* 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.
In order to 1,3-cyclopentanedione, tert-butyl peroxybenzoate is used as a raw material, the reaction steps are as follows:In the reaction flask by adding 1,3-cyclopentanedione (0.098g, 1mmol), tert-butyl peroxybenzoate (0.58g, 3mmol), CuCl (0.01g, 0 . 1mmol) and 2 ml acetic acid, 120 °C reaction;TLC until the complete end tracking of the reaction;After the reaction the crude product by column chromatography (petroleum ether: ethyl acetate = 40:1), to obtain the target product (yield 68percent).
Reference：
[1] Patent: CN105254483, 2016, A, . Location in patent: Paragraph 0044
2
[ 110-15-6 ]
[ 79-03-8 ]
[ 765-69-5 ]
Reference：
[1] Organic Letters, 2017, vol. 19, # 15, p. 3958 - 3961
[2] Journal of Organic Chemistry, 1982, vol. 47, # 23, p. 4491 - 4498
[3] Organic Syntheses, 1992, vol. 70, p. 226 - 226
3
[ 17082-61-0 ]
[ 534-15-6 ]
[ 765-69-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 21, p. 3966 - 3970
4
[ 4505-54-8 ]
[ 765-69-5 ]
[ 4800-04-8 ]
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 2296,2298
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 2296,2298
5
[ 781-38-4 ]
[ 765-69-5 ]
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 2296,2298
6
[ 393125-77-4 ]
[ 765-69-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 14, p. 3275 - 3279
Reference：
[1] Bulletin de la Societe Chimique de France, 1955, p. 1036
[2] Organic Syntheses, 1973, vol. Coll. Vol. V, p. 747
9
[ 108-30-5 ]
[ 79-03-8 ]
[ 765-69-5 ]
Reference：
[1] Australian Journal of Chemistry, 1982, vol. 35, # 4, p. 799 - 808
10
[ 765-69-5 ]
[ 67-63-0 ]
[ 20279-38-3 ]
[ 924-88-9 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 26, p. 9299 - 9302
11
[ 765-69-5 ]
[ 74-88-4 ]
[ 3883-58-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With potassium hydroxide In 1,4-dioxane; waterHeating / reflux Stage #2: With hydrogenchloride In water at 120℃; for 0.25 h;
The published procedure was followed. (Agosta, W. C.; Smith, A. B. J. Org. Chem. 1970, 35, 3856) A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H2O (25 mL)/dioxane (75 mL) was heated at reflux. After 5 h, a solution of KOH (2 g) and MeI (2.4 mL) in H2O (5 mL)/dioxane (15 mL) was added and after another 3 h at reflux the solution was allowed to stir at room temperature overnight. In the morning, the reaction was continued by addition of a solution of KOH (2 g) and MeI (2.4 mL) in H2O (5 mL)/dioxane (15 mL) and heating at reflux. After 4 h, the mixture was allowed to cool to room temperature and was extracted with ether (1?100 mL, 3?75 mL). The combined ether extracts were evaporated, the residue combined with HCl (50 mL 10percent), and the resulting mixture was placed in a 120 C. oil bath until boiling was observed (ca. 15 min.). The mixture was then allowed to cool to room temperature, was neutralized by addition of NaHCO3 solution (150 mL, saturated) and the resulting mixture then extracted with CH2Cl2 (4?75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93percent) which was used directly in the next step.
93%
With potassium hydroxide In 1,4-dioxane; water at 20℃; Reflux
Synthesized according to Agosta and Smith, J. Org. Chem., 35: 3856 (1970). A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in water (25 mL)/dioxane (75 mL) was heated at reflux. After 5 hours, a solution of KOH (2 g) and Mel (2.4 mL) in water (5 mL)/dioxane (15 mL) was added and after another 3 hours at reflux, the solution was stirred at room temperature overnight. A solution of KOH (2 g) and Mel (2.4 mL) in water (5 mL)/dioxane (15 mL) was added to the overnight reaction and heating at reflux. After 4 hours, the mixture was cooled to room temperature and extracted with ether (1×100 mL, 3×75 mL). The combined ether extracts were evaporated, the residue combined with 10percent HCl (50 mL), and the resulting mixture placed in a 120° C. oil bath until it began boiling (ca. 15 minutes). The mixture was cooled to room temperature, neutralized by addition of saturated NaHCO3 solution (150 mL) and the resulting mixture extracted with CH2Cl2 (4×75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93percent) which was used directly in the next step.
36%
Stage #1: With sodium hydroxide In water at 0 - 20℃; for 0.25 h; Stage #2: at 20℃; Stage #3: With hydrogenchloride In water for 1 h; Reflux
2-Methyl-1,3-cyclopentanodione (7) (1 eq, 351 mmol, 39.4 g) was added to a solution of NaOH (1 eq, 351 mmol, 14.1 g) in water (75 mL) at 0 °C. After stirring for 15 min, the solution was evaporated under reduced pressure to dryness. Sodium salt of 7 was obtained with quantitative yield. To a suspension of sodium salt of 7 (47.4 g) in DMF (300 mL), MeI (1.5 eq, 526.5 mmol, 33.0 mL) was added and resulting mixture was stirred vigoriously overnight. Then, the reaction mixture was poured into water (2 L) and extracted with CHCl3 (4x100 mL). The combined extracts were washed with water (5x150 mL) and brine (200 mL), dried over anh. MgSO4 and concentrated under reduced pressure to yield dark oil (35.7 g). The oil was dissolved in 12percent HCl (330 mL) and refluxed for 1 h. The reaction mixture was cooled to rt, neutralized (to pH = 7) with 20percent aq. NaOH. Then, sat. aq. solution of Na2CO3 (100 mL) was added and the product was extracted with CHCl3 (4x100 mL). The combined extracts were washed with brine (100 mL), dried over anh. MgSO4 and evaporated under reduced pressure to afford 8 (15.79 g, 36percent). Physical state: pale brown solid.; IR (neat, cm-1): 2980, 1719, 1459, 1286, 993.; 1H NMR (400 MHz, CDCl3), δ (ppm): 2.80 (s, 4H), 1.15 (s, 6H).
Reference：
[1] Patent: US2004/157901, 2004, A1, . Location in patent: Page 10
[2] Patent: US9334262, 2016, B2, . Location in patent: Page/Page column 62
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5721 - 5726
[4] Advanced Synthesis and Catalysis, 2016, vol. 358, # 9, p. 1392 - 1397
[5] Organic Letters, 2000, vol. 2, # 7, p. 933 - 936
[6] Journal of Organic Chemistry, 1982, vol. 47, # 23, p. 4491 - 4498
[7] Tetrahedron Letters, 2017, vol. 58, # 45, p. 4285 - 4288
[8] Tetrahedron Letters, 1996, vol. 37, # 39, p. 7119 - 7122
[9] Organic Letters, 2016, vol. 18, # 19, p. 4836 - 4839
[10] Journal of the Chemical Society. Perkin transactions 1, 1970, vol. 1, p. 10 - 18
[11] Patent: WO2012/125886, 2012, A1, . Location in patent: Page/Page column 107; 108
[12] Organic Letters, 2013, vol. 15, # 17, p. 4485 - 4487
With toluene-4-sulfonic acid; In benzene; at 110℃;Dean-Stark;
A round bottomed flask was charged with 2-methyl-1,3-cyclopentadione (1.5 g, 13.37 mmol, 1.0 eq.) in benzene (20 mL). p-TsOH·H2O (345 mg, 2.01 mmol, 0.15 eq.) was added, followed by isobutanol (6.19 mL, 66.85 mmol, 5.0 eq.). The reaction was tapped with a Dean-Stark apparatus and a condenser, and heated to 110 C overnight. After completion of the reaction (as judged by running TLC; 12 h) the organic layer was concentrated in vacuum. Then the crude product was purified by column chromatography using (70:30 hexanes:EtOAc) to afford 13 as a yellow oil (2.06 g, 92% yield).
34.5 g
With toluene-4-sulfonic acid; In benzene;Reflux;
A solution of 2-methylcyclopentane-1 ,3-dione (27.0 g), 2-methylpropan-1-ol (62.5 g) and TsOH (4.6 g) in benzene (500 mL) was heated to reflux overnight. The solvent was removed in vacuo and the residue was distilled under vacuum to give 3-isobutoxy-2- methylcyclopent-2-enone (34.5 g) as a yellow oil. 1H-NMR (400 MHz, CDCI3) delta ppm 3.92 (d, J = 6.6 Hz, 2H), 2.53-2.70 (m, 2H), 2.32-2.52 (m, 2H), 2.04 (dp, J = 13.3, 6.7 Hz, 1 H), 1.64 (t, J = 1.5 Hz, 3H), 1.01 (d, J = 6.7 Hz, 6H); MS(ES+) m/z 169 (MH+).
General procedure: Obtained by reaction of 2- methyl-1,3-cyclopentadione (2.2 g, 20 mmol) with methyl vinyl ketone (1.8 mL, 22 mmol) by the procedure described for the preparation of 8a. The pure compound was obtained as a colorless oil (3.5 g, 19 mmol, 95%). 1H-NMR (400 MHz, CDCl3): delta 1.04 (s, 3H); 1.79-1.83 (m, 2H); 2.03 (s, 3H); 2.39 (t, J = 7.2 Hz, 2H); 2.67-2.77 (m, 4H).
With lipase AS; In dimethyl sulfoxide; acetone; at 10℃; for 192h;Inert atmosphere; Enzymatic reaction;
General procedure: A mixture of 2-methyl-1,3-cycloalkanedione (2a-c) (0.14 mmol) and lipase AS (28.4 mg, 0.81mol, 0.6 mol%) in a solution of 20% acetone in DMSO (0.7 mL) was incubated under an Ar atmosphere at 10C for 5 min. Methyl vinyl ketone (3) (35 L, 0.42 mmol, 3.0 equiv.) was then added to the reaction mixture and incubated under Ar at 10C for 8 days.
to a solutionof compound 1 (673mg, 6.0mmol) in 1M NaOH(6.0mL) allyl bromide was added (1.45g, 12.0mmol). Thereaction was stirred for 24h at room temperature, and monitoredby TLC (9:1 DCM/MeOH). The mixture was extractedwith dichloromethane (5 × 5mL) and the organic phasewas dried over Na2SO4,filtered and evaporated. The crudeextract was then purified by column chromatography (9:1cyclohexane/ethyl acetate) to obtain compound 3 as a paleyellowoil (yield: 50%, 470mg, 3.0mmol). Rf= 0.55 (7:3cyclohexane/ethyl acetate); 1H NMR (CDCl3, 300MHz): 1.10 (3H, s), 2.35 (2 H, d, J = 8Hz), 2.60-2.80 (4 H, m),5.00-5.10 (2 H, m), 5.50-5.70 (1 H, m). Anal. Calcd forC9H12O2:C, 71.03; H, 7.95. Found: C, 71.12; H, 7.83. ChiralGC retention time: 15.3min.
General procedure: To a solution of 2-methyl-1,3-cycloalkanedione (10 mmol) in THF (30 mL) were successively added lithium iodide (11 mmol, 1.1 equiv) and DBU (11 mmol, 1.1 equiv). After several minutes, a white precipitate was formed. After stirring for 30 min, allyl bromide (20 mmol, 2 equiv) was added to the suspension, and then the mixture was refluxed for 11 h. After cooling at room temperature, the mixture was poured on ice-water and was extracted with ethyl acetate (4×5 mL). The combined organic phase was successively washed with water, a aqueous sodium thiosulfate solution (5%) and brine, then was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (cyclohexane/AcOEt: 70/30) to afford a colorless oil. The metathesis between 2-allyl-2-methyl-1,3-cycloalkanedione and tert-butyl acrylate gave the expected precursor 5a-c according to the previous above procedures.
The published procedure was followed. (Agosta, W. C.; Smith, A. B. J. Org. Chem. 1970, 35, 3856) A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H2O (25 mL)/dioxane (75 mL) was heated at reflux. After 5 h, a solution of KOH (2 g) and MeI (2.4 mL) in H2O (5 mL)/dioxane (15 mL) was added and after another 3 h at reflux the solution was allowed to stir at room temperature overnight. In the morning, the reaction was continued by addition of a solution of KOH (2 g) and MeI (2.4 mL) in H2O (5 mL)/dioxane (15 mL) and heating at reflux. After 4 h, the mixture was allowed to cool to room temperature and was extracted with ether (1?100 mL, 3?75 mL). The combined ether extracts were evaporated, the residue combined with HCl (50 mL 10percent), and the resulting mixture was placed in a 120 C. oil bath until boiling was observed (ca. 15 min.). The mixture was then allowed to cool to room temperature, was neutralized by addition of NaHCO3 solution (150 mL, saturated) and the resulting mixture then extracted with CH2Cl2 (4?75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93percent) which was used directly in the next step.
93%
With potassium hydroxide; In 1,4-dioxane; water; at 20℃;Reflux;
Synthesized according to Agosta and Smith, J. Org. Chem., 35: 3856 (1970). A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in water (25 mL)/dioxane (75 mL) was heated at reflux. After 5 hours, a solution of KOH (2 g) and Mel (2.4 mL) in water (5 mL)/dioxane (15 mL) was added and after another 3 hours at reflux, the solution was stirred at room temperature overnight. A solution of KOH (2 g) and Mel (2.4 mL) in water (5 mL)/dioxane (15 mL) was added to the overnight reaction and heating at reflux. After 4 hours, the mixture was cooled to room temperature and extracted with ether (1×100 mL, 3×75 mL). The combined ether extracts were evaporated, the residue combined with 10percent HCl (50 mL), and the resulting mixture placed in a 120° C. oil bath until it began boiling (ca. 15 minutes). The mixture was cooled to room temperature, neutralized by addition of saturated NaHCO3 solution (150 mL) and the resulting mixture extracted with CH2Cl2 (4×75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93percent) which was used directly in the next step.
36%
2-Methyl-1,3-cyclopentanodione (7) (1 eq, 351 mmol, 39.4 g) was added to a solution of NaOH (1 eq, 351 mmol, 14.1 g) in water (75 mL) at 0 °C. After stirring for 15 min, the solution was evaporated under reduced pressure to dryness. Sodium salt of 7 was obtained with quantitative yield. To a suspension of sodium salt of 7 (47.4 g) in DMF (300 mL), MeI (1.5 eq, 526.5 mmol, 33.0 mL) was added and resulting mixture was stirred vigoriously overnight. Then, the reaction mixture was poured into water (2 L) and extracted with CHCl3 (4x100 mL). The combined extracts were washed with water (5x150 mL) and brine (200 mL), dried over anh. MgSO4 and concentrated under reduced pressure to yield dark oil (35.7 g). The oil was dissolved in 12percent HCl (330 mL) and refluxed for 1 h. The reaction mixture was cooled to rt, neutralized (to pH = 7) with 20percent aq. NaOH. Then, sat. aq. solution of Na2CO3 (100 mL) was added and the product was extracted with CHCl3 (4x100 mL). The combined extracts were washed with brine (100 mL), dried over anh. MgSO4 and evaporated under reduced pressure to afford 8 (15.79 g, 36percent). Physical state: pale brown solid.; IR (neat, cm-1): 2980, 1719, 1459, 1286, 993.; 1H NMR (400 MHz, CDCl3), delta (ppm): 2.80 (s, 4H), 1.15 (s, 6H).
With potassium hydroxide; In 1,4-dioxane; water; for 11h;Reflux;
A mixture of 2-methylcyclopentane-l,3-dione (49.98 g, 446 mmol), potassium hydroxide (25.5 g, 455 mmol) and iodomethane (30.1 mL, 481 mmol) in dioxane (390 mL) and water (130 mL) was heated to reflux for 5 h. A biphasic mixture of potassium hydroxide (10.4 g), iodomethane (12.5 mL), water (26 mL) and dioxane (78 mL) was added. The mixture was heated at reflux for 3 additional hours and then stirred at ambient temperature overnight. Another portion of a biphasic mixture of potassium hydroxide (10.4 g), iodomethane (12.5 mL), water (26 mL) and dioxane (78 mL) was added. The mixture was heated at reflux for 3 h, cooled to room temperature and extracted with ether (600 mL, then 2x400 mL). The combined extracts were concentrated using a rotavap while keeping the bath temperature at or below room temperature to prevent loss of volatile product. The residue was treated with 10percent hydrochloric acid (250 mL) and placed in a 120 °C oil bath until it started to boil (~15 min). The mixture was cooled with an ice-water bath, diluted with water (250 mL) and treated with careful addition of sodium carbonate until carbon dioxide release stopped. The pH of the solution was 8-9. The mixture was extracted with dichloromethane (4x200 mL). The combined extracts were dried (MgS04), filtered and concentrated while keeping water bath at or below room temperature. The residue was further dried under vacuum briefly to remove residual solvent to give 2,2- dimethylcyclopentane-l,3-dione as tan solid (38.1 g, 68percent yield). XH NMR (400 MHz, chloroform-if) delta ppm 2.81 (4 H, s), 1.16 (6 H, s); LC retention time: 0.990 (analytical HPLC Method F).
With 1,4-diaza-bicyclo[2.2.2]octane; In 1,2-dimethoxyethane; at 20℃; for 24h;
To a solution of 2-methylcyclopentane-1 ,3-dione (20 g, 178.2 mmol) and pent-1-en-3-one (15 g, 178.2 mmol) in dimethoxyethane (400 mL) was added 1 ,4-diazabicyclo[2.2.2]octane (20 g, 178.2mmol). The mixture was stirred for 24 hours at room temperature. The mixture was acidified with 1 N hydrochloric acid to pH = 4.5 and the organics were extracted with diethyl ether (200 mL x 3). The organic layer was washed with brine (100 mL x 3) dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a light yellow oil (21.9 g, Yield: 63%). 1H NMR (400 MHz, CDCI3) delta 2.91 - 2.69 (m, 4H), 2.46 - 2.34 (m, 4H), 1.90 (t, J = 1.2 Hz, 2H), 1.11 (s, 3H), 1.01 (t, J = 7.4 Hz, 3H) ppm; Mass spectrum (ESI +ve) m/z 197 (M + H+).
Stage #1: succinic acid With Aluminum Chloride In nitromethane for 2h; Inert atmosphere;
Stage #2: propionyl chloride In nitromethane at 100℃; for 2h; Inert atmosphere;
1.S1; 2-5 S1,Preparation of 2-methyl-1,3-cyclopentanedione:
Add 400g (3.0mol) of anhydrous aluminum chloride to a 2L three-necked flask, then add 400mL of nitromethane to dissolve the anhydrous aluminum chloride, stir mechanically under nitrogen protection, after the anhydrous aluminum chloride is completely dissolved, slowly at room temperature A total of 118g (1.0mol) succinic acid was added in three batches, the addition was completed, the reaction was stirred for 2h, 278g (3.0mol) propionyl chloride was added dropwise, and the mixture A was heated at 100°C to reflux for 2h after cooling, and then reduced pressure The solvent was distilled off, then the product was poured into crushed ice and stirred, a reddish-brown solid precipitated out, filtered under reduced pressure, and the filter cake was washed alternately three times with 100 mL of cold water (0°C) and 100 mL of cold toluene (0°C).Take out the filter cake, put it in a 2L three-necked flask, add 1L of water and 5g of activated carbon, heat to reflux for 0.5h, filter while hot to precipitate white needle-like crystals, filter and dry to obtain a white solid product 105 g of 2-methyl-1,3-cyclopentanedione, the yield is 92.9%, and the purity is 99.2%.
63%
Stage #1: succinic acid With Aluminum Chloride; nitromethane at 20℃; for 1h; Inert atmosphere;
Stage #2: propionyl chloride at 80℃; for 3h; Inert atmosphere;
Stage #1: succinic acid With Aluminum Chloride In nitromethane for 3.5h; Reflux; Inert atmosphere;
Stage #2: propionyl chloride In nitromethane for 2.5h; Reflux; Inert atmosphere;
2-Methyl-1,3-cyclopentanedione (1.50 g, 13.4 mmol, 1 eq) was dissolved in 1M aq. NaOH (15.0 mL) before addition of benzyl bromide (3.20 mL, 26.8 mmol, 2.0 eq). The resulting mixture was vigorously stirred (1000 rpm) at room temperature for 44 hours. The reaction mixture was extracted with EtOAc (3 x 20 mL). The organic extracts were combined, washed with brine (20 mL), dried (MgSO4) and evaporated in vacuo to give a yellow oil. The yellow oil was purified by flash chromatography (5-10-15% EtOAc in petroleum ether) to give 2- benzyl-2-methylcyclopentane-1,3-dione (2.025 g, 75%) as an off-white solid.
50%
With sodium hydroxide; at 20℃; for 36h;
to asolution of compound 1 (650mg, 5.8mmol) in 1M NaOH(5.8mL) benzyl bromide was added (1.98g, 11.6mmol).The reaction was stirred for 36h at room temperatureand monitored by TLC (7:3 cyclohexane/EtOAc). Themixture was then extracted with ethyl acetate (3 × 5mL)and the organic phase was dried over Na2SO4and evaporated.The crude extract was purified by column chromatography(9:1 cyclohexane/EtOAc). Compound 7 wasobtained as a white solid (yield: 50%, 587mg, 2.9mmol);mp 50C; Rf= 0.58 (7:3 cyclohexane/ethyl acetate); 1HNMR (CDCl3, 300MHz): 1.20 (3H, s), 2.00-2.10 (2H,m), 2.50-2.60 (2H, m), 2.95 (2H, s), 7.00-7.05 (2H, m),7.20-7.30 (3H, m). Anal. Calcd for C13H14O2:C, 77.20;H, 6.98. Found C, 77.42; H, 7.06., Chiral GC retentiontime: 18.1min.
General procedure: To a suspension of the 2-methyl-1,3-cycloalkanedione (50 mmol) in water (125 mL) was added acrolein (75 mmol, 1.5 equiv). The mixture was stirred at room temperature for 18 h. Then, water and the excess of acrolein were evaporated under reduced pressure. The wet solid obtained was stirred with dichloromethane (50 mL). After 15 min, the slight suspension was filtered and the filtrate is dried over MgSO4. After filtration, the solution was concentrated in vacuo to afford the corresponding 2-methyl-2-propionaldehyde-1,3-cycloalkane-dione (quantitative yields) of a sufficient purity for the next step. The aldehyde (50 mmol) and the appropriate Wittig reagent (75 mmol) were warmed at 80 C in toluene (150 mL) in presence of benzoic acid (50 mmol) for 18 h. The solution was successively washed with bicarbonate aqueous solution and brine. The organic solution was then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via column chromatography (CH2Cl2/AcOEt: 98/2) to give a colorless oil (75-96% yields).
(R)-7a-methyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-Methylcyclopentane-1,3-dione With <i>L</i>-proline In dimethyl sulfoxide at 15 - 25℃; for 6h;
Stage #2: methyl vinyl ketone In dimethyl sulfoxide at 15 - 25℃; for 145h;
Stage #3: With pyridinium p-toluenesulfonate In benzene for 2h; Heating;
80 % ee
With trifluorormethanesulfonic acid; 3-nitrobenzoic acid In 2-methyltetrahydrofuran at 55℃; for 2h; Overall yield = 79 %; enantioselective reaction;
Multi-step reaction with 2 steps
1: 100 percent / triethylamine / acetonitrile / 20 °C
2: (S)-5,6-dimethyl-2-(pyrrolidin-2-yl)-1H-benzimidazole; TFA / tetrahydrofuran / 48 h / 20 °C
Multi-step reaction with 2 steps
1.1: 98 percent / AcOH / H2O / 4 h / 75 °C
2.1: H-(S)-β3hPhe-OH / dimethylformamide / 96 h / 20 °C / dark
2.2: H2SO4 / dimethylformamide / 4 h / 90 °C
Multi-step reaction with 3 steps
1: acetic acid / water / 16 h / 70 °C
2: <i>L</i>-proline / N,N-dimethyl-formamide / 16 h / 20 °C
3: toluene-4-sulfonic acid / dichloromethane / 16 h / 20 °C
Multi-step reaction with 2 steps
1.1: acetic acid / water / 4 h / 70 °C / Darkness; Inert atmosphere
2.1: <i>L</i>-proline / N,N-dimethyl-formamide / 72 h / 15 - 16 °C / Inert atmosphere; Darkness
2.2: -20 - -15 °C / Inert atmosphere
Multi-step reaction with 3 steps
1: acetic acid / water / 4 h / 75 °C / Darkness; Inert atmosphere; Schlenk technique
2: <i>L</i>-proline / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Schlenk technique
3: sulfuric acid / N,N-dimethyl-formamide / 4.5 h / 95 °C / Inert atmosphere; Schlenk technique
Multi-step reaction with 3 steps
1: acetic acid / water / 4 h / 75 °C
2: <i>L</i>-proline / N,N-dimethyl-formamide / 96 h / 20 °C
3: sulfuric acid / N,N-dimethyl-formamide / 5 h / 95 °C
With potassium fluoride; triethylamine; In water; dimethyl sulfoxide; ethyl acetate;
EXAMPLE II-29 In 60 mL of dimethyl sulfoxide was dissolved 3.0 g of <strong>[356783-16-9]3,6-dichloro-2-pyrazinecarbonitrile</strong>. After adding 3.0 g of potassium fluoride, the mixture thus obtained was stirred at 90-100 C. for 2 hours. The reaction mixture was returned to room temperature, to which were successively added 2.1 g of 2-methyl-1,3-cyclopentandione and 7.2 ml of triethylamine. The mixture thus obtained was stirred at room temperature for one hour. The reaction mixture was added to a mixture of 50 mL of ethyl acetate and 200 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=2:1] to obtain 1.7 g of 6-fluoro-3-[(2-methyl-3-oxo-1-cyclopenten-1-yl)oxy]-2pyrazinecarbonitrile as a yellow-colored solid product. IR (KBr) cm-1: 2238, 1707, 1676 1H-NMR (CDCl3) delta: 1.72(3H,t,J=1.8 Hz), 2.58-2.68(2H,m), 2.76-2.91(2H,m), 8.29(1H,d,J=8.1 Hz)
4,5-Dihydro-6-(4-((2-methyl-3-oxo-1-cyclopentenyl)amino)phenyl)-5-methyl-3(2H)-pyridazinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In ethanol;
EXAMPLE 5 4,5-Dihydro-6-(4-((2-methyl-3-oxo-1-cyclopentenyl)amino)phenyl)-5-methyl-3(2H)-pyridazinone (Compound No. 15) STR13 A mixture of 0.51 g of 4,5-dihydro-6-(4-aminophenyl)-5-methyl-3(2H) pyridazinone and 0.28 g of 2-methyl-cyclopentane-1,3-dione in 5 ml of ethanol and 5 ml of acetic acid was refluxed over night. After cooling, the solution was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluding solvent: chloroform:methanol=20:1) and recrystallized from methanol to give 0.32 g of the title compound. m.p. 285-286 C.
With hydrogenchloride; potassium hydroxide; sodium hydrogencarbonate; methyl iodide; In 1,4-dioxane; water;
2,2-Dimethyl-cyclopentane-1,3-dione (2). The published procedure was followed. (Agosta, W. C.; Smith, A. B. J. Org. Chem. 1970, 35, 3856) A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H2O (25 mL)/dioxane (75 mL) was heated at reflux. After 5 h, a solution of KOH (2 g) and MeI (2.4 mL) in H2O (5 mL)/dioxane (15 mL) was added and after another 3 h at reflux the solution was allowed to stir at room temperature overnight. In the morning, the reaction was continued by addition of a solution of KOH (2 g) and MeI (2.4 mL) in H2O (5 mL)/dioxane (15 mL) and heating at reflux. After 4 h, the mixture was allowed to cool to room temperature and was extracted with ether (1*100 mL, 3*75 mL). The combined ether extracts were evaporated, the residue combined with HCl (50 mL 10percent), and the resulting mixture was placed in a 120° C. oil bath until boiling was observed (ca. 15 min.). The mixture was then allowed to cool to room temperature, was neutralized by addition of NaHCO3 solution (150 mL, saturated) and the resulting mixture then extracted with CH2Cl2 (4*75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93percent) which was used directly in the next step.
tert-butyl 9-(2-methyl-3-oxocyclopent-1-en-1-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In isopropyl alcohol; at 120℃; for 16h;Sealed tube;
Step A: tert-butyl 9-(2-methyl-3-oxocyclopent-1-en-1-yl)-3,9-diazaspiro [5.5]undecane-3-carboxylate: To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (INTERMEDIATE 26; 119mg, 0.468 mmol) in a microwave tube was added 2-propanol (7 ml) followed by 2-methyl-l,3-cyclopentadione (62.9 mg, 0.561 mmol). The tube was sealed and heated at 120C for 16 hr. The reaction was concentrated, diluted with ethyl acetate, and washed with saturated NaHC03 (lx). Organic layer was dried overNa2S04, filtered and concentrated to yield tert-butyl 9-(2-methyl-3-oxocyclopent-l-en-l-yl)-3,9-diazaspiro [5.5] undecane -3 -carboxylate.
tert-butyl 4-(2-methyl-3-oxocyclopent-1-en-1-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate; acetic acid; In toluene; at 130℃; for 12h;Dean-Stark;
In a 100 mL round bottom flask, tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 1.95 mmol) was mixed with 2-methylcyclopentane-l,3-dione (284 mg, 2.54 mmol), ammonium acetate (30.1 mg, 0.390 mmol) and acetic acid (0.447 mL, 7.80 mmol) in toluene (20 mL) and heated at 130C for 12 hours. A Dean-Stark trap was applied to remove generated water during the reaction. After the reaction was cooled to room temperature, the solvent was removed and residue was dissolved in ethyl acetate (40 mL) and washed with IN NaOH (aqueous) (20 mL), brine (20 mL) and dried over anhydrous sodium sulfate. Concentration on rotavapor gave crude product that was used without further purification. LC-MS (IE, m/z): 351.3 [M+l]+.
3-[(4,5-dimethoxy-2-nitrophenyl)methoxy]-2-methylcyclopent-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With potassium carbonate; In tetrahydrofuran; dimethyl sulfoxide;Inert atmosphere;
Potassium carbonate (2.07 g, 15.0 mmol) was added to 2-methyl-1,3-cyclopentanedione (1.68 g, 15.0 mmol) in 50 ml of THF / DMSO at 1:1 mixture in solution. After stirring for 30 minutes,A solution of <strong>[53413-67-5]1-(bromomethyl)-4,5-dimethoxy-2-nitrobenzene</strong>(4.14 g, 15.0 mmol) in 40 mL of a 1: 1 mixture of THF / DMSO was added dropwise via an addition funnel over 15 minutes. The resulting reaction mixture was stirred under a nitrogen atmosphere overnight. DI water (150 mL) was added, and the mixture was extracted three times with 75 mL EtOAc. The combined organic layers were washed three times with DI water and once with saturated aqueous NaCl solution, then dried over MgSO4, filtered,And concentrated to a yellow solid. Purified via suction filter chromatography (SiO2, eluent ramped from 1/1 to 5/1 EtOAc / hexanes) to provide a yellow solid,It was triturated with 3: 1 hexane / EtOAc. The desired product (1.78 g, 39% yield) was then collected as a pale yellow solid via filtration.
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