* 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.
Reference：
[1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
2
[ 51114-94-4 ]
[ 4521-22-6 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
3
[ 51114-94-4 ]
[ 22009-37-6 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
4
[ 51114-94-4 ]
[ 26673-30-3 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
5
[ 51114-94-4 ]
[ 26673-32-5 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
6
[ 590-92-1 ]
[ 603-35-0 ]
[ 51114-94-4 ]
Yield
Reaction Conditions
Operation in experiment
87%
for 15 h; Reflux
General procedure: To a round-bottom flask was added 5a (5.0 mmol), P(Ph)3 (20.0 mmol) and dry MeCN (10.0 mL). The mixture was stirred vigorously and heated to reflux. After the refluxing was ceased (15 h), the solution was concentrated. The residue was rinsed consecutively with benzene (3 x 10 mL), hexanes (10 mL), and ether (2 x 10 mL). The crystalline white solid was dried to give 6a (1.8 g, 87percent) [26] 6b-d were prepared according to the procedure described as 6a.
78.4%
at 100℃; for 23 h;
General procedure: A mixture of triphenylphosphine (1 g, 0.0038 mol) and ω-chloropropionic acid (0.43 g, 0.0038 mol) was melted ona water bath at a temperature 100 °C for 21 h. The melt was treated with water, a part of the solid compound was transferred into solution, an insoluble in water white precipitate of unreacted triphenylphosphine and formed in the course of the reaction triphenylphosphine oxide was filtered off. The aqueous filtrate was concentrated, a white precipitate formed was washed with diethyl ether. The yield was 0.95 g (57.2percent),
68%
at 20℃; Heating / reflux
(2-Carboxy-ethyl) -triphenyl-phosphonium bromide Reflux a solution of triphenylphosphine (91.3 g, 348 mmol, 1.05 equivalents) and 3- bromopropionic acid (50.7 g, 331 mmol) in acetonitrile (250 ml) for three hours, allow to sit at room temperature overnight. Add ether (400 ml) and cool in the freezer for two hours. Filter solids, rinse with ether, and dry solids under high vacuum to obtain the title compound (94.1 g, 68percent). NMR (400 MHz, CDC13) : 8 3.15 (m, 2H), 3. 73 (m, 2H), 7.69- 7.83 (m, 15H).
65.2 g
for 5 h; Inert atmosphere; Reflux
Under a nitrogen gas stream, a 500-ml reactor was charged with 3-bromopropionic acid (1-C)(169 mmol, 25 g), triphenylphosphine (19651.42 g),dehydrated acetonitrile (70 ml) was added. After completion of the addition, the mixture was stirred for 5 hours under reflux.After cooling to room temperature, the reaction solution was concentrated. The solid was washed with ethyl acetate to obtain 65.2 g of wittig-salt (1-D).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 21, p. 5878 - 5881
[2] Journal of the American Chemical Society, 2011, vol. 133, # 31, p. 12304 - 12310
[3] Chemistry of Natural Compounds, 1990, vol. 26, # 4, p. 486 - 487[4] Khimiya Prirodnykh Soedinenii, 1990, # 4, p. 568 - 569
[5] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 275 - 284
[6] Russian Chemical Bulletin, 1993, vol. 42, # 4, p. 760 - 763[7] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1993, # 4, p. 791 - 794
[8] ChemMedChem, 2018, vol. 13, # 12, p. 1238 - 1245
[9] Heterocycles, 2000, vol. 53, # 5, p. 1085 - 1110
[10] Small, 2016, p. 4541 - 4552
[11] Russian Chemical Bulletin, 2016, vol. 65, # 5, p. 1313 - 1318[12] Izv. Akad. Nauk, Ser. Khim., 2016, p. 1313 - 1318,6
[13] Patent: WO2005/92854, 2005, A1, . Location in patent: Page/Page column 50
[14] Journal of Materials Chemistry B, 2015, vol. 3, # 24, p. 4904 - 4912
[15] J. Gen. Chem. USSR (Engl. Transl.), 1978, vol. 48, p. 818 - 822[16] Zhurnal Obshchei Khimii, 1978, vol. 48, # 4, p. 897 - 902
[17] Canadian Journal of Chemistry, 1973, vol. 51, p. 3299 - 3301
[18] Journal of Medicinal Chemistry, 2013, vol. 56, # 11, p. 4580 - 4596
[19] Applied Catalysis A: General, 2014, vol. 470, p. 183 - 188
[20] Patent: KR2015/135792, 2015, A, . Location in patent: Paragraph 0183; 0184; 0185; 0187
[21] Patent: JP6043226, 2016, B2, . Location in patent: Paragraph 0094; 0096
7
[ 600-05-5 ]
[ 603-35-0 ]
[ 51114-94-4 ]
Reference：
[1] Russian Journal of General Chemistry, 2005, vol. 75, # 12, p. 1889 - 1894
8
[ 603-35-0 ]
[ 51114-94-4 ]
Reference：
[1] Russian Journal of General Chemistry, 2013, vol. 83, # 7, p. 1359 - 1364[2] Zh. Obshch. Khim., 2013, vol. 83, # 7, p. 1359 - 1364,6
9
[ 51114-94-4 ]
[ 93742-85-9 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760
With sodium hydride; In tetrahydrofuran; dimethyl sulfoxide; mineral oil; at 0 - 20℃; for 4.5h;
[0338] Step A: The mixture of <strong>[51114-94-4](2-carboxyethyl)triphenylphosphonium bromide</strong> (20.0 g, 54.0 mmol) and 4-methoxybenzaldehyde (6.5 g, 53.5 mmol) in anhydrous DMSO (64 mL) was added slowly to the suspension of 60percent NaH in mineral oil (4.3 g, 107 mmol) in anhydrous tetrahydrofuran (32 mL). The reaction mixture was stirred at 0 °C for 30 minutes then warmed to room temperature over 4 hours. The reaction mixture was quenched with IN HCl (150 mL) and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50 percent EtOAc in hexanes) to provide (E)-4-(4-methoxyphenyl)but-3-enoic acid (557) (5.7 g, 55.0percent) as a yellow solid.
55.0%
[0330] Step A: The mixture of <strong>[51114-94-4](2-carboxyethyl)triphenylphosphonium bromide</strong> (20.0 g, 54.0 mmol) and 4-methoxybenzaldehyde (6.5 g, 53.5 mmol) in anhydrous DMSO (64 mL) was added slowly to the suspension of 60percent NaH in mineral oil (4.3 g, 107 mmol) in anhydrous tetrahydrofuran (32 mL). The reaction mixture was stirred at 0 0C for 30 minutes then warmed to room temperature over 4 hours. The reaction mixture was quenched with IN HCl (150 mL) and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50 percent EtOAc in hexanes) to provide (.pound.)-4-(4-methoxyphenyl)but-3-enoic acid (557) (5.7 g, 55.0percent) as a yellow solid.
A mixture of the product of step a (6.6 g, 30.46 MMOL), carboxyethyl- triphenylphosphonium bromide (15.2 g, 36.6 MMOL), THF (30 ml) and DMSO (50 ml) is cooled to +5°C, and NaH (60percent in petroleum jelly, 2. 92 g, 73.0 MMOL) is then added in two portions. The reaction mixture is stirred overnight at room tem- perature, cooled to +5°C and then hydrolyse by addition of 200 ML of water. The aqueous phase is basified by addition of 1N sodium hydroxide, extracted with ether, acidified to pH 1 by addition of 35percent hydrochloric acid, and then extracted with ether. The resulting ether phase is washed with water, dried (NA2SO4) and concentrated. Flash chromatography on silica (50/50 ethyl ACETATE/HEPTANE) of the obtained residue gives the expected product (5. 15 9, YIELD : 62percent). m. p. = 102°C 1H NMR-CDCI3-B (PPM) : 0.94 (t, 3H); 1.41-1. 67 (m, 4H); 2.46 (t, 2H) ; 3.26 (d, 2H) ; 3.86 (s, 3H) ; 6.14 (DT, 1H) ; 6.40 (d, 1H) ; 6.78 (d, 1H) ; 7.22 (dd, 1H) ; 7.41 (d, 1H).
4- (3-Fluoro-phenyl)-but-3-enoic acid To a suspension of 3-fluoroaldehyde (13.4 ml, 126 mmol) and (2-carboxy-ethyl)- triphenyl-phosphonium bromide (62.85 g, 151 mmol, 1. 20 equivalents) in anhydrous dichloromethane (150 ml) at 0°C under nitrogen add potassium t-butoxide portion wise (315 mmol, 2.50 equivalents) over two hours and stir at room temperature overnight. Dilute with water, wash with dichloromethane (2x), acidify the aqueous layer with 1N hydrochloric acid to pH 1, dilute with ether, wash with water (2x), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (24.28 g,-99percent, contains approximately 1.6 g triphenylphophine oxide). NMR (400 MHz, CDC13) : 8 3.26 (d, 2H), 6.32 (m, 1H), 6.48 (d, 1H), 6.95 (t, 1H), 7.08 (d, 1H), 7.14 (d, 1H), 7.27 (m, 1H).
ethyl 4-(1-hydroxy-2-naphthyl)-3-butenoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With hydrogenchloride; sulfuric acid; In tetrahydrofuran; ethanol; dimethyl sulfoxide; mineral oil;
EXAMPLE 8 Ethyl 4-(1-hydroxy-2-naphthyl)-3-butenoate, E isomer A suspension of sodium hydride (60percent in mineral oil; 1.94 g, 0.049 mole) in dry tetrahydrofuran (20 mL) was stirred at 0°. A solution of 1-methoxymethoxy-2-naphthaldehyde (2.00 g, 0.009 mole) and 2-carboxyethyl-triphenylphosphonium bromide (prepared by the procedure of H. S. Corey, J. R. D. McCormick, and W. E. Swensen, J. Am. Chem. Soc. 86, 1884 (1964); 9.60 g, 0.023 mole) in dry dimethyl sulfoxide (15 mL) was added over 20 minutes. The mixture was allowed to warm to room temperature over 1.25 hours, then stirred at room temperature for 30 minutes. 1.0N hydrochloric acid (10 mL) was added dropwise, followed by stirring for an additional 20 minutes. The crude material was isolated by extraction with ethyl acetate and dissolved in absolute ethanol (200 mL), treated with 10 drops of concentrated sulfuric acid, and heated at reflux for 6 hours. The cooled solution was diluted with water, and the crude product isolated by extraction with ethyl acetate. The resulting oil was chromatographed with 9:1 petroleum ether/ether, to provide a solid which was recrystallized (hexane) to give the title compound (0.35 g, 15percent) as a tan solid, mp 83°-84°.
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 3.16667h;
(Reference example 6) 4-(2,4-Dimethylphenyl)butyric acid (2-Carboxyethyl)triphenylphosphonium bromide (150 g, 361 mmol) was suspended in tetrahydrofuran (500 mL) and 2,4-dimethylbenzaldehyde (55.4 mL, 397 mmol) was added thereto. A solution of potassium t-butoxide (81.1 g, 722 mmol) in tetrahydrofuran (300 mL) was added thereto under nitrogen atmosphere over 10 minutes and the mixture was stirred under ice-cooling for 3 hours. Water was added to the reaction mixture to stop the reaction and the temperature of the liquid was returned to room temperature. The mixture was concentrated under reduced pressure, a 8N aqueous sodium hydroxide solution was added thereto to bring pH to 11 and ether was added thereto to separate it. A 12N aqueous hydrochloric acid solution was added to an aqueous phase to bring pH to 2 and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-6:1) to obtain 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, yield: 54percent). 10percent Palladium-carbon (7.96 g, 50percent hydrous) was added to a solution of the obtained 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, 195 mmol) in methanol (400 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain the title compound (64.4 g, yield: 84percent).
(2-Carboxyethyl)triphenylphosphonium bromide (2.7 g, 6.59 mmol) was added to a solution of 3-fluorobenzaldehyde (0.5 ml_, 4.71 mmol) in anhydrous tetrahydrofuran (23 ml_). The suspension was cooled to -78°C and potassium tert- butoxide (1.7 g, 15.08 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight under argon. Water (20 ml_) was added, and tetrahydrofuran was removed under reduced pressure. Water (20 ml_) was added to the resulting solution, and the aqueous layer was extracted with ethyl acetate (50 ml_). The aqueous layer was acidified with 37percent aqueous solution of hydrochloric acid to pH 1 and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by flash chromatography on silica gel, eluting with cyclohexane - ethyl acetate (1 :1) to afford 4-(3-fluoro-phenyl)-but-3-enoic acid (0.5 g, 58percent) as a yellowish solid.
To a suspension of <strong>[51114-94-4](2-carboxyethyl)triphenylphosphonium bromide</strong> (CASNo. 51114-94- 4, 1.822 g, 4.256 mmol) and 2-fluoro-4-bromobenzaldehyde (CASNo. 188813-02-7, 0.900 g, 4.256 mmol) in THF (4 mL) and DMSO (4 mL) under nitrogen is added NaH (60percent <n="81"/>suspension in mineral oil, 0.34 g, 8.511 mmol). After 1.5 hours, the mixture is quenched with 1 M aqueous potassium bisulfate and extracted with isopropyl acetate. The combined organic phase is washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue is used in the next step without further purification.
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 1h;
EXAMPLE 81 -(4-(5 -(3 -( 1 -(4-fluorophenyl)cyclohexyl)propyl)- 1 ,2,4-oxadiazol-3 -yl)benzyl)azetidine- -carboxylic acidPreparation 8A: (E)-4-(l-(4-fluorophenyl)cyclohexyl)but-3-enoic acidA)[0151] To a stirred suspension of l-(4-fluorophenyl)cyclohexanecarbaldehyde (160 mg, 0.776 mmol) and 2-carboxyethyl triphenylphosphonium bromide (483 mg, 1.164 mmol) in THF (7 mL) at -78°C was added 1M lithium bis(trimethylsilyl)amide (2.172 mL, 2.172 mmol) in THF dropwise, and the mixture was stirred for 30 mins at -78°C, and 30 mins at a temperatures in the range of from -78°C to room temperature. Next, the mixture was stirred overnight at room temperature. After addition of 3 mL of IN HCl, the mixture was extracted with EtOAc (2x), and the combined extracts were washed with brine, dried over Na2S04 and evaporated to give an oily residue. The residue was purified byCombiflash (24 g silica gel) eluting with 5:95 followed by 3:7 EtOAc -hexane to give (E)-4-(l-(4-fluorophenyl) cyclohexyl)but-3-enoic acid (37.7 mg, 0.144 mmol, 18.53 percent yield) along with the unreacted starting material (41. 5 mg). XH NMR (400 MHz, CC13D) delta ppm 7.28-7.33 (2 H, m), 6.93-6.99 (2 H, m), 5.97 (1 H, dt, J=l 1.64, 1.76 Hz), 5.58 (1 H, dt, J=11.64, 7.25 Hz), 2.59 (2 H, dd, J=7.25, 1.76 Hz), 1.86-1.96 (2 H, m), 1.54-1.76 (8 H, m), 1.22-1.33 (2 H, m).
18.53%
Intermediate 5(E)-4-(l-( -Fluorophenyl)cyclohexyl)but-3-enoic acid[00126] To a stirred suspension of l-(4-fluorophenyl)cyclohexanecarbaldehyde (160 mg, 0.776 mmol) and 2-carboxyethyl triphenylphosphonium bromide (483 mg, 1.164 mmol) in THF (7 mL) at -78 °C was added 1M lithium bis(trimethylsilyl)amide (2.172 mL, 2.172 mmol) in THF dropwise, and the mixture was stirred for 30 mins at -78 °C, and 30 mins at a temperatures in the range of from -78 °C to room temperature. Next, the mixture was stirred overnight at room temperature. After addition of 3 mL of IN HC1, the mixture was extracted with EtOAc (2x), and the combined extracts were washed with brine, dried over Na2S04 and evaporated to give an oily residue. The residue was purified by Combiflash (24 g silica gel) eluting with 5:95 followed by 3:7 EtOAc -hexane to give (E)-4-(l-(4-fluorophenyl) cyclohexyl)but-3-enoic acid (37.7 mg, 0.144 mmol, 18.53percent yield) along with the unreacted starting material (41. 5 mg). XH NMR (400 MHz, CDC13) delta ppm 7.28-7.33 (2 H, m), 6.93-6.99 (2 H, m), 5.97 (1 H, dt, J=11.64, 1.76 Hz), 5.58 (1 H, dt, J=11.64, 7.25 Hz), 2.59 (2 H, dd, J=7.25, 1.76 Hz), 1.86-1.96 (2 H, m), 1.54-1.76 (8 H, m), 1.22-1.33 (2 H, m).
To a suspension of <strong>[51114-94-4](2-carboxyethyl)triphenylphosphonium bromide</strong> 41 (18.8 g, 45 mmol) in dry THF (120 mL) at ?10 °C, under nitrogen atmosphere, was added LiHMDS (12.5 g, 75 mmol). The mixture was stirred for 45 min, and a solution of N-Boc-S-prolinal 16 (3 g, 15 mmol) in dry THF (50 mL) was added over a period of 30 min. The resulting mixture was stirred at 0 °C for 1 h and then quenched by the addition of 5percent aqueous HCl. To the resultant mixture, ethyl acetate (300 mL) was added, the organic layer was separated and washed with saturated NaHCO3 solution (2×150 mL). The combined washings were acidified (pH=2) with dil HCl (5percent aqueous solution) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with water (1×150 mL), brine solution (1×100 mL), dried over anhydrous Na2SO4 and concentrated to give crude 42 (3.1 g) as yellow oil. Crude 42 (3 g, 12 mmol) in ethanol (150 mL) was stirred at room temperature with 10percent Pd?C (0.3 g) in hydrogen atmosphere (40 psi) for 2 h. The catalyst was filtered off, washed with ethanol (20 mL) and the combined filtrate and washing was concentrated. The residue was purified by column chromatography (1percent MeOH/DCM)
A round-bottomed flask was charged with 25b (5.07 g, 12.2 mmol) and THF(60 mL) and cooled to 0 °C. NaHMDS (25.0 mL, 1.0M in THF, 25.0 mmol) wasadded dropwise over 5 min. The reaction was stirred at 0 °C for 1 h, warmed to rt,and stirred for 2 h. After cooling to 78 °C, aldehyde 26a (2.63 g, 11.9 mmol) in THF (3.0 mL) was added via syringe with rinsing (23.0mL THF). The reaction was allowed to warm to rt over 1 h and then stirred for 17 h. Saturated aqueousNH4Cl (100 mL) was added, the layers were separated, and the aqueous layer was extracted with diethyl ether (340 mL). The combined organic layers were was hedwith brine (100 mL) and dried (MgSO4). Column chromatography on silica gel(EtOAc as eluent) yielded bromoacid 27a (2:1 Z=E) as a colorless, transparent liquid (2.30 g, 8.30 mmol, 70percent). Rf 0.27 (1:2 EtOAc=hexanes). 1H NMR (CDCl3,300 MHz): d 5.59 (m, 2H), 3.44 (t, 2H, J6.8 Hz), 3.16 (d, 1.34H, J6.2 Hz),3.10 (d, 0.66H, J6.0 Hz), 2.06 (m, 2H), 1.88 (p, 2H, J6.9 Hz), 1.32?1.47 (m,10H), OH proton not seen. 13C NMR (CDCl3, 100 MHz): d 177.9, 177.8, 135.4,134.0, 120.8, 120.0, 34.02, 33.99, 32.79, 32.78, 32.4 (two signals), 29.23, 29.21,29.16, 29.1, 29.00, 28.96, 28.7 (two signals), 28.1 (two signals), 27.3 (two signals).IR (neat, cm1): 2926 (br, s), 2854 (m), 1709 (s), 1462 (w), 1434 (m), 1292 (w),1250 (s), 1218 (m), 1180 (w), 1089 (w), 1045 (m). HRMS for 27a: Calc. forC12H10721 Ag79BrO2: 382.9770. Found: 382.9754. Difference: 4.18 ppm.
General procedure: A round-bottomed flask was charged with 25b (5.07 g, 12.2 mmol) and THF(60 mL) and cooled to 0 °C. NaHMDS (25.0 mL, 1.0M in THF, 25.0 mmol) was added dropwise over 5 min. The reaction was stirred at 0 °C for 1 h, warmed to rt, and stirred for 2 h. After cooling to 78 °C, aldehyde 26a (2.63 g, 11.9 mmol) in THF (3.0 mL) was added via syringe with rinsing (23.0mL THF). The reaction was allowed to warm to rt over 1 h and then stirred for 17 h. Saturated aqueous NH4Cl (100 mL) was added, the layers were separated, and the aqueous layer was extracted with diethyl ether (340 mL). The combined organic layers were was hedwith brine (100 mL) and dried (MgSO4). Column chromatography on silica gel(EtOAc as eluent) yielded bromoacid 27a (2:1 Z=E) as a colorless, transparent liquid (2.30 g, 8.30 mmol, 70percent).
General procedure: A round-bottomed flask was charged with 25b (5.07 g, 12.2 mmol) and THF(60 mL) and cooled to 0 °C. NaHMDS (25.0 mL, 1.0M in THF, 25.0 mmol) was added dropwise over 5 min. The reaction was stirred at 0 °C for 1 h, warmed to rt,and stirred for 2 h. After cooling to 78 °C, aldehyde 26a (2.63 g, 11.9 mmol) in THF (3.0 mL) was added via syringe with rinsing (23.0mL THF). The reaction was allowed to warm to rt over 1 h and then stirred for 17 h. Saturated aqueous NH4Cl (100 mL) was added, the layers were separated, and the aqueous layer was extracted with diethyl ether (340 mL). The combined organic layers were was hedwith brine (100 mL) and dried (MgSO4). Column chromatography on silica gel(EtOAc as eluent) yielded bromoacid 27a (2:1 Z=E) as a colorless, transparent liquid (2.30 g, 8.30 mmol, 70percent).
(3E)-4-(2,3-dimethylphenyl)but-3-enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of2,3-dimethylbenzaldehyde (17.0 g, 41.0 mmol) in THF (40 mL) was added NaHMDS (41.1 mL, 82.1 mmol) at -20 °C, and the reaction was stirred for 20 min. (2-Carboxyethyl)triphenylphosphonium bromide (5.0 g, 37.3 mmol) was added to the reaction at -78 °C, and reaction was stirred while warming to rt overnight. The solution was diluted with water (50 mL) and extracted with EtOAc (50 x 3 mL). Organics were washed with brine (50 mL), dried (Na2S04), and concentrated to give7.00 g (99percent) of the crude title compound as a yellow solid. [M+H] calc'd for C1zH1402,191; found 191.
With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 2h;
To a suspension in DMSO/THF 1:1 volume/volume (26 mL) of 3-thiophencarboxaldehyde (2.0 g; 18 mmoles) and <strong>[51114-94-4]2-(carboxyethyl) (triphenyl)phosphonium bromide</strong> (8.9 g; 21 mmoles) 5.3 g of potassium t-butoxide are added. The reaction mixture is left under stirring for 2 hours at room temperature. Then the organic phase is washed with water (20 mL) and extracted with chloroform (2 x 20 mL). The solvent is removed and the aqueous phase is acidified with concentrated HCl and extracted with chloroform (2 x 20 mL). The organic phase is recovered and washed with water and dried with sodium sulphate. After filtration, the organic phase is concentrated under vacuum. The obtained residue is purified by chromatography on silica gel by using as eluent a ligroin/ethyl acetate 1:1 volume/volume mixture. 2.3 g of a mixture of the two cis and trans diastereoisomers of the 5-(thiophen-3-il)-pent-4-enoic acid are obtained (yield 70percent). Rf=0.35 (ligroin/ethyl acetate 6/4 volume/volume); 1H NMR (CDCl3) delta (ppm) : 7.29 (m, 1H, ArH), 7.23 (m, 1H, ArH), 7.18 (m, 2H, ArH), 7.09 (m, 2H, ArH), 6.44 (m, 2H, CH), 6.06 (m, 1H, CH), 5.57 (m, 2H, CH), 2.68 (m, 2H, CH2), 2.52 (m, 6H, CH2); 13C NMR (CDCl3) delta (ppm) : 179.2, 179.1, 139.9, 138.2, 128.9, 128.5, 127.9, 125.9, 125.5, 125.2, 124.9, 124.5, 123.1, 121.2, 33.9, 33.8, 27.8, 24.2; FT-IR (film) numax:3098.1, 2923.5, 1693.2, 1410.6, 1267.7, 1242.6, 1206.6, 1155.3, 966.1, 755.4 cm-1.
With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 2h;
0284] To a suspension in DMSO/ THF 1:1 volume/volume (26 mL) of 3-thiophencarboxaldehyde (2.0 g; 18 mmoles) and <strong>[51114-94-4]2-(carboxyethyl) (triphenyl)phosphonium bromide</strong> (8.9 g; 21 mmoles) 5.3 g of potassium t-butoxide are added. The reaction mixture is left under stirring for 2 hours at room temperature. Then the organic phase is washed with water (20 mL) and extracted with chloroform (2×20 mL). The solvent is removed and the aqueous phase is acidified with concentrated HCl and extracted with chloroform (2×20 mL). The organic phase is recovered and washed with water and dried with sodium sulphate. After filtration, the organic phase is concentrated under vacuum. The obtained residue is purified by chromatography on silica gel by using as eluent a ligroin/ethyl acetate 1:1 volume/volume mixture. 2.3 g of a mixture of the two cis and trans diastereoisomers of the 5-(thiophen-3-il)-pent-4-enoic acid are obtained (yield 70percent). Rf=0.35 (ligroin/ethyl acetate 6/4 volume/volume); 1H NMR (CDCl3) delta (ppm): 7.29 (m, 1H, ArH), 7.23 (m, 1H, ArH), 7.18 (m, 2H, ArH), 7.09 (m, 2H, ArH), 6.44 (m, 2H, CH), 6.06 (m, 1H, CH), 5.57 (m, 2H, CH), 2.68 (m, 2H, CH2), 2.52 (m, 6H, CH2); 13C NMR (CDCl3) delta (ppm): 179.2, 179.1, 139.9, 138.2, 128.9, 128.5, 127.9, 125.9, 125.5, 125.2, 124.9, 124.5, 123.1, 121.2, 33.9, 33.8, 27.8, 24.2; FT-IR (film) numax: 3098.1, 2923.5, 1693.2, 1410.6, 1267.7, 1242.6, 1206.6, 1155.3, 966.1, 755.4 cm?1.
3.3 g of the cis and trans mixture of 5-(thiophen-3-yl)-pent-4-enoic acid prepared in example 9a are solubilized in absolute ethanol (50 mL). The compound is then submitted to an hydrogenation reaction with hydrogen (3 atm of H2) on Pd/C 10percent (180 mg) carried out at room temperature for a time of 18 hours. The reaction mixture is then filtered on celite and washed with methanol (3 x 10 mL). The solvent is removed under vacuum, obtaining 2.6 g of the 5-(thiophen-3-yl)-pentanoic acid (yield 80percent). Rf=0.35 (ligroin/ethyl acetate 6/4 volume/volume); 1H NMR (CDCl3) delta (ppm): 8.35 (s, 1H, OH broad), 7.24 (m, 1H, ArH), 6.93 (m, 2H, ArH), 2.66 (m, 2H, CH2), 2.38 (m, 2H, CH2), 1.69 (m, 4H, CH2); 13C NMR (CDCl3) delta (ppm): 179.8, 142.3, 128.2, 125.3, 120.1, 33.9, 29.9, 24.4; FT-IR (film) numax: 2944.3, 2865.4, 1692.9, 1462.7, 1425.3, 1307.6, 1258.2, 1212.9, 1190.2, 930.2, 750.8, 592.0 cm-1.
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