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Structure of 930-30-3 * Storage: {[proInfo.prStorage]}
* 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.
A mixture of cyclopentanone (8.4 g, 0.1 mol), thiourea (15.22 g, 0.2 mol) and iodine (25.38 g, 0.1 mol) was heated overnight at 100° C., then isopropyl ether was added and the mixture heated at reflux for an additional 30 minutes. The solid was collected via filtration, washed with ether, and then dissolved in hot water. The solution was left to cool to RT, was then basified with concentrated ammonia, and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the desired product (5.56 g 40percent yield). ESIMS (m/z) 141.0 (MH+).
Reference：
[1] Journal of the American Chemical Society, 1984, vol. 106, # 6, p. 1750 - 1759
3
[ 88867-81-6 ]
[ 930-30-3 ]
[ 626-96-0 ]
[ 26831-63-0 ]
[ 75308-19-9 ]
[ 91712-45-7 ]
Reference：
[1] Journal of the American Chemical Society, 1984, vol. 106, # 6, p. 1750 - 1759
4
[ 279-35-6 ]
[ 930-30-3 ]
[ 626-96-0 ]
[ 26831-63-0 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 12, p. 3498 - 3503
[2] Journal of the American Chemical Society, 1982, vol. 104, # 12, p. 3498 - 3503
Reference：
[1] Journal of Organic Chemistry, 1979, vol. 44, # 2, p. 3474 - 3482
7
[ 930-30-3 ]
[ 41171-91-9 ]
Yield
Reaction Conditions
Operation in experiment
60.2%
With triethylamine hydrochloride In methanol at 20℃; for 4 h;
To a solution of cyclopent-2-enone (5 g, 61 mmol) and potassium cyanide (4.75 g, 73 mmol) in methanol (100 mL)Triethylamine hydrochloride (12.5 g, 42 mmol) was added and reacted for 4 hours at room temperature. The solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound (4g, 60.2 percent).
53%
With triethylamine hydrochloride In methanol; water at 20℃; Inert atmosphere
To a solution of triethylamine hydrochloride (117.4 g, 854 mmol), potassium cyanide (35.9 g, 630 mmol) in mixture of water (150 mL) and methanol (150 mL) was added dropwise solution of cyclopent-2-en-1 -one (50 g, 610 mmol) in methanol (60 mL). The mixture was stirred at room temperature overnight. The organic solvent was concentrated and the remaining aqueous phase extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried over magnesium sulfate and crude product was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (1 :1 ) to afford the title compound as yellow oil (35 g, 53percent).1H NMR (400 MHz, CDCl3): 3.25-3.15 (m, 1 H), 2.62-2.52 (m, 2H), 2.52-2.40 (m, 2H), 2.40-2.20 (m, 2H).
11.5 g
With triethylamine hydrochloride In methanol at 20℃;
A mixture of KCN (19.0 g), water (200 ml), MeOH (200 ml) and Et3N HCl (50.0 g) was stirred at rt, and cyclopentenone was added dropwise slowly. After the addition was completed the mixture was stirred at rt overnight. The solution was concentrated to remove most of methanol and to the aqueous layer was added acetic acid (2 ml) to bring the pH to 6 -7, followed by extraction with DCM (three times). The combined organic layer was concentrated, and the resulting residue was purified by column chromatography on silica gel (PE/EA=5/1 to 4/1) to afford 3-cyanocyclopentanone (11.5 g) as a yellow oil.
7.5 g
With triethylamine hydrochloride In methanol at 20℃; for 4 h;
Step 1 (0747) A solution of compound 22-1 (10 g, 122 mmol), KCN (9.5 g, 146 mmol) and Et3N.HCl (25 g, 83 mmol) in MeOH (150 mL) was stirred at rt for 4 h. The mixture was concentrated; the residue was re-dissolved in EtOAc. The solution was washed with water and brine, dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (PE: EA=5:1) to give 7.5 g of compound 22-2. 1H NMR (400 MHz, CDCl3): δ 3.13-3.51 (m, 1H), 2.56-2.63 (m, 1H), 2.16-2.48 (m, 5H).
With potassium cyanide; triethylamine hydrochloride In methanol at 20℃; for 4 h;
A solution of compound 22-1 (10 g, 122 mmol), KCN (9.5 g, 146 mmol) and Et3N-HCl (25 g, 83 mmol) in MeOH (150 mL) was stirred at rt for 4 h. The mixture was concentrated; the residue was re-dissolved in EtOAc. The solution was washed with water and brine, dried over Na2S04, concentrated. The residue was purified by silica gel chromatography (PE: EA = 5: 1 ) to give 7.5 g of compound 22-2. 1H NMR (400 MHz, CDC13): δ 3.13 - 3.51 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.16 - 2.48 (m, 5 H).
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 15, p. 5144 - 5155
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 5, p. 2164 - 2167
[3] Patent: WO2013/28670, 2013, A1, . Location in patent: Page/Page column 119; 120
Reference：
[1] Australian Journal of Chemistry, 1994, vol. 47, # 10, p. 1833 - 1841
12
[ 930-30-3 ]
[ 7677-24-9 ]
[ 1312418-37-3 ]
[ 41171-91-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2011, vol. 89, # 5, p. 535 - 543
13
[ 930-30-3 ]
[ 13012-38-9 ]
Reference：
[1] Journal of the American Chemical Society, 1996, vol. 118, # 29, p. 7002 - 7003
14
[ 930-30-3 ]
[ 91658-36-5 ]
[ 13012-38-9 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 15, p. 5144 - 5155
15
[ 930-30-3 ]
[ 13725-38-7 ]
Reference：
[1] Patent: WO2014/74675, 2014, A1,
16
[ 930-30-3 ]
[ 75-52-5 ]
[ 81266-47-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With L-arginine In water at 25℃; for 24 h; Green chemistry
General procedure: Method A: In a 4-mL vial, cyclohex-2-enone (0.5 mmol, 48 μL), internal standard (t-amyl alcohol, 0.05 mmol, 5.5 μL), amino acid (625 μL of 400 mM), nitromethane (0.55 mmol, 30 μL) were added in water (1311.5 μL). The reaction mixture was stirred at 25 °C. After 24 or 48 h, the reactionmixture (100 μL) was retrieved and extracted with MTBE (1 mL). The MTBE layer was analyzed by gas chromatography.
Reference：
[1] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 12, p. 3671 - 3674
[2] Acta Chimica Hungarica, 1983, vol. 113, # 3, p. 303 - 308
[3] Acta Chimica Hungarica, 1983, vol. 113, # 3, p. 303 - 308
[4] Tetrahedron Asymmetry, 2008, vol. 19, # 16, p. 1934 - 1940
[5] Tetrahedron Asymmetry, 2008, vol. 19, # 16, p. 1934 - 1940
17
[ 930-30-3 ]
[ 3001-72-7 ]
[ 81266-47-9 ]
Reference：
[1] Patent: US4827032, 1989, A,
18
[ 930-30-3 ]
[ 4248-19-5 ]
[ 847416-99-3 ]
Yield
Reaction Conditions
Operation in experiment
36%
With bismuth(III) nitrate In dichloromethane at 27℃; for 5 h;
To a stirred suspension of cyclopent-2-en-1-one 36 (2.50 g, 3.05 mmol) in DCM (60 mL), was added boc amine (3.60 g, 3.05 mmol) and stirred for 10-15 mm. Bismuth nitrate (14.70 g, 3.05 mmol) was charged portion wise and allowed to stir at room temperature for about 5h. After completion of reaction, the reaction mixture was diluted with DCM & was filtered through celite bed, filtrate obtained was quenched with saturated NaHCO3 solution, DCM layer was separated, and aqueous layer was extracted with DCM, combined organic extracts were dried over Na2SO4 and concentrated to obtain crude compound. The crude was further purified by combiflash using 10-15 percent ethyl acetate in hexane to obtain tert-butyl (3-oxocyclopentyl)carbamate 64 as a white solid (6.50 g, 36percent yield). MS: 200.20 (M+H).
Stage #1: at 20℃; for 18 h; Stage #2: With sodium carbonate In methanol; water
Mix cyclopentenone (100 g, 1.2 mol) and phthalimide (170 g, 1.2 mmol) in MeOH (900 mL) and stir for 18 h at ambient temperature. Stir vigorously with a mechanical stirrer and add 2 M aqueous Na2CO3 (80 mL). After approximately 2 h, a thick white precipitate will form. Stir at room temperature for 48 h. Collect the white solid by vacuum filtration and rinse with methanol. Suspend the solid in water (300 mL) and stir for 3 h. Collect the solid and dry in a vacuum oven at 40° C. overnight to give 195 g (71percent) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.85-7.77 (m, 4H), 4.90 (m, 1H), 2.67 (ddd, 1H, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, 1H, J=18.5, 9.2 Hz), 2.45 (m, 1H), 2.32-2.21 (m, 3H); MS (m/z): 230 (M+1, weak).
71%
With sodium carbonate In methanol; water at 20℃; for 26 h;
PREPARATION 1(R,S)-2-(3-Oxo-cyclopentyl)-isoindole-1,3-dione While stirring vigorously with a mechanical stirrer, 2 M aqueous Na2CO3 (79 mL, 0.158 mol) is added to a slurry of cyclopentenone (100 g, 1.22 mol) and phthalimide (180 g, 1.22 mol) in MeOH (886 mL). After approximately 2 h, a thick white precipitate will form. The mixture is stirred at room temperature for 24 h. The white solid is collected by vacuum filtration and rinsed with methanol (1 L). The solid is suspended in water (1 L) and stirred for 3 h. The solid is collected and dried in a vacuum oven at 40° C. overnight to give 198 g (71percent) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.85-7.77 (m, 4H), 4.90 (m, 1H), 2.67 (ddd, 1H, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, 1H, J=18.5, 9.2 Hz), 2.45 (m, 1H), 2.32-2.21 (m, 3H); ES/MS m/z 230 (M+1, weak). NOTE: The product will readily undergo the retro-Michael reaction upon treatment with aqueous base.
71%
With sodium carbonate In methanol; water at 20℃;
Preparation 1; (^^^-(S-Oxo-cyclopenty^-isoindole-ljS-dione; While stirring vigorously with a mechanical stirrer, 2 M aqueous Na2CO3 (79 mL,0.158 mol) is added to a slurry of cyclopentenone (100 g, 1.22 mol) and phthalimide (180 g, 1.22 mol) in MeOH (886 mL). After approximately 2 h, a thick white precipitate will form. The mixture is stirred at room temperature for 24 h. The white solid is collected by vacuum filtration and rinsed with methanol (1 L). The solid is suspended in water (1 L) and stirred for 3 h. The solid is collected and dried in a vacuum oven at 40 0C <n="30"/>overnight to give 198 g (71percent) of the title compound as a white solid. IH NMR (DMSO- dβ) δ 7.85-7.77 (m, 4H), 4.90 (m, IH), 2.67 (ddd, IH, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, IH, J=18.5, 9.2 Hz), 2.45 (m, IH), 2.32-2.21 (m, 3H); ES/MS m/z 230 (M+ 1, weak). NOTE: The product will readily undergo the retro-Michael reaction upon treatment with aqueous base.
48.7%
With sodium carbonate In methanol; water at 0 - 20℃; for 16.5 h;
[0603] To a slurry of cyclopentenone (5 g, 60.9 mmol) and phthalimide (9 g, 61.1 mol) in MeOH (440 mL) was added aqueous Na2CO3 solution (2 M, 4 mL, 8 mmol) dropwise at 0 oC for 30 min. The reaction was stirred at room temperature for 16 hrs. After filtration, the filter cake was washed with cooled MeOH, dried under vacuum to give the title compound (6.8 g, 48.7percent yield) as white solid. LC/MS (ESI) m/z: 230 [M+H]+.
48.7%
With sodium carbonate In methanol; water at 0 - 20℃; for 16.5 h;
To a slurry of cyclopentenone (5 g, 60.9 mmol) and phthalimide (9 g, 61.1 mol) in MeOH (440 mL) was added aqueous Na2CO3solution (2 M, 4 mL, 8 mmol) dropwise at 0° C. for 30 main. The reaction mixture was stirred at room temperature for 16 hrs. After filtration, the filter cake was washed with cooled MeOH and dried under vacuum to give the title compound (6.8 g, 48.7percent yield) as white solid. LCMS: LC/MS (ESI) m/z: 230 [M+H]+
44%
With sodium carbonate In methanol at 20℃; for 20 h; Inert atmosphere
To a mixture of cyclopent-2-en-1-one (10.0 g, 121.8 mmol, 10.2 mL, 1.0 eq) and isoindoline-1,3-dione (17.9 g, 121.8 mmol, 1.0 eq) in MeOH (90 mL) was added Na2CO3 (2 M, 7.92 mL, 0.13 eq) dropwise. The solution was stirred at 20 °C for 20 h and the precipitated solid was collected, washed with MeOH (50 ml) and dried to give the crude product. The crude product was further washed with DCM (200 mL) and dried to give compound 07-1-1 (13.5 g, 53.0 mmol, 44percent yield).
With L-arginine; In water; at 25.0℃; for 24.0h;Green chemistry;
General procedure: Method A: In a 4-mL vial, cyclohex-2-enone (0.5 mmol, 48 muL), internal standard (t-amyl alcohol, 0.05 mmol, 5.5 muL), amino acid (625 muL of 400 mM), nitromethane (0.55 mmol, 30 muL) were added in water (1311.5 muL). The reaction mixture was stirred at 25 C. After 24 or 48 h, the reactionmixture (100 muL) was retrieved and extracted with MTBE (1 mL). The MTBE layer was analyzed by gas chromatography.
With pyridine N-oxide; N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;Inert atmosphere;
To a solution of cyclopentenone (500 mg, 6.09 mmol) and pyridine-N-oxide (870 mg, 9.14 mmol) in CH3CN (30 mL) was added NBS (1.08 g, 6.09 mmol) at 0 C. The resulting mixture was warmed to rt and stirred for 24 h. After volatile material was removed under reduced pressure, the resulting residue was purified by column chromatography (SiO2, hexane/AcOEt=7/1) to give 32 (967 mg, yield 99%) as a brown oil. Spectral data were identical to the reported data.24
85 - 87%
Experimental Procedures-Part 2:; Step 1 - Bromination of cyclopentenone:; Procedure:; A 3 L round bottom flask with a magnetic stir bar, nitrogen inlet, addition runnel and internal temperature probe was charged with 2-cyclopentenone (100 g, 1225 mmol) in 1.25 L CH2Cl2 and cooled to -20 0C. HBr (27.3 mL, 245 mmol) was added and the light yellow solution stirred for 5 min. The addition funnel was charged with bromine (61.9 mL, 1225 mmol) and it <n="58"/>was added dropwise over 1 h while maintaining the internal temperature between -24 and -20 0C. The bromine was decolorized rapidly during the addition. The yellow solution was stirred at -20 0C for 30 min until TLC indicated consumption of starting enone. Pyridine (149 mL, 1837 mmol) was added dropwise, maintaining the internal temperature below -20 0C. Upon complete addition, the solution was stirred at 0 0C for 1 h. The reaction was quenched with 1 M Na2S2O3 (1 L) and diluted with MTBE (2 L). The organic phase was washed with 1 M HCl (2 x 1 L) followed by H2O (1 L). The dark organic phase was dried using Na2SO4 then filtered. The remainder of the CH2Cl2 was solvent switched to MTBE until an ultimate ratio OfMTBErCH2Cl2 of 8:1 was reached. The dark solution was stirred with 30% (60 g) DARCO KB-B overnight. The DARCO was removed by filtration through a short pad of solka floe to afford a colorless solution. Solvent was removed in vacuo to provide 170 g of 15 as a white crystalline solid (95.83 wt%, 87% isolated yield).
54%
Using a previously reported bromination procedure,3 a round-bottom flask charged with 2-cyclopenten-1-one (4.873 g, 59.3 mmol), Oxone (21.902 g, 71.3 mmol, 1.2 equiv.), and CH2Cl2 (133 mL)underwent addition of 2N HBr (65 mL, 130 mmol, 2.2 equiv.). The mixture was stirred in the dark at rtfor 2 h. After, NEt3 (26.5 mL, 190.0 mmol, 3.2 equiv.) was added slowly and the mixture was stirred for 14 h at rt. The reaction was quenched upon addition of 3% HCl (100 mL). The organic phase of themixture was obtained and was washed with 3% HCl (100 mL), brine (100 mL), and dried with MgSO4.The solvent was removed under reduced pressure to obtain a brown oil. Crystallization from a mixtureof hexanes / Et2O at 0 C and rinsing with cold hexanes afforded 14 (5.123 g, 54%) as an ambercrystalline solid.
30%
2- Cyclopentenone (1 mmol) and OXONE (1.2 mmol) were dissolved in dry DCM in a 2 necked flask. 2 N HBr (2.2 mmol) was added and the solvent turned orange. TEA (2 mL) was added carefully after stirring at room temperature for 4 h. After stirring overnight at room temperature, the reaction mixture was neutralized by pH control, extracted with ethyl acetate, and the organic phase was dried over MgSO4 and the solvent was evaporated in a rotary evaporator [22]. Brown solid (30%).Phenyl boronic acid (1.5 mmol), Na2CO3 (3 mmol) was added to a stirred mixture under nitrogen by adding a 1/1 10 mL toluene/water mixture. 19 was added via dissolution in toluene. Finally, moles of 2% Pd (PPh3)4 were added and heated at 100 C under nitrogen. After 24 h, it was cooled to room temperature. Extraction was carried out with ethyl acetate and the organic phase was dried over MgSO4 and then the solvent was evaporated in a rotary evaporator. Light yellow oil (30%). 1H NMR (500 MHz, DMSO) delta 8.10 (t, J=2.8 Hz, 1H), 7.69 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.30 (t, J=7.3 Hz, 1H), 2.51-2.46 (m, 4H). 13C NMR (126 MHz, DMSO) delta 206.39 (C]O), 160.01 (CAr), 140.65 (Cq), 130.80 (Cq), 127.38 (CHArx2), 127.18 (CH), 125.80 (CHArx2), 34.57 (CH2), 25.00 (CH2). LC-MS m/z: [M+H]: 159. Dimethyl malonate (1.5 mmol) in a 2 necked flask was placed under nitrogen and dissolved in 10 mL dry THF and cooled to 0 C. After 30 min NaH (3 mmol) was added rapidly under nitrogen and the reaction continued at 0 C. After 1 h 20 (1 mmol) was added to the reaction medium. The reaction was allowed to warm to room temperature and allowed to stir for 4 h. The reaction was terminated by TLC and LC-MS control. Extraction was carried out with 1 N HCl and DCM. The organic phase was dried over MgSO4 and then the solvent was evaporated in a rotary evaporator. The column was purified by column chromatography with a 4:1 mixture of EA: Hxn solution. Colorless oil (70%). 1H NMR (500 MHz, CDCl3) delta 7.33 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.4 Hz, 1H), 7.09 (d, J=7.2 Hz, 2H), 3.69 (s, J=9.7 Hz, 3H), 3.49 (d, J=7.0 Hz, 1H), 3.35 (s, 3H), 3.30 (d, J=12.2 Hz, 1H), 3.09-2.97 (m, 1H), 2.61-2.51 (m, 1H), 2.50-2.34 (m, 2H), 1.86-1.72 (m, 1H). 13C NMR (126 MHz, CDCl3) delta 215.74 (C]O), 168.16 (C]O), 168.07 (C]O), 136.77 (Car), 129.03(CHarx2), 128.65 (CHarx2), 127.38 (CHar), 59.60 (CH), 54.23 (CH), 52.47 (CH3), 52.18 (CH3), 43.90 (CH), 37.88 (CH2), 25.06 (CH2). LCMS m/z: [M+H] found 291.20. C16H18O5 requires 290.31.
With hydrogenchloride; bromine; triethylamine; In tetrachloromethane; hexane;
Step 1 2-Bromo-2-cyclopenten-1-one To a 0 C solution of 2-cyclopenten-1-one (125 g, 1.52 mol) in CCl4(1.2 L) in a three-neck flask equipped with an overhead stirrer was added a solution of bromine (269 g, 1.68 mol) in CCl4(400 mL) dropwise over 4 h, maintaining an internal temperature <2 C. A solution of Et3N (310 mL, 2.22 mol) in CCl4(200 mL) was then added dropwise over 1.5 h, maintaining an internal temperature <10 C. The resulting suspension was warmed to r.t. for 1 h, then cooled to 0 C and filtered. The filtrate was washed with two 700 mL portions of 3M HCl and 500 mL of brine, then filtered through cotton. Concentration provided 228 g of an orange oil which was crystalized from 150 mL of 2:1 hexane: ether to provide 191 g of the title compound. 1H NMR (CD3COCD3) delta 7.94 (1H, t), 2.72 (2H, m), 2.46 (2H, m).
With bromine; triethylamine; In dichloromethane;
Example D Method D: Procedure for Preparation of 4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 20) A solution of 2-cyclopentene-1-one (Intermediate D1, commercially available from Aldrich) (1.5 mL, 17.5 mmol) in CH2Cl2 (40 mL) at 0 C. was treated with bromine (0.86 mL, 16.6 mmol) in CH2Cl2 (30 mL) over 10 min. (see: J. Org Chem. 1982 47, 5088 incorporated herein by reference). The mixture was allowed to stir at 0 C. for one hour. Triethylamine (3.8 mL) was added and the mixture was allowed to stir at rt for 1.5 h. The mixture was diluted with CH2C2, washed with 10% HCl. The combined layers were washed with sat. NaHCO3, brine and dried over Na2SO4. The mixture was filtered and evaporated to give 2-bromo-cyclopent-2-enone (Intermediate D2, 2.85 g).
With bromine; triethylamine; In dichloromethane;
Example D Method D: Procedure for Preparation of 4-(2-isobutyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 20) A solution of 2-cyclopentene-1-one (Intermediate D1, commercially available from Aldrich) (1.5 mL, 17.5 mmol) in CH2Cl2 (40 mL) at 0 C. was treated with bromine (0.86 mL, 16.6 mmol) in CH2Cl2 (30 mL) over 10 min. (see: J. Org Chem. 1982 47, 5088 incorporated herein by reference). The mixture was allowed to stir at 0 C. for one hour. Triethylamine (3.8 mL) was added and the mixture was allowed to stir at rt for 1.5 h. The mixture was diluted with CH2Cl2, washed with 10% HCl. The combined layers were washed with sat. NaHCO3, brine and dried over Na2SO4. The mixture was filtered and evaporated to give 2-bromo-cyclopent-2-enone (Intermediate D2, 2.85 g).
With bromine; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Step 1: To a stirred solution of cyclopent-2-enone (1.70 g, 20.7 mmol) in CH2Cl2 (20 mL), bromine (3.27 g, 20.7 mmol) in CH2Cl2 (10 mL) and Et3N (3.29 g, 31.1 mmol) in CH2Cl2 (10 mL) were added at 0 C. under a nitrogen atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was filtered through celite, washing with CH2Cl2, and the filtrate was concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded 2-bromocyclopent-2-enone.
Example D Method D: Procedure for preparation of [4-(2-ISOBUTYL-CYCLOPENT-2-ENYLMETHYL .-13-] dihydro-imidazole-2-thione (Compound 20) 1) ber2 NaBH4 OH NiCI2dppp OH 2 NEt Br CeCI Br 3 ) s BrMg Intermediate D1 Intermediate D2 Intermediate D3 Intermediate D4 s 1) Hg (OAc) 2 1) TosMIC HNtS EVE 2) NH3, MEOH NH 2) LiCI04 +~ 3) PhOC (S) CI NaHC03, H20 4) NEt3' Intermediate D5 4) NEt3 Compound 20 A solution [OF 2-CYCLOPENTENE-1-ONE] (Intermediate D1, commercially available from Aldrich) (1.5 mL, 17.5 mmol) in [CH2C12] (40 mL) at [0 C] was treated with bromine (0.86 mL, 16.6 mmol) in [CH2C12] (30 mL) over 10 min. (see: J. Org Chem. 1982 47, 5088 incorporated herein by reference). The mixture was allowed to stir at 0 [C] for one hour. Triethylamine (3.8 mL) was added and the mixture was allowed to stir at rt for 1.5h. The mixture was diluted with [CH2CL2,] washed with 10% HCl. The combined layers were washed with sat. NaHCO3, brine and dried over [NA2S04. THE] mixture was filtered and evaporated to give 2-bromo-cyclopent-2-enone (Intermediate D2,2. 85 g). The bromoenone (Intermediate [D2,-17.] 5 mmol) was dissolved in 0.4M [CECL3No.7H2O ] in MeOH (66 mL) at [0 C.] Sodium borohydride was added portion- wise and stirring was continued for 10 min. after addition was complete. The mixture was quenched with saturated [NH4CL] and extracted with ether. The combined organic layers were washed with sat. [NH4CL,] [H20,] brine, and dried over [NA2S04,] filtered and evaporated to dryness. The material was purified by column chromatography 15% EtOAc: Hx to give 2-bromo-cyclopent-2-enol (Intermediate [D3,-2G,] 70% over 2 steps). The alcohol (Intermediate D3,16 mmol) in THF [(30 ML)] at [0 C] was treated with isobutyl magnesium bromide (40 mmol). The catalyst, 1,3- bis (diphenylphosphino) propane nickel [(II)] chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3h. (see: Organ [ET AL.] J. Org. Chem. 1997, 62, 1523, incorporated herein by reference). The reaction mixture was cooled to rt and quenched with sat. [NH4CL] solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over [NA2S04,] filtered and concentrated under vacuum. The oil was purified by chromatography on Si02 with 20% EtOAc: Hx to yield 2-isobutyl-cyclopent-2-enol (Intermediate D4). Use of 2-isobutyl-cyclopent-2-enol (Intermediate D4) in Method A produced [4-(2-ISOBUTYL-CYCLOPENT-2-ENYLMETHYL)-1,] 3-dihydro-imidazole-2- thione (Compound 20). [LEI] NMR (300 MHz, [CD30D-D4)] : 5 6.55 (s, 1H), 5.38 (s, 1H), 2.80-2. 68 (m, 2H), 2.26-2. 18 [(M,] 3H), 2.03-1. 73 (series of m, 4H), 1.58-1. 51 (m, 1H), 0.93 (d, J= 6. 3 Hz, 3H), 0.83 (d, J= 6.3 Hz, 3H).
3-((4-methoxyphenyl)thio)cyclopentan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With tetra(n-butyl)ammonium hydroxide; In ethanol; water; at 20℃; for 0.0166667h;Green chemistry;
General procedure: Into a round-bottom flask charged with a magnetic stirbar was added an appropriate Michael acceptor (1.0 equiv). This material was dissolved in enough EtOH to produce a 0.1 M solution. After stirring to ensure dissolution, mercaptan (1.0 equiv) was added, and the mixture was stirred until homogenous. After this time, TBA-OH (40wt% in H2O, 1 mol% ) was added in one portion, and the mixturewas stirred until deemed complete by TLC analysis. The mixture was then partitioned between deionized H2O (50 mL) and Et2O (50mL). After removing the organic layer, the residual product was extracted from the aqueous layer using an additional portion of Et2O (50 mL). The combined organic layers were then washed with deionized H2O (50 mL) then brine (50 mL). After drying (MgSO4), the crude product was concentrated under reduced pressure, then, if necessary, purified via column chromatography.
(S)-2-[3-((2S,3R,4R,5S,6R)-3-Acetylamino-4,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-ylsulfanyl)-cyclopentylamino]-6-amino-hexanoic acid[ No CAS ]
With sodium acetate; acetic acid;palladium diacetate; antimony(III) chloride; at 25℃; for 24h;
Palladium (II) acetate (0.23 g, 0.1 eq) and antimony (III) chloride (0 23 g, 0 1 eq) are added to a solution of 80 mL acetic acid containing 2-cyclopenten-l-one, 2, (0.82 g, 10 mmol), sodium acetate (1.6 g, 20 mmol) and 4-tertbutyldimethyylsilyloxyphenyl boronic acid, 4, (2.54 g, 10 mmol) under nitrogen The reaction is stirred for 24 hours at 250C, the black precipitate is filtered off and the filtrate diluted with 250 mL of brine, then extracted twice with 50 mL of methylene chloride The organic layer is stirred with saturated bicarbonate solution for 30 minutes, washed with brine and dried over magnesium sulfate. The solvent is removed and chromatographed to provide 3-(4'- hydroxyphenyl)cyclopentanone.
With potassium cyanide; triethylamine hydrochloride; In methanol; at 20℃; for 4h;
A solution of compound 22-1 (10 g, 122 mmol), KCN (9.5 g, 146 mmol) and Et3N-HCl (25 g, 83 mmol) in MeOH (150 mL) was stirred at rt for 4 h. The mixture was concentrated; the residue was re-dissolved in EtOAc. The solution was washed with water and brine, dried over Na2S04, concentrated. The residue was purified by silica gel chromatography (PE: EA = 5: 1 ) to give 7.5 g of compound 22-2. 1H NMR (400 MHz, CDC13): delta 3.13 - 3.51 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.16 - 2.48 (m, 5 H).
Ru[(1S,2S)-N-toluenesulfonyl-1,2-diphenylethylenediamine]-hexamethylbenzene; In toluene; at 30℃; for 48h;
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C = 50) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 84 L (1.0 mmol) of 2-cyclopentenone, 133 L (1.0 mmol) of dimethyl methylmalonate, and 1 mL of toluene were placed in a 20 mL Schlenk tube and stirred at 30C for 48 hours. This solution was purified by flash column chromatography (hexane/acetone = 90/10, SiO2) to give 116 mg (51% yield) of the title compound. The optical rotation [?]D25 was +87.2(c 1.00, CHCl3). The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane : 2-propanol = 80 : 20, flow rate 1.5 mL/min, detection at 210 nm) and it was found to be 97 %ee.
24%
[(eta6-C6Me6)Ir((S,S)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine)]; In tert-butyl alcohol; at 40℃; for 24h;
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C = 50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 L (1.0 mmol) of 2-cyclopentenone, 133 L (1.0 mmol) of dimethyl methylmalonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40C for 24 hours. This solution was purified by flash column chromatography (hexane/acetone = 90/10, SiO2) to give 54 mg (24% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane : 2-propanol = 80 : 20, flow rate 1.5 mL/min, detection at 210 nm) and it was found to be 76 %ee.
With sodium acetate; acetic acid;palladium diacetate; antimony(III) chloride; at 25℃; for 24h;
A.: 3-(4-iodophenyI)cyclopentanone (1) 0.23g palladium(II) acetate (0.1 eq) and 0.23g antimony(III) chloride (0.1 eq) were added to 80 mL acetic acid solution of 2-cyclopenten-l-one 0.82g (10 mmol), 4- iodophenylboronic acid-2.48g (10 mmol) and sodium acetate 1.6g (20 mmol) under N2 atmosphere. After being stirred for 24 hours at 250C, the black precipitation was filtered off and the filtrate was diluted with 250 mL of brine, and then extracted twice with 50 mL methylene chloride. The organic extraction was stirred with saturated NaHCO3 solution for 30 minutes, then washed with brine and dried over MgSO4. Removal of solvent resulted in a yellow oil, further purification by flash column (chloroform) gave 1.92g (67%) product as a white solid. J. Org. Chem., 1995, 60, 883-888.1H NMR (CDCl3) delta 7.63 (d, 2H, ArH), 7.00 (d, 2H, ArH), 3.35 (m, IH, ArCHCC), 2.7-1.8 (m, 6H, cyclo-pentyl);13C NMR (CDCl3) 6218, 143, 138, 129, 95, 46, 42, 39, 31.
67%
With sodium acetate; antimony(III) chloride;palladium diacetate; In acetic acid; at 25℃; for 24h;
O.23g palladium(II) acetate (0.1 eq) and 0.23g antimony(III) chloride (0.1 eq) were added to 80 mL acetic acid solution of 2-cyclorhoenten-l-one 0.82g (10 mmol), <strong>[5122-99-6]4-iodophenylboronic acid</strong> 2.48g <n="26"/>(10 mmol) and sodium acetate 1.6g (20 mmol) under N2 atmosphere. After being stirred for 24 hours at 250C, the black precipitation was filtered off and the filtrate was diluted with 250 mL of brine, and then extracted twice with 50 mL methylene chloride. The organic extract was stirred with saturated NaHCO3 solution for 30 minutes, then washed with brine and dried over MgSO4. Removal of solvent resulted in a yellow oil, further purification by flash column (chloroform) gave 1.92g (67%) product as a white solid. J. Org. Chem., 1995, 60, 883-888. 1H NMR (CDCl3) delta 7.63 (d, 2H, ArH), 7.00 (d, 2H, ArH), 3.35 (m, IH, ArCHCC), 2.7-1.8 (m, 6H, cyclo- pentyl); 13C NMR (CDCl3) 5218, 143, 138, 129, 95, 46, 42, 39, 31.
6.5 g
With sodium acetate; antimony(III) chloride; palladium diacetate; acetic acid; at 25℃; for 2h;Inert atmosphere;
Intermediate 3A: 3 -(4-iodophenyl)cyclopentanoneTo a solution of cyclopent-2-enone (3.39 g, 0.0407 mol), sodium acetate (6.659 g, 0.08 13 mol) and <strong>[5122-99-6](4-iodophenyl)boronic acid</strong> (10 g, 0.0407 mol) in acetic acid (325 mL) was added palladium (II) acetate (0.9728 g, 0.00406 mol) and antimony (III) chloride (0.9279 g, 0.00406 mol) under a nitrogen atmosphere. After being stirred for 2 hours at 25 C, the black precipitation was filtered off and the filtrate was diluted with brine and then extracted twice with dichloromethane. The organic extraction was stirred with saturated sodium bicarbonate for 30 minutes, then washed with brine and dried over sodium sulfate. Removal of the solvent resulted in a yellow oil. Further purification (flash column, chloroform eluent) gave a 6.5 g of 3-(4-iodophenyl)cyclopentanone as a white solid.
With sulfuric acid; In nitromethane; ethyl acetate; isopropyl alcohol;
Example 1 3-(Nitromethyl)cyclopentanone STR30 100 g of 2-cyclopentenone are dissolved together with 666 ml of nitromethane and 5 g of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in 1.1 l of isopropanol, and the solution is left to stand at room temperature for 5 h. The isopropanol is then substantially distilled in vacuo, and the residue is dissolved in ethyl acetate and the solution is washed twice with 0.5 l of dilute sulphuric acid each time. The organic phase is dried with sodium sulphate and evaporated. In this way 154 g (88% of theory) of 3-(nitromethyl)cyclopentanone are obtained sufficiently pure for the next reaction. Rf=0.52 CH2 Cl2: CH3 OH=99:1
With sodium iodide; In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
alpha,alpha,alpha',alpha'-Tetrabromo-o-xylene (200 g, 0.48 mole) was dissolved in 2000 mL of dimethylformamide. 2-Cyclopentene-1-one (40 g, 0.25 mole) was added, along with 500 g sodium iodide. The mixture was heated overnight at 80C. The mixture was cooled and poured into 2 L of ice water containing sodium bisulfide (20 g). The solids were collected and recrystallized from ethanol to give 65 g of benz[f]indan-1-one.
In the similar manner to Example 1, the above obtained <strong>[10493-98-8]hydroxycyclopentenone</strong> was converted into 2-cyclopentenone in a yield of 93 %.
A 250 mL round-bottomed flask equipped with a rubber septum and nitrogen inlet needle is charged with l-bromo-4-octylbenzene (5.77 g, 21.43 mmol) in Et2O (10.7 ml) at room temperature. The resulting solution is cooled to 0 0C. After 5 min BuLi (8.21 ml, 21.43 mmol) solution is added dropwise via syringe over 20 min. The reaction mixture was allowed to stir at 0 0C for 30 min. The resulting solution is then cooled to -78 0C. After 10 min trimethyl borate (2.395 ml, 21.43 mmol) is added dropwise via syringe over 5 min. The reaction mixture is allowed to stir at -78 0C for 30 min. The reaction mixture is treated with 20 mL of saturated NH4Cl and 50 ml of toluene. The aqueous phase is separated and extracted with two 50-mL portions of toluene. The organic phases are combined and concentrated. The residue is further diluted with toluene and concentrated to remove water and then dried in vacuo. The resulting white pasty solid is used directly in the next transformation. The crude borate is transferred to a 200 ml round-bottomed flask equipped with a reflux condenser outfitted with a nitrogen inlet adapter while acetylacetonatobis(ethylene)rhodium(I) (0.166 g, 0.643 mmol) and (R)-BINAP enantiomer (0.480 g, 0.772 mmol) are added in one portion each. The flask is evacuated and filled with nitrogen (three cycles to remove oxygen). To the solid is added dioxane (40 ml), cyclopent-2-enone (1.796 ml, 21.43 mmol), and water (4 ml) each dropwise via syringe. The resulting suspension is heated at 100 0C for 16 h. The resulting orange/brown solution is allowed to cool to room temperature. The orange/brown solution is concentrated and the brown residue is taken up in ether and washed with IN HCl solution. A tan emulsion forms. The emulsified mixture is separated and extracted with EtOAc. The aqueous phases are also extracted with EtOAc. The combined organic phases are washed with 10% NaOH and Brine, then concentrated to afford a brown oil. The crude sample is purified via chromatography on silica gel to afforded 1258 mg of colorless oil.
benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester[ No CAS ]
benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of 1.26 g (5.9 mmol) of <strong>[34097-60-4]methyl phenylsulfonylacetate</strong> in 20 mL of MeOH at 0C, 0.22 mL (1.17 mmol, 0.2 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added. After 15 min, 0.53 g (6.5 mmol, 1.1 eq) of cyclopent-2-enone were added. The reaction mixture was allowed to reached RT within 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc 1: 1 yielded 1.34 g (77%) of benzenesulfonyl- (3-oxo-cyclopentyl)-acetic acid methyl ester as a racemic mixture of diastereomers, colorless oil, MS: 297 (MH+).
Mix cyclopentenone (100 g, 1.2 mol) and phthalimide (170 g, 1.2 mmol) in MeOH (900 mL) and stir for 18 h at ambient temperature. Stir vigorously with a mechanical stirrer and add 2 M aqueous Na2CO3 (80 mL). After approximately 2 h, a thick white precipitate will form. Stir at room temperature for 48 h. Collect the white solid by vacuum filtration and rinse with methanol. Suspend the solid in water (300 mL) and stir for 3 h. Collect the solid and dry in a vacuum oven at 40 C. overnight to give 195 g (71%) of the title compound as a white solid. 1H NMR (DMSO-d6) delta 7.85-7.77 (m, 4H), 4.90 (m, 1H), 2.67 (ddd, 1H, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, 1H, J=18.5, 9.2 Hz), 2.45 (m, 1H), 2.32-2.21 (m, 3H); MS (m/z): 230 (M+1, weak).
71%
With sodium carbonate; In methanol; water; at 20℃; for 26h;
PREPARATION 1(R,S)-2-(3-Oxo-cyclopentyl)-isoindole-1,3-dione While stirring vigorously with a mechanical stirrer, 2 M aqueous Na2CO3 (79 mL, 0.158 mol) is added to a slurry of cyclopentenone (100 g, 1.22 mol) and phthalimide (180 g, 1.22 mol) in MeOH (886 mL). After approximately 2 h, a thick white precipitate will form. The mixture is stirred at room temperature for 24 h. The white solid is collected by vacuum filtration and rinsed with methanol (1 L). The solid is suspended in water (1 L) and stirred for 3 h. The solid is collected and dried in a vacuum oven at 40 C. overnight to give 198 g (71%) of the title compound as a white solid. 1H NMR (DMSO-d6) delta 7.85-7.77 (m, 4H), 4.90 (m, 1H), 2.67 (ddd, 1H, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, 1H, J=18.5, 9.2 Hz), 2.45 (m, 1H), 2.32-2.21 (m, 3H); ES/MS m/z 230 (M+1, weak). NOTE: The product will readily undergo the retro-Michael reaction upon treatment with aqueous base.
71%
With sodium carbonate; In methanol; water; at 20℃;
Preparation 1; (^^^-(S-Oxo-cyclopenty^-isoindole-ljS-dione; While stirring vigorously with a mechanical stirrer, 2 M aqueous Na2CO3 (79 mL,0.158 mol) is added to a slurry of cyclopentenone (100 g, 1.22 mol) and phthalimide (180 g, 1.22 mol) in MeOH (886 mL). After approximately 2 h, a thick white precipitate will form. The mixture is stirred at room temperature for 24 h. The white solid is collected by vacuum filtration and rinsed with methanol (1 L). The solid is suspended in water (1 L) and stirred for 3 h. The solid is collected and dried in a vacuum oven at 40 0C <n="30"/>overnight to give 198 g (71%) of the title compound as a white solid. IH NMR (DMSO- dbeta) delta 7.85-7.77 (m, 4H), 4.90 (m, IH), 2.67 (ddd, IH, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, IH, J=18.5, 9.2 Hz), 2.45 (m, IH), 2.32-2.21 (m, 3H); ES/MS m/z 230 (M+ 1, weak). NOTE: The product will readily undergo the retro-Michael reaction upon treatment with aqueous base.
48.7%
With sodium carbonate; In methanol; water; at 0 - 20℃; for 16.5h;
[0603] To a slurry of cyclopentenone (5 g, 60.9 mmol) and phthalimide (9 g, 61.1 mol) in MeOH (440 mL) was added aqueous Na2CO3 solution (2 M, 4 mL, 8 mmol) dropwise at 0 oC for 30 min. The reaction was stirred at room temperature for 16 hrs. After filtration, the filter cake was washed with cooled MeOH, dried under vacuum to give the title compound (6.8 g, 48.7% yield) as white solid. LC/MS (ESI) m/z: 230 [M+H]+.
48.7%
With sodium carbonate; In methanol; water; at 0 - 20℃; for 16.5h;
To a slurry of cyclopentenone (5 g, 60.9 mmol) and phthalimide (9 g, 61.1 mol) in MeOH (440 mL) was added aqueous Na2CO3solution (2 M, 4 mL, 8 mmol) dropwise at 0 C. for 30 main. The reaction mixture was stirred at room temperature for 16 hrs. After filtration, the filter cake was washed with cooled MeOH and dried under vacuum to give the title compound (6.8 g, 48.7% yield) as white solid. LCMS: LC/MS (ESI) m/z: 230 [M+H]+
44%
With sodium carbonate; In methanol; at 20℃; for 20h;Inert atmosphere;
To a mixture of cyclopent-2-en-1-one (10.0 g, 121.8 mmol, 10.2 mL, 1.0 eq) and isoindoline-1,3-dione (17.9 g, 121.8 mmol, 1.0 eq) in MeOH (90 mL) was added Na2CO3 (2 M, 7.92 mL, 0.13 eq) dropwise. The solution was stirred at 20 C for 20 h and the precipitated solid was collected, washed with MeOH (50 ml) and dried to give the crude product. The crude product was further washed with DCM (200 mL) and dried to give compound 07-1-1 (13.5 g, 53.0 mmol, 44% yield).
With sodium carbonate; In methanol; water; at 20℃; for 22h;
Example 58A 2-(3-oxocyclopentyl)isoindoline-1,3-dione A slurry of methanol (88 mL), 2-cyclopenten-1-one (10.2 mL, 122 mmol), and phthalimide (17.9 g, 122 mmol) was stirred at ambient temperature and sodium carbonate (2M in water, 7.92 mL, 15.8 mmol) was added. After 22 hours, the thick white slurry was filtered and washed with MeOH (100 mL). Water (100 mL) was added to the wet cake, stirred for 1 hour, and filtered. The solid was washed with water (50 mL) and dried in a vacuum oven at 50 C. for 14 hours to provide the title compound (17.8 g, 78.0 mmol, 64% yield). MS (DCI) M/Z 247 [M+NH4]+.
With sodium carbonate; In methanol; at 20℃; for 24h;
To a slurry of Compound 1 (6.5 g, 79 mmol) and Compound 2 (10.2 g, 69 mmol) in MeOH (100 mL) was added a aqueous Na2C03 (6 mL, 2 N, 12 mmol), and stirred at rt for 24 h. The solid was collected by filteration, washed with MeoH and dried in vacuo, which was used in the next step (14 g, crude). LCMS: 230.2 [M+l].
With N-Methyldicyclohexylamine;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;
STEP 1: 3-(2-FLUOROPYRIDIN-3-YL)CYCLOPENT-2-ENONE To a round bottom flask was added bis(tri-t-butyl)phosphine palladium (0.591 g, 1.156 mmol) before sealing and evacuating and backfilling with nitrogen. Subsequently, cyclopent-2-enone (7.48 mL, 93 mmol), N-cyclohexyl-N-methylcyclohexanamine (14.73 mL, 69.4 mmol), and <strong>[36178-05-9]3-bromo-2-fluoropyridine</strong> (4.07 g, 23.13 mmol) were added before adding dioxane (25 mL). The reaction mixture was stirred under nitrogen at 110° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude compound was purified by column chromatography (ethyl acetate/dichloromethane) to give 3-(2-fluoropyridin-3-yl)cyclopent-2-enone was afforded as an orange solid. MS (ESI, pos. ion) m/z: 178.0 (M+1).
A mixture of cyclopentanone (8.4 g, 0.1 mol), thiourea (15.22 g, 0.2 mol) and iodine (25.38 g, 0.1 mol) was heated overnight at 100 C., then isopropyl ether was added and the mixture heated at reflux for an additional 30 minutes. The solid was collected via filtration, washed with ether, and then dissolved in hot water. The solution was left to cool to RT, was then basified with concentrated ammonia, and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the desired product (5.56 g 40% yield). ESIMS (m/z) 141.0 (MH+).
With lithium hydroxide;(eta6-1,4-dihydroxybenzene)(eta2,eta2-cyclooctadiene-1,5)rhodium tetrafluoroborate; In 1,2-dimethoxyethane; water; at 50℃;
General procedure ETo a solution of 2-cyclopenten-l-one (400 mumol) in 400 mul_ DME were added boronic acid (480 mumol, 1.2 eq.), (COD)Rh(l,4-dihydroquinone)BF4 (1 mol%) in 100 muL DME, and LiOH (4 mol%) in 600 muL water. After shaking the mixture overnight at 50 0C, the solvent was removed in vacuo. The crude intermediate ketone was dissolved in DCE containing acetic acid (1.2 eq.). An amine (1 eq.) in DCE was added followed by NaBH(OAc)3 (1.2 eq.) The mixture was shaken overnight at r. t., filtered and the solvents were removed in vacuo. The residue was redissolved in 750 muL DMSO and purified by preparative HPLC-MS.; Example 55. (lR)-(N)-[(lR/S,3R/S)-3-[4-acetamidophenyl]cyclopentyl]-l-(3- methoxyphenyl)ethanamine (mixture of stereoisomers) (compound 1054)General procedure E was followed using (4-acetylaminophenyl)boronic acid as the boronic acid and (R)-l-(3-methoxyphenyl)ethylamine as the amine. LC-MS (method B): RT = 3.99, M = 352.
With pyrrolidine; In dichloromethane; at 20℃; for 24h;
General procedure: To a solution of alpha,beta-unsaturated ketones 3 (0.30 mmol) in CH2Cl2 (0.6 mL) at room temperature was added pyrrolidine (0.060 mmol) followed by addition of 2-arylacetate or 2-arylacetonitrile 2 (0.45 mmol). The resulting solution was stirred at room temperature until complete consumption of alpha,beta-unsaturated ketones 3 was observed as determined by TLC. The resulting mixture was direct purified by silica gel chromatography to afford desired compounds 4 and 5.
methyl (4-chlorophenyl)(3-oxocyclopentyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
Example 66AMethyl(4-chlorophenyl)(3-oxocyclopentyl)acetate; Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were initially charged in 150 ml of THF, the mixture was cooled to -30 C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to -20 C., 15 g (81.25 mmol) of methyl(4-chlorophenyl)acetate, dissolved in 90 ml of THF, were added slowly and the mixture was stirred at this temperature for 2 h. The reaction solution was then cooled to -78 C., and 7.2 ml (86.1 mmol) of 2-cyclopentene-1-one, dissolved in 60 ml of THF, were added slowly. After the addition had ended, the solution was stirred at this temperature for 1 h. After TLC check (mobile phase cyclohexane/ethyl acetate 9:1), saturated ammonium chloride solution was added and the mixture was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72% of theory) of the title compound as a yellowish oil.GC-MS (Method 1): Rt=7.02 min; m/z=266 (M)+ (diastereomer 1); Rt=7.04 min; m/z=266 (M)+ (diastereomer 2).MS (DCI): m/z=284 (M+NH4)+.
72%
Example 86AMethyl (4-chlorophenyl)(3-oxocyclopentyl)acetate; Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were initially charged in 150 ml of THF, the mixture was cooled to -30 C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to -20 C., 15 g (81.25 mmol) of methyl (4-chlorophenyl)acetate, dissolved in 90 ml of THF, were added slowly and the mixture was stirred at this temperature for 2 h. The reaction solution then cooled to -78 C., and 7.2 ml (86.1 mmol) of 2-cyclopenten-1-one, dissolved in 60 ml of THF, were added slowly. After the addition had ended, the solution was stirred at this temperature for another hour. After TLC (mobile phase cyclohexane/ethyl acetate 9:1), saturated aqueous ammonium chloride solution was added and the product was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72% of theory) of the title compound as a yellowish oil.GC-MS (Method 1): Rt=7.02 min; m/z=266 (M)+ (diastereomer 1); Rt=7.04 min; m/z=266 (M)+ (diastereomer 2).MS (DCI): m/z=284 (M+NH4)+.
72%
Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were initially charged in 150 ml of THF, the mixture was cooled to -30 C. and 42.3 ml (105.75 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to -20 C., 15 g (81.25 mmol) of methyl (4-chlorophenyl)acetate, dissolved in 90 ml of THF, were added slowly and the mixture was stirred at this temperature for 2 h. The reaction solution then cooled to -78 C., and 7.2 ml (86.1 mmol) of 2-cyclopenten-1-one, dissolved in 60 ml of THF, were added slowly. After the addition had ended, the solution was stirred at -78 C. for another hour. After TLC (mobile phase cyclohexane/ethyl acetate 9:1), saturated aqueous ammonium chloride solution was added and the product was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72% of theory) of the title compound as a yellowish oil. GC-MS (Method 1): Rt=7.02 min, m/z=266 (M)+ (diastereomer 1); Rt=7.04 min, m/z=266 (M)+ (diastereomer 2). MS (DCI): m/z=284 (M+NH4)+.
General procedure: The starting 5,15-disubstituted porphyrins 1 were purified by silica gel column chromatography (CH2Cl2) followed by recrystallization from CH2Cl2/hexane, and dried over silica gel for 10 h under a reduced pressure (1 mmHg) at 110 C just before their use. An oven-dried 100 mL three-necked flask equipped with a magnetic stirring bar, a reflux condenser, and rubber septum was charged with a porphyrin 1 (0.2 mmol). The flask was evacuated and flushed with argon (three times), and then absolute THF (80 mL) was added. To the solution was added an ethereal solution of PyMe2SiCH2Li (prepared by adding 1.3 mL of 1.58 M tBuLi in pentane to a solution of 2.4 mmol <strong>[13737-04-7]2-pyridyltrimethylsilane</strong> in 3 mL of ether, followed by stirring at -78 C for 2 h)5 via a cannula at -78 C. After being stirred at -78 C for 5 min, the cooling bath was removed and the mixture was stirred at room temperature. The reaction was complete within 3 h, having been monitored by TLC. Upon completion of the reaction, the mixture was cooled to -78 C, and then an ethereal solution of an enone or an alkenoate (3 mmol) and TMSCl (4 mmol, 435 mg, 0.51 mL) was added. After being stirred at -78 C for 10 min, the mixture was warmed to room temperature, stirred for 3 h, and recooled to 0 C. To the cooled mixture was added 10 mL of 0.1 M HCl. The resulting solution was stirred for 10 min at 0 C, and then DDQ (2 mmol, 454 mg) was added. After being stirred at room temperature for 12 h, the mixture was concentrated under a reduced pressure. The resulting residue was dissolved in CH2Cl2 (ca. 100 mL) and the solution was poured into brine. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, concentrated in vacuo, and subjected to chromatography on silica gel using 0-10% hexane/CH2Cl2 as an eluent. The eluate was evaporated and the resulting solid was purified by recrystallization from CH2Cl2/hexane to afford the meso activated alkenyl-substituted meso-formyl porphyrin 3.
General procedure: The starting 5,15-disubstituted porphyrins 1 were purified by silica gel column chromatography (CH2Cl2) followed by recrystallization from CH2Cl2/hexane, and dried over silica gel for 10 h under a reduced pressure (1 mmHg) at 110 C just before their use. An oven-dried 100 mL three-necked flask equipped with a magnetic stirring bar, a reflux condenser, and rubber septum was charged with a porphyrin 1 (0.2 mmol). The flask was evacuated and flushed with argon (three times), and then absolute THF (80 mL) was added. To the solution was added an ethereal solution of PyMe2SiCH2Li (prepared by adding 1.3 mL of 1.58 M tBuLi in pentane to a solution of 2.4 mmol <strong>[13737-04-7]2-pyridyltrimethylsilane</strong> in 3 mL of ether, followed by stirring at -78 C for 2 h)5 via a cannula at -78 C. After being stirred at -78 C for 5 min, the cooling bath was removed and the mixture was stirred at room temperature. The reaction was complete within 3 h, having been monitored by TLC. Upon completion of the reaction, the mixture was cooled to -78 C, and then an ethereal solution of an enone or an alkenoate (3 mmol) and TMSCl (4 mmol, 435 mg, 0.51 mL) was added. After being stirred at -78 C for 10 min, the mixture was warmed to room temperature, stirred for 3 h, and recooled to 0 C. To the cooled mixture was added 10 mL of 0.1 M HCl. The resulting solution was stirred for 10 min at 0 C, and then DDQ (2 mmol, 454 mg) was added. After being stirred at room temperature for 12 h, the mixture was concentrated under a reduced pressure. The resulting residue was dissolved in CH2Cl2 (ca. 100 mL) and the solution was poured into brine. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, concentrated in vacuo, and subjected to chromatography on silica gel using 0-10% hexane/CH2Cl2 as an eluent. The eluate was evaporated and the resulting solid was purified by recrystallization from CH2Cl2/hexane to afford the meso activated alkenyl-substituted meso-formyl porphyrin 3.
acetylacetonatobis-(ethylene)rhodium(I); (+)-2,2'-O,O-(1,1'-binaphthyl)-dioxo-N,N-diethylphospholidine; In 1,4-dioxane; water; at 20 - 105℃; for 0.666667h;Inert atmosphere;
Intermediate (9)[4-((S)-3-Oxo-cyclopentyl)-phenyl]-carbamic acid benzyl esterIn a 50 mL round bottom flask was charged with Rh(acac)(C-2H )2 (acetylacetonatobis-(ethylene)rhodium(l), CAS 12082-47-2) (54 mg, 0.21 mmol, 3 mol%) and (S)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1 -a:3,4- a']dinaphthalen-4-yl)- diethylamine (from Strem Chemicals, Inc. CAS: 252288-04-3) (210 mg, 0.542 mmol, 7.5 mol%). To this was added 18 mL of dioxane and 1 .8 mL of water. The flask was purged with N2/vacuum cycle 3 times. The solution was stirred at rt for 5 min. 4- Benzyloxycarbonylamino-boronic acid (CAS 192804-36-7) (5.39 g, 19.8 mmol, 2.28 equiv.) was added in powder form and the solution was heated in a pre-heated oil bath set at 105C externally and was kept at that temperature for 5 min to ensure the inside and outside temperature was in equilibrium. To this was added slowly cyclopentenone (710 mg, 8.66 mmol, 1 equiv.) in liquid neat form drop-wise, and the resulting mixture was stirred at 105C (external temperature) for 35 min. The reaction was cooled to rt and quenched with NaHCO3 aq (15 mL) and EtOAc 20 mL. The two layers were separated and the aqueous layer was extracted with EtOAc (2X20 mL). The combined extracts were washed with NaHCO3 aq. (10 mL), and brine (10 mL), and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with EtOAc. The filtrate was concentrated to dryness. The residue was dissolved in 30% EtOAc in heptane and loaded onto a 50 g silica gel column, eluted with 30% EtOAc in heptane to obtain a crude product. This was crystallized from 30% EtOAc in heptane to obtain 2.15 g (80% yield) of the title compound as a very white crystalline material, m.p. 96.3-98.5C.LC/MS: RT =3.20 min. MS (ESI) m/z = 310 (M+H+)[a]D = -28.4 in chloroform (c = 0.5 g/100 mL); Chiral HPCL: ee = 57.3%. Chiral HPLC conditions: Agilent 1200 HPLC system; CHIRALCEL OD-H, 150 mm x 4.6 mm ID, 5 micron; Heptane : Ethanol = 50:50; Flow rate: 0.70 mL/min; Detection: UV 220 nm; injection volume: 10 mu.1H NMR (300MHz, CDCI3) delta: 7.37 (m, 5H), 7.26-7.18 (m, 4H), 6.62 (s, 1 H), 5.21 (s, 2H), 3.38 (m, 1 H), 2.65 (dd, 7.5 Hz, 18.3 Hz, 1 H), 2.50-2.23 (m, 4H), 1 .95 (m, 1 H).
With triethylamine;[Rh(norbornadiene)(+)BINAP]BF4; In 1,4-dioxane; water; at 25℃; for 6h;Inert atmosphere;
Preparation 10. (S)-3-(4-hydroxy-3-trifluoromethyl-phenyl)-cyclopentanone [Rh(S-BINAP)(nbd)]BF4 (0.03 mmol) and <strong>[1243143-45-4]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenol</strong> (preparation 9) (1.5 mmol) were added to a 25 mL-flask containing a magnetic stir bar and a septum inlet. The flask was flushed with argon. Triethylamine (1.5 mmol) and 2-cyclopenten-1-one (1.0 mmol) dissolved in 1,4-dioxane -H2O (6:1, 3 mL) were then added. The mixture was stirred for 6 h at 25 C. Brine was added, the mixture was extracted with ethyl acetate, and the solvents were removed in vacuo to afford the title compound. 1H NMR (300 MHz, DMSO) delta 10.37 (bs, 1H), 7.45-7.36 (m, 2H), 6.97 (d, 1H), 3.43-3.23 (m, 1H), 2.57-2.44 (m, 1H), 2.37-2.17 (m, 4H), 1.96-1.77 (m, 1H).
With triethylamine;[Rh((R)-BINAP)(norbornadiene)]BF4; In methanol; at 100℃; for 0.333333h;Sealed vial; Microwave reactor;
[Rh(R-BINAP)(nbd)]BF4 (0.22 mmol) and (4-ethoxycarbonylmethylphenyl)boronic acid pinacol ester (8.6 mmol) were dissolved in 5 mL MeOH in a sealed 20 mL MW- vial. The flask was flushed with argon. A solution of triethylamine (8.6 mmol) and 2- cyclopenten-l-one (21.5 mmol) in MeOH (5 mL), degassed with argon, was then added. The mixture was heated for 20 min at 100 C in a microwave reactor. The reaction mixture was diluted with 40 mL DCM, washed twice with sat. NaHC03 and H20, dried over MgS04, filtered, and concentrated in vacuo affording a dark oil. Purification by flash chromatography (gradient of 0-50% EtOAc in heptane) afforded the title compound as a pale yellowish oil.LH NMR (300 MHz, CDCI3) delta 7.29 - 7.18 (m, 4H), 4.15 (q, J = 7.2 Hz, 2H), 3.60 (s, 2H), 3.47 - 3.33 (m, 1H), 2.72 - 2.60 (m, 1H), 2.52 - 2.22 (m, 4H), 2.05 - 1.90 (m, 1H), 1.26 (d, J = 7.1 Hz, 3H).
With triethylamine;[Rh((R)-BINAP)(nbd)] tetrafluoroborate; In 1,4-dioxane; water; at 80℃; for 0.25h;Inert atmosphere; Microwave irradiation;
A 20 mL microwave vial was charged with 2-chlorpyridine-5-boronic acid (1.57 g, 10 mmol) and [Rh((R)-BINAP)(nbd)] tetrafluoroborate (275 mg, 0.3 mmol), then capped and backfilled with argon. In a second flask 2-cyclopenten-l-one (0.8 mL, 10 mmol) was taken up in dioxane/water 6: 1 (10 mL) and degassed with argon for 15 min before adding triethylamine (1.4 mL, 10 mmol), degassing was continued for 5 min before the solution was transferred to the microwave vial with a syringe. The reaction mixture was heated in a microwave reactor at 80 C for 15 min.Extractive workup with brine and ethyl acetate and subsequent concentration under high vacuum to remove deborylated by-product yielded the title compound : 870 mg (48%).1H NMR (300 MHz, CDCI3) delta 8.32 (d, J = 2.5 Hz, 1H), 7.55 (dd, J = 8.4, 2.6 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 3.58 - 3.31 (m, 1H), 2.84 - 2.63 (m, 1H), 2.62 - 2.43 (m, 2H), 2.43 - 2.16 (m, 2H), 2.12 - 1.88 (m, 1H).
With potassium tert-butylate;[Rh((R)-BINAP)(nbd)] tetrafluoroborate; In 1,4-dioxane; at 80℃; for 1.5h;
A round bottom flask was charged with tBuOK (5.6 g, 50 mmol) and dioxane (150 mL) and the slurry was degassed for 20 min. Cyclopentenone (21.5 g, 250 mmol) was added and degassing continued for 5 min before addition of 2-fluoro-5-(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)-pyridine (11.0 g, 50 mmol) and [Rh((R)-BINAP)(nbd)] tetrafluoroborate (1.1 g, 1.3 mmol), then the reaction mixture was heated on an oilbath at 80 C for 90 min. The crude was concentrated in vacuo and purified by flash chromatography (eluent: 30 % ethylacetate in heptane) to yield the title compound : 6.2 g (70%).1H NMR (300 MHz, CDCI3) delta 8.13 (s, 1H), 7.70 (td, J = 8.1, 2.6 Hz, 1H), 6.93 (dd, J = 8.4, 3.0 Hz, 1H), 3.62 - 3.26 (m, 1H), 2.82 - 2.61 (m, 1H), 2.54 - 2.42 (m, 2H), 2.41 - 2.15 (m, 2H), 2.11 - 1.86 (m, 1H).
With triethylamine;[Rh((R)-BINAP)(nbd)] tetrafluoroborate; In methanol; at 80℃; for 0.25h;Microwave irradiation; Inert atmosphere;
A 20 mL microwave vial was charged with <strong>[348098-29-3]2-(methylthio)pyrimidine-5-boronic acid</strong> (2.75 g, 16.2 mmol) and [Rh((R)-BINAP)(nbd)] tetrafluoroborate (904 mg, 0.6 mmol), then capped and backfilled with argon. In a second flask 2-cyclopenten-l- one (7.0 mL, 81 mmol) was taken up in MeOH (6 mL) and degassed with argon for 15 min before adding triethylamine (2.3 mL, 16.2 mmol), degassing was continued for 5 min before the solution was transferred to the microwave vial with a syringe. The reaction mixture was heated in a microwave reactor at 80 C for 15 min. Extractive workup with brine and ethyl acetate and subsequent purification by flash chromatography (eluent: 0-50 % ethylacetate in heptane) yielded the title compound : 592 mg (20%).1H NMR (300 MHz, CDCI3) delta 8.46 (s, 2H), 3.46 - 3.21 (m, 1H), 2.83 - 2.62 (m, 1H), 2.58 (s, 3H), 2.55 - 2.41 (m, 2H), 2.41 - 2.20 (m, 2H), 2.05 - 1.90 (m, 1H).
With triethylamine hydrochloride; In methanol; at 20℃; for 4h;
To a solution of cyclopent-2-enone (5 g, 61 mmol) and potassium cyanide (4.75 g, 73 mmol) in methanol (100 mL)Triethylamine hydrochloride (12.5 g, 42 mmol) was added and reacted for 4 hours at room temperature. The solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound (4g, 60.2 %).
53%
With triethylamine hydrochloride; In methanol; water; at 20℃;Inert atmosphere;
To a solution of triethylamine hydrochloride (117.4 g, 854 mmol), potassium cyanide (35.9 g, 630 mmol) in mixture of water (150 mL) and methanol (150 mL) was added dropwise solution of cyclopent-2-en-1 -one (50 g, 610 mmol) in methanol (60 mL). The mixture was stirred at room temperature overnight. The organic solvent was concentrated and the remaining aqueous phase extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried over magnesium sulfate and crude product was purified by chromatography on silica gel eluting with a gradient of petroleum ether and ethyl acetate (1 :1 ) to afford the title compound as yellow oil (35 g, 53%).1H NMR (400 MHz, CDCl3): 3.25-3.15 (m, 1 H), 2.62-2.52 (m, 2H), 2.52-2.40 (m, 2H), 2.40-2.20 (m, 2H).
11.5 g
With triethylamine hydrochloride; In methanol; at 20℃;
A mixture of KCN (19.0 g), water (200 ml), MeOH (200 ml) and Et3N HCl (50.0 g) was stirred at rt, and cyclopentenone was added dropwise slowly. After the addition was completed the mixture was stirred at rt overnight. The solution was concentrated to remove most of methanol and to the aqueous layer was added acetic acid (2 ml) to bring the pH to 6 -7, followed by extraction with DCM (three times). The combined organic layer was concentrated, and the resulting residue was purified by column chromatography on silica gel (PE/EA=5/1 to 4/1) to afford 3-cyanocyclopentanone (11.5 g) as a yellow oil.
7.5 g
With triethylamine hydrochloride; In methanol; at 20℃; for 4h;
Step 1 (0747) A solution of compound 22-1 (10 g, 122 mmol), KCN (9.5 g, 146 mmol) and Et3N.HCl (25 g, 83 mmol) in MeOH (150 mL) was stirred at rt for 4 h. The mixture was concentrated; the residue was re-dissolved in EtOAc. The solution was washed with water and brine, dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (PE: EA=5:1) to give 7.5 g of compound 22-2. 1H NMR (400 MHz, CDCl3): delta 3.13-3.51 (m, 1H), 2.56-2.63 (m, 1H), 2.16-2.48 (m, 5H).
With bis(1,5-cyclooctadiene)nickel(0); bicyclo[2.2.1]hepta-2,5-diene; gadolinium(III) trifluoromethanesulfonate; In tetrahydrofuran; at 20℃; for 4h;
A.1.6.1. 2-Bromo-3-oxocyclopentanecarbonitrile Bicyclo[2.2.1]hepta-2,5-diene (0.84 g, 9.14 mmol), followed by Gd(OTf)3 (1.84 g, 3.05 mmol), 2-cyclopenten-1-one (5.00 g, 60.9 mmol) and TMS-CN (9.25 g, 91.4 mmol) were added to a degassed solution of Ni(cod)2 (0.84 g, 3.04 mmol) in THF (160 mL) and the mixture was stirred at RT for 4 h. Subsequently, the mixture was quenched with solid NaHC03 and aq. sat. NaHC03 and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgS04 and cone, in vacuo. The residue, a yellow oil, was dissolved in THF/H20 (450 mL, 9: 1). At 0C, NBS (11.98 g, 67.3 mmol) was added and the mixture was stirred at 0C for 30 min. Subsequently, the mixture was quenched with aq. sat. Na2S03 and extracted with EtOAc. The comb. org. layers were washed with aq. 5% NaHC03 and brine, dried over Na2S04, and cone, in vacuo. The residue was re- dissolved in EtOAc, washed multiple times with aq. 5% NaHC03 and brine, the combined org. layer were dried over Na2S04, and cone, in vacuo to provide a brown liquid. H-NMR (CDCI3) delta: 4.42 (d, J = 7.7 Hz, 0.5 H), 4.34 (d, J = 5.8 Hz, 0.5 H), 3.43-3.40 (m, 0.5 H), 3.33-3.28 (m, 0.5 H), 2.72-2.26 (m, 4 H).
With L-proline; In dimethyl sulfoxide; at 20℃; for 24h;
General procedure: To a stirred solution of compound 1 (0.574mmol) and catalyst (0.115mmol) in DMSO (0.5mL) at room temperature, was added a Michael acceptor (2.0equiv). The mixture was stirred at ambient temperature for 24h while being monitored by TLC. The reaction mixture was then quenched by adding water (5mL) and the aqueous layer was extracted three times with DCM (30mL). The combined organic layers were dried over MgSO4, which was subsequently removed by filtration. The concentrated extract was subjected to silica gel for purification to afford the desired. The crude product was purified by column chromatography (EtOAc/hexane, 50:50; Rf=0.2) to afford the product (165mg, 67%) as a semi-solid. [alpha]D20=+215.0 (c 0.1, CHCl3) 1H NMR (400MHz, CDCl3): delta 8.22 (d, J=7.16Hz, 2H), 7.45 (d, J=8.56Hz, 2H), 5.27 (s, 2H), 4.25 (s, 1H), 4.03 (s, 1H), 3.29 (t, 1H), 3.17 (d, 1H), 2.97-2.95 (d, J=11.05Hz, 1H), 2.55-2.39 (dd, J=17.91, 8.58Hz, 2H), 2.19 (d, J=9.49Hz, 2H), 2.04 (d, J=7.08Hz, 1H), 1.80 (d, J=19.61Hz, 1H), 1.34 (d, J=4.80Hz, 3H) ppm. 13C NMR (100MHz CDCl3): delta 215.3, 208.0, 164.9, 161.0, 140.8, 128.7, 124.5, 76.6, 66.5, 66.2, 64.9, 50.2, 42.1, 40.9, 38.4, 38.0, 23.6, 21.9ppm. HRMS (ESI-) m/z calcd for C21H22N2O8: 430.1376; found [M-H] 429.1440.
methyl N-acetyl-R-(3-oxocyclopentyl)cysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With tetra(n-butyl)ammonium hydroxide; In ethanol; water; at 20℃; for 1.5h;Green chemistry;
General procedure: Into a round-bottom flask charged with a magnetic stirbar was added an appropriate Michael acceptor (1.0 equiv). This material was dissolved in enough EtOH to produce a 0.1 M solution. After stirring to ensure dissolution, mercaptan (1.0 equiv) was added, and the mixture was stirred until homogenous. After this time, TBA-OH (40wt% in H2O, 1 mol% ) was added in one portion, and the mixturewas stirred until deemed complete by TLC analysis. The mixture was then partitioned between deionized H2O (50 mL) and Et2O (50mL). After removing the organic layer, the residual product was extracted from the aqueous layer using an additional portion of Et2O (50 mL). The combined organic layers were then washed with deionized H2O (50 mL) then brine (50 mL). After drying (MgSO4), the crude product was concentrated under reduced pressure, then, if necessary, purified via column chromatography.
3-(2,3,4-trimethoxyphenyl)cyclopent-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; XPhos; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere;
General procedure: A solution of 4-methoxybromobenzene (2.67 mmol)and cyclopent-2-en-1-one (3.2 mmol) in DMSO was stirred at ambient temperaturefor 10 min under nitrogen, and treated with Na2CO3 (8.01mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.53 mmol).The reaction mixture was degassed with nitrogen for 10 min and treated withPd(PPh3)2Cl2 (0.13 mmol) and X-Phos (0.26mol), and stirred at 100 0C for 12 h. The reaction mixture was cooledto ambient temperature, diluted with water, and extracted with AcOEt (3 x 50ml). The combined organic layers were washed with brine, dried over anhydrousNa2SO4, and evaporated. Flash chromatograph on silica gel(AcOEt:cyclohexane 1:3) provided the Heck coupling product as brown solid (340mg, 68%).
3-(2,4-dimethylphenyl)cyclopent-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; XPhos; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere;
General procedure: A solution of 4-methoxybromobenzene (2.67 mmol)and cyclopent-2-en-1-one (3.2 mmol) in DMSO was stirred at ambient temperaturefor 10 min under nitrogen, and treated with Na2CO3 (8.01mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.53 mmol).The reaction mixture was degassed with nitrogen for 10 min and treated withPd(PPh3)2Cl2 (0.13 mmol) and X-Phos (0.26mol), and stirred at 100 0C for 12 h. The reaction mixture was cooledto ambient temperature, diluted with water, and extracted with AcOEt (3 x 50ml). The combined organic layers were washed with brine, dried over anhydrousNa2SO4, and evaporated. Flash chromatograph on silica gel(AcOEt:cyclohexane 1:3) provided the Heck coupling product as brown solid (340mg, 68%).
3-(benzothiophen-5-yl)cyclopent-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; XPhos; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere;
General procedure: A solution of 4-methoxybromobenzene (2.67 mmol)and cyclopent-2-en-1-one (3.2 mmol) in DMSO was stirred at ambient temperaturefor 10 min under nitrogen, and treated with Na2CO3 (8.01mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.53 mmol).The reaction mixture was degassed with nitrogen for 10 min and treated withPd(PPh3)2Cl2 (0.13 mmol) and X-Phos (0.26mol), and stirred at 100 0C for 12 h. The reaction mixture was cooledto ambient temperature, diluted with water, and extracted with AcOEt (3 x 50ml). The combined organic layers were washed with brine, dried over anhydrousNa2SO4, and evaporated. Flash chromatograph on silica gel(AcOEt:cyclohexane 1:3) provided the Heck coupling product as brown solid (340mg, 68%).
With bismuth(III) nitrate; In dichloromethane; at 27℃; for 5h;
To a stirred suspension of cyclopent-2-en-1-one 36 (2.50 g, 3.05 mmol) in DCM (60 mL), was added boc amine (3.60 g, 3.05 mmol) and stirred for 10-15 mm. Bismuth nitrate (14.70 g, 3.05 mmol) was charged portion wise and allowed to stir at room temperature for about 5h. After completion of reaction, the reaction mixture was diluted with DCM & was filtered through celite bed, filtrate obtained was quenched with saturated NaHCO3 solution, DCM layer was separated, and aqueous layer was extracted with DCM, combined organic extracts were dried over Na2SO4 and concentrated to obtain crude compound. The crude was further purified by combiflash using 10-15 % ethyl acetate in hexane to obtain tert-butyl (3-oxocyclopentyl)carbamate 64 as a white solid (6.50 g, 36% yield). MS: 200.20 (M+H).
(1SR,2RS)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
To a solution of l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole(3.04 g, 20.0 mmol) in THF (30 mL), n-butyl lithium (1.63 M solution in hexane;12.7 mL, 20.7 mmol) was added dropwise at -78 C. for 7 minutes. The reaction solution was stirred for 30 minutes, and boron trifluoride-ethyl ether(3.14 mL,25.0 mmol) was then added thereto. The reaction solution was further stirred for 10 minutes. Then, cyclopentene oxide (2.08 mL, 24.0 mmol) was added thereto, and the reaction solution was stirred at -78 C. for 3 hours. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (15mL) was added, followed by extraction four times with ethyl acetate (20 mL).The thus obtained organic layer was dried over anhydrous sodium sulfate. Afterconcentration under reduced pressure, the residue was purified with silica gelchromatography (hexane/ethyl acetate=l: 4) to yield the title compound (1.54 g,33%) in the form of a diastereomeric mixture as a colorless oil.
4-{2-ethoxy-1-[2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate-5,6-dihydro-4H-cyclopentyl[c][1,2,5]oxadiazole-2-oxide}-1-methyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; potassium carbonate; p-toluenesulfonyl chloride; In N,N-dimethyl-formamide; at 10℃; for 3h;
j0185] The QRO1000-IN-01 (2.2 mmol, 1.0 eq.) and the QR01035-IN-01 (2.6 mmol, 1.2 eq.) were dissolved in 20 ml of dimethylformamide, and the resultant solution is cooled to 10 C. Then, potassium carbonate (2.6 mmol, 1.2 eq.), p-toluenesulfonyl chloride (2.6 mmol, 1.2 eq.), and the catalyst dimethylaminopyridine were added to the solution, and the resultant mixture was stirred for 3 h. Afier the completion of the reaction, water was added to the reaction solution, extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine. Crude product was purified by column chromatography to give the title compound QR01035, its structure being confirmed by ECMS and NMRH spectra.
With bis(1,5-cyclooctadiene)rhodium chloride; potassium hydroxide; In 1,4-dioxane; water; at 20℃; for 1.5h;Inert atmosphere;
According to scheme 3, step i: To a mixture of Rh(COD)Cl2 (180.17 mg, 0.37 mmol) in dioxane (20 mL) and H2O (4 mL) was added KOH (4.10 g, 73.08 mmol). The resulting mixture was stirred at 20C under N2 for 0.5 hour. Then to the resulting mixture was added the solution of cyclopent-2-en-1-one (6.00 g, 73.08 mmol) and <strong>[55499-44-0](2,4-dimethylphenyl)boronic acid</strong> (21.92 g, 146.16 mmol) in dioxane (20 mL) dropwise at 20C. The resulting mixture was stirred at 20C for 1.5 hours. LCMS showed the desired product. The reaction mixture was diluted with 200 mL ethyl acetate and washed by water (60 mL x 3). Then the organic phase was dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1). The intermediate 19 (11.00 g, 80% yield) was obtained as a yellow liquid. 1H NMR (CDCl3; 400MHz) delta 7.17-7.10(m, 1 H), 7.07-7.02 (m, 2H), 3.67-3.54 (m, 1 H), 2.70-2.60 (m, 1 H), 2.55-2.45(m, 1H), 2.43-2.39 (m, 1H), 2.381 (s, 3H), 2.37-2.35 (m,1 H), 2.34 (s, 3H), 2.31-2.26 (m,1 H), 2.10-1.96 (m,1 H).
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