5). ir (KBr): 1715, 1660, 1620 cm-1. Anal: Calcd. for C16 H19 NO3: C, 70.31; H, 7.01; N, 5.13. Found: C, 70.42; H, 7.10; N, 5.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h; | To a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (1 eq) and TRIETHYLPHOSPHONOACETATE (1.1 eq) in THF (0.3M) at rt was added dropwise potassium t-butoxide (1.1 eq, 1M, THF). The mixture was stirred at rt 3h, quenched with HCl 10%, diluted with ether, washed with a NAHC03 solution, brine, dried over MGS04, filtered and concentrated. Flash chromatography (Hexane : EtOAc; 90: 10 to 70: 30) afforded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In tetrahydrofuran; water; | Preparation 57 Ethyl 3-(3-nitrophenyl)-2-pentenoate To a solution of sodium hydride (60% dispersion in oil, 40 g, 1.0 mol) in tetrahydrofuran (2 l) stirred at -10 C. under nitrogen was added triethylphosphonoacetate (224 g, 1.0 mol) dropwise over 30 min. To the mixture was added <strong>[17408-16-1]3-nitropropiophenone</strong> (180 g, 1 mol) at such a rate that the temperature was maintained below 10 C. The mixture was allowed to warm to room temperature and was stirred for 18 h. Water (1.5 l) was added, and the mixture was extracted with diethyl ether (2*1 l). The combined extracts were washed with water (1 l), dried (MgSO4), filtered and concentrated in vacuo and the residue was purified by silica column (4*2 kg) chromatography eluding with hexane:diethyl ether (12:1). Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (105 g, 42%). NMR (CDCl3): 1.1 (t, 3H), 1.35 (t, 3H), 3.15 (q, 2H), 4.2 (q, 2H), 6.05 (s, 1H), 7.55 (t, 1H), 7.75 (d, 1H), 8.2 (d, 1H), 8.3 (s, 1H). MS (thermospray): M/Z [MH+] 250.0; C13H15NO4+H requires 250.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In tetrahydrofuran; water; | Preparation 13 Ethyl (E)-3-(3-nitrophenyl)-2-pentenoate To a solution of sodium hydride (60% dispersion in oil, 40 g, 1.0 mol) in tetrahydrofuran (2 l) stirred at -10 C. under nitrogen was added dropwise over 30 minutes triethylphosphonoacetate (224 g, 1.0 mol). <strong>[17408-16-1]3-Nitropropiophenone</strong> (180 g, 1 mol) was added portionwise such that the temperature was maintained below 10 C. The mixture was allowed to warm to room temperature and was stirred for 18 h. Water (1.5 l) was added, and the mixture was extracted with diethyl ether (2*1 l). The combined extracts were washed with water (1 l), dried (MgSO4), filtered and concentrated in vacuo and the residue was purified by silica column (4*2 kg) chromatography eluding with 12:1 hexane/diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (105 g, 42%). NMR (CDCl3) delta: 1.08 (t, 3H), 1.33 (t, 3H), 3.13 (q, 2H), 4.22 (q, 2H),6.05 (s, 1H), 7.56 (t, 1H), 7.76 (d, 1H), 8.21 (d, 1H), 8.30 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH; In tetrahydrofuran; water; | Reference Example 1 To a suspension of 60% NaH (33.8 g) in tetrahydrofuran (2 liters) is added dropwise triethylphosphonoacetate (189 ml) under ice-cooling, and the mixture is stirred at room temperature for 1.5 hour. To the mixture is added 1-(p-toluenesulfonyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (150 g) in portions at room temperature, and the mixture is stirred at 50 C. for 8 hours. To the reaction solution is added water, and the mixture is extracted three time with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystals are collected by filtration, washed with n-hexane, and dried to give 1-(p-toluenesulfonyl)-5-ethoxycarbonylmethylidene-2,3,4,5-tetrahydro-1H-benzazepine (170.4 g). White powder 1 H-NMR (CDCl3, 200 MHz) delta ppm: 1.09, 1.31 (3H, each t, each J=7.1 Hz), 1.44-1.90 (2H, m), 2.15-2.50 (1H, m), 2.36, 2.37 (3H, each s), 2.57-2.89 (1H, m), 3.65-4.03 (2H, m), 3.97, 4.14 (2H, each q, each J=7.1 Hz), 5.29, 5.62 (1H, each s), 6.98-7.76 (8H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In tetrahydrofuran; mineral oil; | D.1 Ethyl-3-(5,6-dihydro-2H-pyran-3-yl)acrylate To a stirred suspension of sodium hydride (60% in mineral oil; 1.43 g, 35.7 mmoles) in 50 ml tetrahydrofuran, at room temperature, was added dropwise triethyl phosphonoacetate (8.35 g, 37.2 mmoles) under a nitrogen atmosphere. The reaction mixture was stirred for 15 minutes. To this was added dropwise a solution of 3.34 g (29.8 mmoles) of <strong>[13417-49-7]3-formyl-5,6-dihydro-2H-pyran</strong>e (Japan Kokai 59-167,584 to BASF) in 20 ml tetrahydrofuran. The resulting mixture was stirred for 1 hour. The reaction was quenched by adding acetic acid. Then, the reaction mixture was concentrated and an aqueous sodium bicarbonate solution was added. The organic substance was extracted with ethyl acetate The extract was washed with brine, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified by column chromatography on silica gel eluted with 25% ethyl acetate-hexane to yield 3.1 g of the title compound. The NMR spectrum showed absorption at 1.26-1.38 (m, 3H), 2.34 (br., 2H), 3.8 (t, 2H, J=5 Hz), 4.15-4.30 (m, 4H), 5.63 (d, 1H, J=17 Hz), 6.28 (br., 1H) and 7.21 (d, 1H, J=17 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | To a solution of a 60% dispersion of NaH in mineral oil (0.31 g, 7.75 mmol) in DME (2 mL) at - 30 C was added a solution of ethyl 2-phosphonoacetate (1.46 mL, 7.29 mmol) in DME (13 mL), and the mixture was stirred at this temperature for 30 min. To this solution was added a solution of <strong>[372120-55-3]3-bromo-4-(trifluoromethyl)benzaldehyde</strong> (44) (1.68 g, 6.63 mmol) in DME (3 mL), and the reaction was stirred at -30 C for 1.5 h and then poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated NH4C1 solution and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product that was purified by column chromatography (150 mL Si02, ethyl acetate :hexanes 5:95) to give 45 (2.1 188 g, 98%) as a colorless crystalline solid: 1H NMR (400 MHz, CDC13) ? 7.84 (s, 1H), 7.69 (d, J= 8.0, 1H), 7.59 (d, J= 16.0, 1H), 7.52 (d, J= 8.0, 1H), 6.50, (d, J= 16.0, 1H), 4.27 (q, J= 7.2, 2H), 1.34 (t, J= 7.2, 3H); 13C NMR (100.6 MHz, CDC13) ? 165.9, 141.0, 139.2, 133.8, 131.4, 130.7, 130.4, 128.3, 128.2, 128.1, 128.1, 126.4, 123.9, 122.2, 121.2, 120.6, 120.5, 60.9, 14.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: Preparation 36Eth yl (2Z)-d i h yd rof u ra n -3(2/-/)- yl id e n eacetateMETHOD HSodium hydride (60percent dispersion in oil, 0.65 g, 16.3 mmol) was cooled to 0°C under nitrogen before adding anhydrous THF (20 mL). Triethyl phosphonoacetate (3 mL, 15.1 mmol) was added slowly over 40 minutes to control gas evolution. A solution of 3-oxo- tetrahydrofuran (1 g, 11 .62 mmol) in anhydrous THF (2 mL) was added and the reaction gradually warmed to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (3 x 50 mL) and water (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50percent ethyl acetate in heptane gradient elution) to afford the title compound as an oil (1 .29 g, 71 percent yield).1HNMR (CDCI3): ? 1 .3 (m, 3H), 2.7 (m, 1 H), 3.05 (m, 0.7H), 3.2 (m, 0.3H), 3.9 (t, 1 H), 3.95 (t, 0.7H), 4.15 (m, 2H), 4.4 (m, 0.7H), 4.6-4.7 (m, 0.6H), 4.75 (m, 1 H), 5.7-5.85 (m, 1 H).LCMS ( 2 min) Rt = 1 .23 min MS m/z 157 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200 g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about 50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of 9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2- methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about 0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about 0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4- (dimethylamino)crotonate as an oily mass. Yield: 89percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 1: Synthesis of (E)-ethyl 3-(4-bromo-3-methoxyphenyl)acrylate (6*)NaH (60percent in mineral oil, 85mg, 21.3mmol) was suspended in THE at 0 00 andtriethylphosphonoacetate (4.38 g, 19.6mmol) was added. The mixture was stirred for30mm, then <strong>[43192-34-3]4-bromo-3-methoxybenzaldehyde</strong> (3.9g, 18.lmmol) in THE was added. The reaction was stirred for lh, quenched with a sat. aq. NH4OI solution and extracted with TBME. The combined organic phases were dried on Mg504, filtered, and evaporated in vacuo to yield desired product 6* as a white solid (5.16g, 100percent)which was used in the following step without further purification. MS (ES) C12H13BrO3 requires: 284/286, (M-f-H) not found. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.5% | 4-Propylbenzaldehyde(si) (10.0 g), ethyl diethylphosphonoacetate (18.2g) and toluene (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Sodium ethoxide in ethanol solution(20percent; 27.6 g) was added at the same temperature, and the stirring was continued for another 2 hours. After the reaction mixture had been returned to 25° C, thestirring was continued for another 2hours. The reaction mixture was treated with water, and the aqueous layer wasextracted with toluene. The combined organic layers were washed with water, andthen dried over anhydrous magnesium sulfate. The solution was concentratedunder reduced pressure, and the residue was purified by col- 50 umn chromatography with a mixed solvent of toluene and heptane(toluene:heptane=2:l by volume) as an eluent and silica gel as a stationaryphase powder. The purified product was dissolved in 2-propanol (150 ml), towhich Pd/C (0.91 g) was added. The mixture was stirred at room temperature 55 under a hydrogen atmosphere until hydrogen absorption had ceased. Afterthe reaction had been completed, Pd/C was removed, and then solvent wasdistilled off. The residue was purified by column chromatography with tolueneas an eluent and silica gel as a stationary phase powder to give ethyl 60 3-(4-propylphenyl) propionate (s2) (14.2 g). The yield based on thecompound (si) was 95.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In toluene; at 20℃;Darkness; | General procedure: Compound 1a-9a (1.0mmol) was dissolved in toluene (70mL) in a flask which was wrapped with tin foil, sodium hydride (1.5mmol) and triethyl phosphonoacetate (1.0mmol) was added respectively. Then the reaction solution was stirred at room temperature under dark until TLC analysis showed complete conversion. Extracted with EtOAc, the combined organic phase was washed with saturated brine (50mL×3), and dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography (PE/EA=8: 1) to give a pale yellow solid (1b-9b). The synthetic routes are similar to PL [7,12]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium ethanolate; In ethanol; toluene; at 0 - 20℃; for 6h; | The compound (T-69) (20.0 g), phosphonoethyl acetate (22.5 g) and toluene (300 ml) were placed in a reactor and cooled to 0 ° C.Sodium ethoxide (20percent ethanol solution) (34.2 g) was slowly added thereto, returned to room temperature and stirred for 6 hours.After the insolubles were removed, the reaction mixture was poured into water and the aqueous layer was extracted with toluene.The organic layer formed simultaneously with water washing was dried over anhydrous magnesium sulfate.The solution was concentrated under reduced pressure and the residue was purified with silica gel chromatography using toluene to obtain compound (T-70) (23.3 g; 90percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Tetrahydrofuran (100 mL) was cooled to 0 ° C under nitrogen, and sodium hydride (1.95 g, 48.8 mmol, 60 mass percent) was added portionwise.Subsequently, triethyl phosphonoacetate (10.9 g, 48.6 mmol) was added.After the obtained reaction mixture was stirred at this temperature for 20 minutes, a solution of <strong>[31191-08-9]5-hydroxypyridine-2-carbaldehyde</strong> 30a (2.00 g, 16.2 mmol) in tetrahydrofuran (10 mL) was added dropwise.After adding water (100 mL), the mixture was quenched with hydrochloric acid (1 mol/L), and the organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 mL×4).The combined organic layers were dried over anhydrous sodium[ethyl acetate / petroleum ether (v / v) = 1 / 1] purified to give the title compound30b (2.66 g, 85percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.11% | To a suspension of sodium hydride (60percent in mineral oil, 0.44 g, 10.9 mmol, 1.2 eq) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (2.44 g, 10.9 mmol, 1.2 eq) dropwise at 0°C and the mixture was allowed to stir at the same temperature for 30 minutes. To this mixture was added a solution of <strong>[27258-32-8]1-methyl-1H-pyrazole-3-carbaldehyde</strong> (1.0 g, 9.09 mmol,1.0 eq) in THF (5 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with saturated aq. NH4C1 (100 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness under vacuum to afford crude which was purified by Combi-Flash on silica gel using ethyl acetate15 hexane system as eluent to afford ethyl (2E)-3-(1-methyl-1H-indol-3-yl)prop-2-enoate (0.70 g,61.11percent).LCMS: 181 [M+1] |
Tags: Triethyl Phosphonoacetate | C-C Bond Formation | Phosphoruses | Organic Building Blocks | Synthetic Reagents | 867-13-0
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