* 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.
Cyclobutanone (0.5 g, 7.14 mmol) and (ethoxycarbonylmethylen)-triphenylphosphorane (2.7 g, 7.75 mmol) were heated to 125 to 140° C. in seal tube for 24 h. Reaction mixture was cooled to room temperature; 50 mL of pentane was added and stirred for 20 min. Then reaction mixture was filtered. Pentane layer was evaporated without applying pressure. Crude product was purified by column chromatography (silica gel 60-120 mesh, diethyl ether and n-pentane was used as eluent) afforded colorless oil. Yield: 0.7 g, 70percent.1H NMR (400 MHz, CDCl3): δ 1.27 (t, J=7.0 Hz, 3H), 2.04-2.13 (m, 2H), 2.83 (t, J=8.0 Hz, 2H), 3.13 (t, J=8.0 Hz, 2H), 4.10-4.17 (m, 2H), 5.58 (t, J=2.2 Hz, 1H)
Reference：
[1] Patent: US2012/295874, 2012, A1, . Location in patent: Page/Page column 245
[2] Journal of the American Chemical Society, 1973, vol. 95, # 6, p. 1849 - 1859
2
[ 1829-34-1 ]
[ 1099-45-2 ]
[ 91-64-5 ]
[ 33491-30-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 10, p. 2170 - 2173
Intermediate 390A: Ethyl (E)- -(lH-pyrazol-4-yl)acrylate To a stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (2 g, 20.8 mmol) in THF (30 mL) was added (carbothoxymethylene)triphenylphosphorane (8 g, 22.9 mmol). The reaction mixture was then heated at 70 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (3percent methanol /chloroform) to isolate ethyl 3-(lH-pyrazol-4-yl)acrylate (2.5 g, 73percent yield). NMR (400 MHz, DMSO-de) delta 13.14 (br s, IH), 8.18 (s, IH), 7.93 (s, IH), 7.57 (d, J=15.6 Hz, IH), 6.32 (d, J=16.1 Hz, IH), 4.15 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.3 Hz, 3H); LCMS m/z 165 (M-H).
60%
In tetrahydrofuran; at 70℃; for 8h;Inert atmosphere;
(E)-ethyl 3- ( lH-pyrazol-4-yl)acrylate[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836g, 2.4 mmol) was added to a solution of iH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70°C under anitrogen atmosphere for 8h. HPLC/MS analysis indicated completion of the reaction and both E and Z isomers of product were observed. The reaction mixture was cooled down to room temperature and evaporated in vacuo to get the crude product. This crude was purified by silica gel column chromatography using 0-80percent EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions, pure (E)-ethyl 3-( H-pyrazol-4-yl)acrylate (0.198g, 60percent) as a white solid. ES+ (M+H)+ 167
60%
In tetrahydrofuran; at 20 - 70℃; for 8h;Inert atmosphere;
[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836 g, 2.4 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 THF (6 mL) at room temperature. This solution was heated at 70° C. under a nitrogen atmosphere for 8 h. [0446] HPLC/MS analysis indicated completion of the reaction and both E and Z isomers of product were observed. The reaction mixture was cooled down to room temperature and evaporated in vacuo to get the crude product. This crude was purified by silica gel column chromatography using 0-80percent EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions, pure (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.198 g, 60percent) as a white solid. ES+(M+H)+167
General procedure: To a stirred solution of ethyl 2-(triphenylphosphoranylidene)acetate (3.83 g, 11.0 mmol) in CH2Cl2 (30.0 mL) was added isatin (1.47 g, 10.0 mmol) at 0 °C. After stirring for 8 h at 0 °C, the mixture was concentrated by rotary evaporation. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=3:1?10:1) to afford the compound 1a as a red solid (1.78 g, 82 percent).
To a solution of li/-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (300 mg, 3.12 mmol) was added ethyl 2-(triphenylphosphoranylidene)acetate (1360 mg, 3.90 mmol) in toluene (10 mL). The mixture was heated at 90 °C for 2 h. The solvent was removed in vacuo. The crude material was purified by flash chromatography to afford Example 7A (450 mg, 2.71 mmol, 87percent yield) as a white solid. LCMS (ES): m/z 167.1 [M+H]+.
A solution of 8 and 10 (1.5 eq.) in CHCl3 (50 mL) was heated to reflux. After TLC analysis indicated thatthe reaction was completed, the reaction mixture was concentrated under reduced pressure and purified bysilica gel chromatography (ethyl acetate/hexane = 10/90) to afford trienoate 11. Conversion of 11 toaldehyde 12 was performed as above for the synthesis of 8 using DIBAL-H and MnO2. Finally, 12 wasreacted with 9 as before to produce tetraenone 2p (18percent overall yield).
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