* 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 oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5 h;
C. 2,3-Dihydrobenzofuran-4-carboxaldehyde DMSO (8.10 mL, 114 mmol) was added at -78°C to a stirred solution of oxalyl chloride in CH2Cl2 (40 mL of a 2M solution). A solution of Part B 2,3-dihydrobenzofuran-4-methanol (8.53 g, 56.9 mmol) in CH2Cl2 (35 mL) was added dropwise, and the solution stirred at -78°C for 30 min. Triethylamine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min. and diluted with CH2Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to give 2,3-dihydrobenzofuran-4-carboxaldehyde as an oil (8.42 g, 100percent) that was used without purification.
100%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 0.5 h;
DMSO (8.10 mL, 114 mmol) was added at -78°C to a stirred solution of oxalyl chloride in CH2Cl2 (40 mL of a 2M solution). A solution of (2,3-dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH2Cl2 (35 mL) was added dropwise, and the solution stirred at -78°C for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH2Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100percent) that was used without purification.
Stage #1: With osmium(VIII) oxide In tetrahydrofuran; water at 20℃; for 0.5 h; Stage #2: With sodium periodate In tetrahydrofuran; water at 20℃; for 1 h;
To a solution of 4-ethenyl-2,3 - dihydro-1-benzofuran (5 g, 34.20 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) and water (50 mL) was added 0504 (440 mg, 1.73 mmol, 0.05 equiv). The resulting solution was stirred for 30 mm at 20 °C. Then Na104 (14.7 g, 68.69 mmol, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature. The resulting solution was diluted with 100 mL of water. Then the resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5 g (99percent) of 2,3-dihydro-1-benzofuran-4-carbaldehyde as light brown oil.
69%
Stage #1: With ozone In dichloromethane Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;
Ozone was bubbled into a stirring cold solution of (3 g, 21 mmol, prepared as described in WO 9933460) in dichloromethane (50 mL). The reaction was monitored by TLC (20:1 hexane/ethyl acetate). Upon completion of the reaction the mixture was purged with nitrogen for a few minutes followed by the addition of Hunig's base (N,N-ethyldiisopropylamine, 5.44 g, 42 mmol). Stirring was continued while the reaction warmed to RT. The reaction was washed with 0.5 N HCl, water, and then brine. The organic layer was dried over MgSO4; filtered and concentrated in vacuo. The title compound (oil, 2.10 g, 69percent yield) was isolated via silica gel using 10percent ethyl acetate in hexanes.
With triethylamine In dichloromethane; dimethyl sulfoxide
C. 2,3-Dihydrobenzofuran-4-carboxaldehyde STR39 DMSO (8.10 mL, 114 mmol) was added at -78° C. to a stirred solution of oxalyl chloride in CH2 Cl2 (40 mL of a 2M solution). A solution of Part B 2,3-dihydrobenzofuran-4-methanol (8.53 g, 56.9 mmol) in CH2 Cl2 (35 mL) was added dropwise, and the solution stirred at -78° C. for 30 min. Triethylamine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min. and diluted with CH2 Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to give 2,3-dihydrobenzofuran-4-carboxaldehyde as an oil (8.42 g, 100percent) that was used without purification.
Reference：
[1] Patent: US6011059, 2000, A,
4
[ 68-12-2 ]
[ 289058-20-4 ]
[ 209256-42-8 ]
Reference：
[1] Patent: CN106588841, 2017, A, . Location in patent: Paragraph 0058-0060
5
[ 166599-84-4 ]
[ 209256-42-8 ]
Reference：
[1] Patent: EP1027043, 2004, B1,
6
[ 83228-39-1 ]
[ 209256-42-8 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6775 - 6781
7
[ 864147-85-3 ]
[ 209256-42-8 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6775 - 6781
8
[ 186191-19-5 ]
[ 209256-42-8 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6775 - 6781
With piperidine; acetic acid; In benzene; for 18h;Heating; Continuous removal of water;
To a solution of 2,3-dihydrobenzofuran-4-aldehyde (1g, 6.7 mmol) (Example 2, Part C) and dimethyl malonate 0.89 g, 6.7 mmol) in benzene (30 mL) was added piperidine (0.11 g, 1.4 mmol) and acetic acid (0.40 g, 6.7 mmol). The resulting solution was stirred for 18 hr with continuous removal of water. The solution was cooled to ambient temperature and concentrated. The residues was chromatographed on silica gel (ethyl acetat:hexane, 3:7) to give the title compound (1.5g).
D. trans-3-(2,3-Dihydro-4-benzofuranyl)-2-pronenoic acid A solution of <strong>[209256-42-8]2,3-dihydrobenzofuran-4-carboxaldehyde</strong> (8.42 g, 56.9 mmol) and malonic acid (11.86 g, 114 mmol) in pyridine (30 mL) and pyrrolidine (1 mL) was heated at reflux for 6 hr. The solution was cooled and poured into cold water (400 mL). The mixture was made strongly acidic with 12 N HCl to give a pale yellow precipitate that was filtered and air dried. The pale yellow powder was recrystallized from isopropanol to give white flakes (10.3 g, 95.3%, mp: 205-207C). Anal. for C11H10O3: Calc'd, C, 69.46; H, 5.30. Found, C, 69.36; H, 5.17. 1H NMR (300 MHz, CDCl3) delta7.76 (d, 1H, J=16.1 Hz), 7.15 (t, 1H, J=7. 8 Hz), 7.07 (d, 1H, J=7.8 Hz), 6.81 (d, 1H, J=7.8 Hz), 6.37 (d, 1H, J=16.1 Hz), 4.62 (t, 2H, J=8.8 Hz), 3.33 (t, 2H, J=8.8 Hz).
82%
With pyrrolidine; pyridine; at 120℃; for 2h;
A mixture of 2,3 - dihydro-1-benzofuran-4-carbaldehyde (3.5 g, 23.62 mmol, 1.00 equiv), (4.9 g, 47.09 mmol, 2.00 equiv), pyrrolidine (1.4 mL), Pyridine (35 mL) was heated for 2 h at 120 C. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers were combined. The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.7 g (82%) of (2E)-3-(2,3-dihydro-1-benzofuran-4- yl)prop-2-enoic acid as a light yellow solid.
With oxalyl dichloride; dimethyl sulfoxide; In dichloromethane; at -78℃; for 0.5h;
C. 2,3-Dihydrobenzofuran-4-carboxaldehyde DMSO (8.10 mL, 114 mmol) was added at -78C to a stirred solution of oxalyl chloride in CH2Cl2 (40 mL of a 2M solution). A solution of Part B 2,3-dihydrobenzofuran-4-methanol (8.53 g, 56.9 mmol) in CH2Cl2 (35 mL) was added dropwise, and the solution stirred at -78C for 30 min. Triethylamine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min. and diluted with CH2Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to give 2,3-dihydrobenzofuran-4-carboxaldehyde as an oil (8.42 g, 100%) that was used without purification.
100%
DMSO (8.10 mL, 114 mmol) was added at -78C to a stirred solution of oxalyl chloride in CH2Cl2 (40 mL of a 2M solution). A solution of (2,3-dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH2Cl2 (35 mL) was added dropwise, and the solution stirred at -78C for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH2Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) that was used without purification.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 18h;
Diethyl (N-methoxy-N-methyl-carbamoylmethyl) phosphonate (4.0 g, 16.7 mmol) was added dropwise to a suspension of sodium hydride (671 mg, 60% dispersion in mineral oil, 16.7 mmol) in THF (75 mL) at 0C. A solution of <strong>[209256-42-8]2,3-dihydrobenzofuran-4-carboxaldehyde</strong> (3.0 g, 15.2 mmol) in THF (25 mL) was added dropwise. The resulting suspension was allowed to warm to room temperature. After 18 h, water (60 mL) was added and the solution was extracted three times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over K2CO3, and concentrated to give a pale red oil, 3.5 g (100%).
To a stirring solution of the aldehyde from step A Example 33 (400 mg, 2.7 mmol) in dichloromethane (40 mL) was added carbethoxymethylene-triphenylphosphorane (1.41 g, 4.05 mmol). The reaction was refluxed for 16 hrs. and the solvent was removed in vacuo. The title compound (white solid, 533 mg, 91% yield) was isolated from a silica gel column using 20% ethyl acetate in hexanes as the eluent.
To a solution of 4-ethenyl-2,3 - dihydro-1-benzofuran (5 g, 34.20 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) and water (50 mL) was added 0504 (440 mg, 1.73 mmol, 0.05 equiv). The resulting solution was stirred for 30 mm at 20 C. Then Na104 (14.7 g, 68.69 mmol, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature. The resulting solution was diluted with 100 mL of water. Then the resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5 g (99%) of 2,3-dihydro-1-benzofuran-4-carbaldehyde as light brown oil.
69%
Ozone was bubbled into a stirring cold solution of (3 g, 21 mmol, prepared as described in WO 9933460) in dichloromethane (50 mL). The reaction was monitored by TLC (20:1 hexane/ethyl acetate). Upon completion of the reaction the mixture was purged with nitrogen for a few minutes followed by the addition of Hunig's base (N,N-ethyldiisopropylamine, 5.44 g, 42 mmol). Stirring was continued while the reaction warmed to RT. The reaction was washed with 0.5 N HCl, water, and then brine. The organic layer was dried over MgSO4; filtered and concentrated in vacuo. The title compound (oil, 2.10 g, 69% yield) was isolated via silica gel using 10% ethyl acetate in hexanes.
To a solution of the aldehyde A (1.0 g, 6.75 mmol) in dichloromethane (40 mL) was added triphenylphosphoranylidene-2-propanone (3.2 g, 10.12 mmol). The reaction was refluxed for 16 hrs and the solvent was removed in vacuo. The title compound (white solid, 1.86 g, 99% yield) was purified via silica gel chromatography using 5% ethyl acetate in hexanes as the eluent.
D. trans-3-(2,3-Dihydro-4-benzofuranyl)-2-propenoic acid STR40 A solution of <strong>[209256-42-8]2,3-dihydrobenzofuran-4-carboxaldehyde</strong> (8.42 g, 56.9 mmol) and malonic acid (11.86 g, 114 mmol) in pyridine (30 mL) and pyrrolidine (1 mL) was heated at reflux for 6 hr. The solution was cooled and poured into cold water (400 mL). The mixture was made strongly acidic with 12 N HCl to give a pale yellow precipitate that was filtered and air dried. The pale yellow powder was recrystallized from isopropanol to give white flakes (10.3 g, 95.3%, mp: 205-207 C.). Anal. for C11 H10 O3: Calc'd, C, 69.46; H, 5.30. Found, C, 69.36; H, 5.17. 1 H NMR (300 MHz, CDCl3)delta 7.76 (d, 1H, J=16.1 Hz), 7.15 (t, 1H, J=7.8 Hz), 7.07 (d, 1H, J=7.8 Hz), 6.81 (d, 1H, J=7.8 Hz), 6.37 (d, 1H, J=16.1 Hz), 4.62 (t, 2H, J=8.8 Hz), 3.33 (t, 2H, J=8.8 Hz).
With triethylamine; In dichloromethane; dimethyl sulfoxide;
C. 2,3-Dihydrobenzofuran-4-carboxaldehyde STR39 DMSO (8.10 mL, 114 mmol) was added at -78 C. to a stirred solution of oxalyl chloride in CH2 Cl2 (40 mL of a 2M solution). A solution of Part B 2,3-dihydrobenzofuran-4-methanol (8.53 g, 56.9 mmol) in CH2 Cl2 (35 mL) was added dropwise, and the solution stirred at -78 C. for 30 min. Triethylamine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min. and diluted with CH2 Cl2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to give 2,3-dihydrobenzofuran-4-carboxaldehyde as an oil (8.42 g, 100%) that was used without purification.
Under an atmosphere of nitrogen, 46. 8 g of Mg was mixed with 220 g of the oil obtained in Preparation Example 1 in 1. 1 L of tetrahydrofuran. 100 mL of a 4-chloro-2, 3-dihydrobenzisilane Grignard reagent prepared in a conventional manner was added as an initiator. The resulting mixture was heated under reflux and stirred for 18 hours. The reaction was terminated by mass spectrometry at 0% of the starting material in the reaction system by gas chromatography, and the mixture was cooled to a temperature below 20 C.In another 3 L flask, 133. 51 g of DMF and 660 mL of THF were added. Add the above steps to obtain the format reagent (the residual Mg does not move with the solution) and keep the temperature below 35 C. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 3 to 4 hours. Cool the mixture to a temperature below 20 C. 600 mL of methyl t-butyl ether was added, and after stirring, 600 mL of water was added and stirring was continued for 30 minutes. Add about 120mL of concentrated HC1, adjust the pH to 2 ~ 3. The layers were separated and the methyl tert-butyl ether layer was washed successively with 500 mL of water and 500 mL of brine. The solvent methyl tert-butyl ether was removed in vacuo at 40 C to give 191 g of the product as a crude product, which was crude 2,3-dihydro-1-benzofuran-4-carbaldehyde. The yield was 90% and the purity was 53%. The intermediate does not require further purification available for the next synthesis step.
3-(2,3-dihydrobenzofuran-4-yl)prop-2-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With piperidine; pyridine; In water; at 90 - 100℃; for 4h;Large scale;
In a 10 L four-necked flask equipped with a thermometer, a mechanical stirrer, a constant pressure dropping funnel and an exhaust gas absorber,(1.3 gg) and piperidine (50 g), stirred to 90 to 100 C with stirring, slowly adding <strong>[209256-42-8]2,3-dihydrobenzofuran-4-carbaldehyde</strong> (1 .OKg) and then adding malonic acid (1.5 kg ).90 ~ 100 C The reaction was continued for 4 hours; then water (4.0 L) was added and the pyridine / water mixture (2.5 L) was distilled off from the reaction flask under reduced pressure.After cooling to room temperature, the reaction solution was adjusted to pH 1 with 37% concentrated hydrochloric acid (4.5 Kg) to precipitate a large amount of solid. (1 lKg) in a vacuum of drying at 40-50 C to give a yield of 85% and a purity of 98% by filtration, 1% hydrochloric acid (3L each) and twice at 40-50 C.
38.5 g
With pyrrolidine; pyridine; for 6h;Reflux;
The 74g preparation example 2 to obtain the crude intermediate product is added to the 200 ml in pyridine (Py), adding 4.3g pyrrolidine, 48.8g malonic acid. Then heating reflux for 6 hours. After the reaction, cooling to 10 C. Adding 360 ml water, then with about 250 ml of concentrated hydrochloric acid to adjust the pH to 1, at this time a large quantity of solid precipitate. At this temperature the stirring 2 hours, filter, to obtain a yellow solid. 50 C vacuum drying 4 hours, to obtain 38.5g yellow solid, yield 43%.
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
<strong>[209256-42-8]2,3-dihydrobenzofuran-4-carbaldehyde</strong> (2.00 g, 13.5 mmol) was dissolved in dry MeOH (30 mL) and the solution cooled to 0 C. NaBH4 (510 mg, 13.5 mmol) was added and the solution stirred at room temperature for 1 hour. Ice water was added and the layers separated. The organicphase was evaporated in vacuo to yield the title compound as colourless crystalline solid (1.90 g, 94%).[00292] AnalpH2_MeOH_4MIN: Rt: 2.00 mm, mlz 151.3 [M+H]+
1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.5%
In tetrahydrofuran; at -10 - 20℃; for 6.5h;
1050 mL (1.05 mol) of a 1.0 M solution of vinyl magnesium bromide in tetrahydrofuran was added to the reaction flask, the stirring was started, the reaction solution was cooled to -10 to -5 C, and 2,3-dihydrobenzofuran-4 was added dropwise. -A solution of formaldehyde (148.2 g, 1.00 mol) in tetrahydrofuran (500 mL), and the temperature of the reaction solution is controlled to not exceed -5 C. After the completion of the dropwise addition, the reaction was maintained at a temperature of -10 to -5 C for half an hour, and then slowly warmed to room temperature to continue the reaction. After 6 hours, 300 mL of a saturated ammonium chloride aqueous solution was added, and after stirring for 30 minutes, extraction was performed with ethyl acetate three times (800 mL × 3). The organic phase was washed once with a saturated sodium chloride solution (300 mL) and water (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 173.6 g of a yellow oil with a yield of 98.5%.
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