* 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.
With potassium carbonate In water at 20℃; for 2 h;
Example 106: methyl 2-(hydroxymethyl)acrylate44percentA saturated aqueous solution (10 mL) of K2CO3 (3.5 g, 117 mmol, 1.6 eq.) was slowly added to a rapidly stirred solution of trimethylphosphonoacetate (5.46 g, 30 mmol, 1.0 eq.) and paraformaldehyde (6.63 g, 48 mmol, 4.0 eq.) at r.t.. After the addition the mixture was stirred for 2 h. Then the mixture was extracted with DCM. The organic layer was concentrated to give the compound (1.5 g, 44percent) as a yellow oil. 1U NMR (400 MHz, CD3OD) δ: 6.29 (s, IH), 5.83 (s, IH), 3.75 (s, 3H), 3.72 (s, 2H).
Reference:
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 6, p. 1929 - 1932[2] Angew. Chem., 2015, vol. 127, # 6, p. 1949 - 1952,4
[3] Tetrahedron, 2008, vol. 64, # 17, p. 3701 - 3712
[4] Patent: WO2011/17561, 2011, A1, . Location in patent: Page/Page column 72
[5] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3539 - 3545
2
[ 50-00-0 ]
[ 5927-18-4 ]
[ 15484-46-5 ]
[ 292638-85-8 ]
Yield
Reaction Conditions
Operation in experiment
56%
With potassium carbonate In water at 23℃;
Acrylate 20. Synthesized by a method adapted from Villieras and Rambaud.2 To around-bottom flask equipped with a stir bar were added trimethyl phosphonoacetate (S1,9.1 mL, 63 mmol, 1.00 equiv) and formaldehyde (S2, 20.5g, 37percent in water, 252 mmol,4.00 equiv). The flask was lowered into a ambient-temperature water bath. To themixture was added a saturated solution of potassium carbonate in water (15.3 g, 110mmol, 1.75 equiv) dropwise via addition funnel over the course of one hour, and stirringwas continued for an additional hour. The reaction mixture was quenched by addition ofsaturated aqueous ammonium chloride (30 mL), then extracted three times with diethylether. The combined organics were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. Methyl acrylate, produced as a side-product,was removed by azeotropic distillation with methanol. The residue was purified byvacuum distillation (~0.5 torr, 44 °C) to afford acrylate 20 as a clear oil (4.07 g, 56percentyield) with minor impurities which were carried forward to the next reaction. Thecharacterization data matched those reported in the literature.3
Stage 2 - Preparation of {4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}acetic acid; To stage 1 product (1.03g, 6.3mmol) in water (10OmL) were added K2CO3 (2.61g, 18.9mmol) then trimethylphosphonoacetate (1.23mL, 7.6mmol) at O0C. Addition was carried out over 10 minutes to avoid the reaction temperature rising above 15C. The reaction mixture was then stirred at RT for 72h. A solution of 1 M HCI was added until pH - 1. The white precipitate was isolated by filtration, washed with water (10OmL), concentrated and dried on the freeze drier to afford the desired product as a white solid (784 mg, 57%). 1H NMR (300MHz, Cf6-DMSO) delta: 12.46 (1 H, br s), 7.69-7.63 (2H, m), 7.31 (2H, d, J=8.1 Hz), 6.74 (1 H, d, J=16.0Hz), 6.63 (1 H, d, J=16.0Hz), 3.72 (3H, s), 3.62 (2H, s).
6-chloro-3,4-dihydro-2H-1-benzopyran-4-ylidene-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
EXAMPLE 17 In a flame dried flask under nitrogen equipped with a mechanical stirrer, trimethyl phosphonoacetate (10.9 g.) was added dropwise to a slurry of 50% sodium hydride (2.9 g.) in 300 ml. freshly dried tetrahydrofuran and stirred at room temperature for 1 hour. A solution of <strong>[37674-72-9]6-chloro-3,4-dihydro-2H-1-benzopyran-4-one</strong> (10 g.) in 100 ml. of freshly dried tetrahydrofuran was added dropwise, keeping the temperature below 30 C. during the addition. The solution was then heated at reflux for 5 hours and stirred at room temperature for 12 hours. The solution was poured into ice-water, extracted with diethyl ether, washed with water and dried over magnesium suflate. The solution was treated with activated charcoal and evaporated under vacuum to yield a yellow oil (6.3 g.). Chromatography on silica gel (900 ml.) eluted with 1:1 hexane:ethyl acetate yielded 6-chloro-3,4-dihydro-2H-1-benzopyran-4-ylidene-acetic acid methyl ester, (1.6 g., 12%), m.p. 113-115 C.
2) To a solution of methyl (dimethoxyphosphoryl) acetate (3.4mL) in toluene (103mL) was added portionwise 60% NaH (0.96g) at 20 to 300C under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise above Solution A at 0 to 100C and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into a mixture of AcOEt and water and adjusted to pH 2 with IN- HCl aq. The separated organic layer was washed with saturated sodium hydrogen carbonate aq., dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give methyl (2E) -3- (5, 6-dichloropyridin-3-yl) acrylate (2.83g).
(E)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-but-2-enoic acid methyl ester[ No CAS ]
(Z)-3-(3,5-difluoro-phenyl)-4,4,4-trifluoro-but-2-enoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,1,3,3-tetramethylguanidine; In dichloromethane; at 0 - 20℃; for 22h;
1-(3,5-Difluorophenyl)-2,2,2-trifluoroethanone (1.0 g, 4.8 mmol) was added to CH2Cl2 (5 mL). Trimethylphosphonoacetate (0.87 g, 4.8 mmol) was added and the mixture was cooled to 0 C. Tetramethylguanidine (0.72 mL, 5.7 mmol) was added dropwise by syringe. The mixture was allowed to attain room temperature slowly and was stirred 22 hours. The reaction mixture was poured into a separatory funnel containing CH2Cl2 (40 mL). The organic phase was washed with distilled water (3*), brine, and then dried over Na2SO4. The solution was filtered and the solvents concentrated to a crude oil, which was flash chromatographed using CH2Cl2 as eluent. This gave the desired product as a yellow oil (1.13 g, 89%; mixture of E/Z isomers).
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 24h;
26A. (E)-Methyl 3-(6-(trifluoromethyl)pyridin-3-yl)acrylate To a stirring solution of trimethyl phosphonoacetate (0.510 mL, 3.14 mmol) in THF (15 mL) at 0 C. was added NaH (88.0 mg, 3.3 mmol). After stirring for ca. 20 min, the slurry was allowed to warm to ambient temperature for 10 min, then cooled again to 0 C. To this was added dropwise 6-(trifluoro-methyl)nicotinaldehyde (500 mg, 2.86 mmol), which is commercially available from Oakwood Products, Inc. (1741 Old Dunbar Rd., West Columbia, S.C. 29172), in THF (5 mL) over 2 min. The bath was allowed to expire and the reaction stirred at ambient temperature for ca. 24 h. The reaction was quenched with H2O (50 mL) then diluted with EtOAc (100 mL). The phases were separated and the organics further washed with H2O (2×20 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 670 mg 26A in ca. 85% purity as a white solid (86% yield). This was taken forward without further purification. m/z (ES+) M+1=232. 1; HPLC tR=1.07 min. 1H NMR (500 MHz, CDCl3) delta 8.84 (dd, J=2.1, 0.6 Hz, 1H), 7.99 (dt, J=8.2, 1.2 Hz, 1H), 7.77-7.65 (m, 2H), 6.59 (d, J=16.2 Hz, 1H), 3.85 (s, 3H).
Intermediate 64-8: Methyl 2-fn r.4rWU4-f4A5.5-tetramethyl-T .3.2-rtioxahorolan-2- vDnhenylkvclohexyDacetateTrimethylphosphonoacetate (1.05X-1.06X) was added dropwise to a suspended solution of t-BuOK (0.70X-0.71X) in 2-MeTHF (10 vol) at 5-1O0C. The resulting solution was stirred at 15-2O0C for 3.5-4.0 hours. The reaction mixture was cooled to 5-1O0C and DIPEA (0.81-0.82X) was added to the reaction at 10-150C. 4-(4-Hydroxyphenyl)cyclohexanone (1.0 X) was added in portions to the above reaction mixture at 10-150C and the resulting solution was stirred at 15-2O0C for 3-6 hours and then sampled for HPLC analysis. NH4C1- sol (5.0X-6.0X) was added to the reaction mixture at 0-150C, and the reaction was quenched. The organic layer was separated and the aqueous layer was extracted with 2- MeTHF (2.5X-3.0X). The two organic extracts were combined and washed with NaHSO3 aq. and then NaCl-solution (2.5X-3.0X) twice. The organic layer was concentrated to 2~3 vol and n-heptane was added to give a suspended solution, and the above mixture was <n="163"/>concentrated to below 3percent of 2-MeTHF residue to give a suspended solution. The mixture was cooled to 0-5 0C, stirred for 1.0-2.0 h, filtered and the cake washed with n-heptane (2 vol X2). Dry in vacuum at below 450C to give the desired phenoxyacrylate product.
With triethylamine; lithium bromide; In tetrahydrofuran; at 5 - 25℃;
Intermediate 29; Methyl (2£)-3-(4-formylphenyl)acrylateLithium bromide (159g, 2.5eq) was dissolved in THF (2L) and cooled to <;5C. Trimethyl phosphonoacetate (1.3eq, 138mL) then triethylamine (204mL, 2eq) were charged at <;10C. 4-Diethoxybenzaldehyde (152.8g, 1eq) was charged over25mins and the reaction allowed to warm to 20 +/- 5C, then the cooling was removed. After 1 h 40min, the reaction was quenched with water, separated, and the aqueous layer extracted with EtOAc. The combined organic phases were washed three times with brine then concentrated to dryness in vacuo. Methanol (0.5L) was charged to the residue and again concentrated to dryness. Methanol (0.75L) and 1 N HCI (0.75L) were charged to the residue and stirred at ambient temperature for 45 min. Water (0.75L) was charged and the product isolated by filtration (128.5g). 1H NMR (30OMHz1CDCI3) delta(ppm): 10.06 (1 H, s), 7.93 (2H, d), 7.71 (3H, m), 6.58 (1 H, d), 3.85 (3H, s).
Na (5.0 mmol) was dissolved in dry MeOH (7 ml) and to the resulting solution methyl trimethylphosphonacetate (3.0 mmol) and a solution of the aldehyde (1.0 mmol) in dry MeOH (1 ml) were added in sequence. The resulting mixture was allowed to react for 24 h at 70 C. The solution was then acidified with HCl (aq) 10%, and extracted with Et2O (3 x 10 ml). The combined organic phases were dried over Na2SO4 and evaporated to dryness yielding the desired product that was used for the next reaction without further purification.
3-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
To a solution of trimethyl phosphino acetate (4.64 mL, 23.5 mmol) in dry DMF (20 mL) was added potassium tert-butoxide (2.14 g, 19.13 mmol) at 0° C. and the mixture was stirred at same temperature over a period of 15 min.To the above mixture a solution of <strong>[156866-52-3](4-Formyl-benzyl)-carbamic acid tert-butyl ester</strong> (3.0 g, 12.75 mmol) in DMF (10 mL) was added drop wise at ice temperature.The reaction mixture was stirred at ice temperature over a period of 45 min.The resulting reaction mixture diluted with ethyl acetate, washed with water, brine and dried over sodium sulfate.The residue obtained upon evaporation of volatiles was purified by column chromatography to give 3-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-acrylic acid methyl ester as colourless solid (1.5 g, 40percent).
With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;
(E)-methyl 3-(l -methyl- lH-pyrazol-4-yl)acrylateCs2C03 (1.304g, 4 mmol) was added to a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100°C overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3 -(1 -methyl- lH-pyrazol-4- yl)acrylate (0.278 g). ES+ (M+H)+ 167
0.278 g
With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃;
Cs2CO3 (1.304 g, 4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364 g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100° C. overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (0.278 g). ES+(M+H)+167
General procedure: To a suspension of potassium tert-butoxide (7.83g, 70mmol, 3.0equiv) in THF (300mL) at 0C was added trimethyl phosphonoacetate (10.6g, 58mmol, 2.5equiv). The resulting clear yellow solution was stirred for 15min at 0C, then a solution of (4-bromo-2-methoxy)benzaldehyde (31b; 5.00g, 23mmol) in THF (20mL) was added dropwise. The resulting mixture was warmed from 0C to room temperature over 16h. The solvent was removed under vacuum, then the crude mixture was diluted with water (50mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (1×50mL), brine (1×50mL), dried (MgSO4), filtered, and concentrated to provide a dark residue. The residue was purified by flash chromatography using 5% EtOAc in hexanes to obtain 3.53g (56%) of product as a white solid: Rf 0.19 (5% EtOAc/hexane; 1H NMR (CDCl3) delta 8.02 (d, 1H), 7.47 (dd, 1H), 7.26-7.22 (m, 1H), 6.93 (t, 1H), 6.84 (d, 1H), 6.62 (d, 1H), 6.2 (s, 1H), 3.83 (s, 3H).
To a suspension of potassium t-butoxide (819 mg, 7.3 mmol, 2.5 equiv) in THF (20 mL) at 0 C was added trimethyl phosphonoacetate (1.30 g, 7.3 mmol, 2.5 equiv). The clear yellow solution was stirred for 10 minutes at 0 C, then <strong>[82257-15-6]4-methoxynicotinaldehyde</strong> (400 mg, 2.92 mmol) was added over 5 min. The resulting suspension was allowed to warm to room temperature over 1.5 h.. The mixture was then diluted with water (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated to yield a crude solid that was purified by flash chromatography (1:1 hexanes:EtOAc). Product-containing fractions were combined, evaporated and dried under high vacuum to yield 368 mg (65%) of product as a pale yellow oil: Rf 0.33 (1:1 hexane:EtOAc); 1H NMR (CDCl3) delta 8.58 (s, 1H), 8.46 (d, 1H), 7.81 (d, 1H), 6.85 (d, 1H), 6.60 (d, 1H), 3.96 (s, 3H), 3.82 (s, 3H).
methyl 3-(4-chloro-2-methoxyphenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a suspension of potassium tert-butoxide (7.83g, 70mmol, 3.0equiv) in THF (300mL) at 0C was added trimethyl phosphonoacetate (10.6g, 58mmol, 2.5equiv). The resulting clear yellow solution was stirred for 15min at 0C, then a solution of (4-bromo-2-methoxy)benzaldehyde (31b; 5.00g, 23mmol) in THF (20mL) was added dropwise. The resulting mixture was warmed from 0C to room temperature over 16h. The solvent was removed under vacuum, then the crude mixture was diluted with water (50mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (1×50mL), brine (1×50mL), dried (MgSO4), filtered, and concentrated to provide a dark residue. The residue was purified by flash chromatography using 5% EtOAc in hexanes to obtain 3.53g (56%) of product as a white solid.
To the Trimethyl phosphonoacetate (55.6 mL, 381 mmol) in 250 mL anhydrous CH2Cl2 cooled to 0 C. was added DBU (48.8 mL, 322 mmol) and the mixture was stirred for 15 min. Aldehyde 59 (40.0 g, 215 mmol) in 50 mL CH2Cl2 was added dropwise. The temperature of the reaction mixture brought to rt and resulting reaction mixture was stirred at rt for 16 h, and then quenched with 100 mL of Water. The mixture was partitioned, and the aq. layer was extracted with CH2Cl2 (3×150 mL). The combined organics were washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel column chromatography (10:1 hexanes/ethyl acetate) to give the desired trans-alpha,beta-unsaturated ester 62 (48.0 g, 92%) as a white solid.
methyl (2E)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere;
(E)-3-(1 -Methyl-1 H-benzotriazol-5-yl)-acrylic acid methyl esterA stirred solution of t-BuOK (2.10 g, 18.6 mmol) in THF (100 ml_) at 0 C under N2was treated with trimethyl phosphonoacetate (4.30 g, 23.3 mmol). After 30 mins, 1- methyl-1 H-1 ,2,3-benzotriazole-5-carbaldehyde (2.50 g, 15.5 mmol) was added slowly in portions. After 1 h, the mixture was treated with NH4CI (aq., sat.), diluted with water and then extracted with n-heptane (x3), resulting in a precipitate which was isolated by filtration. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to dryness, giving a beige solid which was washed with toluene and dried under vacuum. This material was combined with the precipitate above to give the product as a beige solid (3.1 g, 92%). LCMS (M+H)+218, RT 1.12 min.
92%
Intermediate 2 (E)-3-(1 -Methyl-1 H-benzotriazol-5-yl)-acrylic acid methyl ester A stirred solution of t-BuOK (2.10 g, 18.6 mmol) in THF (100 ml) at 0C under N2 was treated with trimethyl phosphonoacetate (4.30 g, 23.3 mmol). After 30 mins, 1 -methyl-1 H-1 ,2,3- benzotriazole-5-carbaldehyde (2.50 g, 15.5 mmol) was added slowly in portions. After 1 hour, the mixture was treated with NH4CI (aq., sat.), diluted with water and then extracted with n- heptane (x3), resulting in a precipitate which was isolated by filtration. The combined organic layers were washed with water and brine, dried over MgS04, filtered and concentrated to dryness, giving a beige solid which was washed with toluene and dried under vacuum. This material was combined with the precipitate above to give the product as a beige solid (3.1 g, 92%). LC-MS m/z 218 (M+H)+ 1 .12 min (ret. time).
3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Example 21 Preparation of Compound AA [3-(4-Trifluoromethylphenyl)-pentanamide] To a chilled (0 C.) solution of lithium bis(trimethylsilyl)amide (1.0 M, 50 mL) was dropwise added a solution of trimethylphosphonoacetate, keeping the temperature below 10 C. The solution was then allowed to warm to room temperature and stirred for an additional five minutes, after which a solution of <strong>[711-33-1]4'-(trifluoromethyl)propiophenone</strong> in THF (25 mL) was added in one portion. The solution was slowly heated to 50 C. for eight hours. The solution was cooled to room temperature, then diluted with a 10% NH4Cl solution (100 mL), and extracted with ethyl acetate (2*100 mL). The organic layers were combined and dried over MgSO4, filtered, and the filtrate concentrated to a white solid which was recrystallized from hexane/ethyl acetate to give 5.42 grams of 3-(4-trifluoromethylphenyl)pent-2-enoic acid methyl ester intermediate (85% yield).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride; In acetonitrile; at 0 - 20℃; for 17.33h;
Lithium chloride (1.1906 g, 1.56 eq.) in acetonitrile (20 mL) solution of 3-hydroxy-methyl-benzaldehyde (2.4528 g) in acetonitrile (10 mL) , phosphonoacetic acid trimethyl (5.1150g, 1.56 eq.) in acetonitrile (10 mL) was mixed at room temperature, the resulting mixed solution, 0 C. with DBU (1,8-diazabicyclo [5.4.0] -7-undecene) (4.2682g, 1.56 eq) in acetonitrile (10 mL ) solution was added over a period of 2 minutes, 20 minutes at 0 C, and the mixture was stirred at room temperature for 17 hours. Was added water (50 mL), extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), dried over magnesium sulfate. The residue obtained by distilling off the solvent, column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (2.5720 g, 74%, colorless oil)
74%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; lithium chloride; In acetonitrile; at 0 - 20℃; for 17.36h;
Lithium chloride (1.1906 g, 1.56 eq.) In acetonitrile (20 mL) solution of acetonitrile (10 mL) solution of <strong>[52010-98-7]3-hydroxymethyl benzaldehyde</strong> (2.4528 g), trimethyl phosphonoacetate (5.1150g, 1.56 eq.) In acetonitrile (10 mL) was mixed at room temperature, the resulting mixed solution, 0 C. with DBU (1,8-diazabicyclo [5.4.0] -7-undecene) (4.2682g, acetonitrile (10 mL of 1.56 eq.)) the solution was added over a period of 2 minutes, 20 minutes at 0 , and the mixture was stirred at room temperature for 17 hours. Was added water (50 mL), extracted with ethyl acetate (250 mL), the organic layer was washed with brine (100 mL), dried over magnesium sulfate. The residue obtained by distilling off the solvent, column chromatography (ethyl acetate: n-hexane = 1: 2) to give the title compound (2.5720 g, 74%, colorless oil).
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed sodium hydride (60%, 1.09 g, 1.10 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of methyl 2-(dimethoxyphosphoryl)acetate (5.41 g, 29.71 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 30 min at 0 C. To this was added a solution of <strong>[60032-57-7]2-methylpyridine-3-carbaldehyde</strong> (3 g, 24.77 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of water, extracted with 2×300 mL of ethyl acetate, washed with 1×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). The collected fraction was concentrated under vacuum to give (E)-methyl 3-(2-methylpyridin-3-yl)acrylate (3.3 g, 75%) as yellow oil. MS: (ES, m/z): 178[M+H]+.
2-(4-amino-1,2,5-oxadiazol-3-yl)-4-dimethoxyphosphoryl-1,4-dihydroimidazol-5-one[ No CAS ]
3-amino-3-(4-amino-1,2,5-oxadiazol-3-yl)-4-dimethoxyphosphoryl-isoxazolidin-5-one[ No CAS ]
4-amino-N'-methoxy-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%; 30%; 15%
With sodium hydride; In toluene; for 6h;Reflux;
General procedure: Trialkylphosphonoacetate (2a or b) (1 mmol) was dissolved inrigorously dried toluene (25 mL) then sodium hydride (1mmol)was added carefully with stirring. Thence, the startingmaterial 1(1 mmol) was added to the mixture which then was refluxed for6 h., the volatile materials were evaporated under reduced pressureand the remaining residue was purified on silica gel columnchromatograph to give compounds 5a,b, 6a,b, and 7a,b
(E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 24h;
Step1 To a stirred solution of <strong>[256417-10-4]2,6-difluoro-4-methoxybenzaldehyde</strong> (5 g, 29.05 mmol, 1 eq) in THF (100 mL) was added trimethylphosphonoacetate (5.03 mL, 34.86 mmol, 1.2eq) and DBU (5.65 mL, 37.76 mmol, 1.3eq). The solution was stirred at RT for 24 h. It was then concentrated in vacuo and dissolved in 1:2 EtOAc/Hexane (250 mL). The resulting solution was washed sequentially with 1 N aq. HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and finally with brine (100 mL). The organic phase was then dried over sodium sulfate, filtered and evaporated under reduced pressure to yield the crude (E)-methyl 3-(2,6-difluoro-4-methoxyphenyl)acrylate as off white solid (5.8 g, 87%). It was used for the next step without further purification.
With potassium carbonate; In tetrahydrofuran; for 15h;Inert atmosphere;
To a mixture of compound 21.8 (2.50 g, 11.25 mmol, 1 eq) and methyl 2- dimethoxyphosphorylacetate 21.7 (2.05 g, 11.25 mmol, 1.63 mL, 1 eq) in THF (30 mL) was added K2C03 (3.11 g, 22.50 mmol, 2 eq) in one portion at 50C under N2. The mixture was stirred at 50 C for 15 hours. The reaction mixture was diluted with H20 30 mL and extracted with EtOAc 90 mL (30 mL x 3). The combined organic layers were washed with brine 50 mL(50 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5:1) to give compound 21.6 (2.40 g, 8.62 mmol, 76.62% yield) as a white solid.[02921 LCMS (ESI): m/z: [M + H] calcd for C14H18N204: 278; found 279; RTO.739 mm.