* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 2001, # 8, p. 1299 - 1305
[2] Journal of the Chemical Society. Perkin Transactions 2, 2001, # 8, p. 1299 - 1305
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5339 - 5356
5
[ 675-20-7 ]
[ 20069-09-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5727 - 5730
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 31, p. 7585 - 7593
6
[ 675-20-7 ]
[ 6052-73-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 31, p. 7585 - 7593
[2] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7757 - 7760
[3] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 313 - 319
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 5, p. 1821 - 1832
7
[ 675-20-7 ]
[ 27219-07-4 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 14, p. 2424 - 2426
8
[ 675-20-7 ]
[ 67-56-1 ]
[ 29840-56-0 ]
Yield
Reaction Conditions
Operation in experiment
72%
With hydrogenchloride In water at 20 - 55℃; for 20 h; Inert atmosphere
To a stirred solution of piperidin-2-one 10-lA (500 mg, 5.05 mmol) in MeOH (10 mL) was passed HCl gas. The reaction mixture was stirred at RT for 4 hr under N2 atmosphere. Then reaction mixture warmed to 55 °C and stirring continued for 16 hr. Reaction solvents were evaporated under reduced pressure and the crude residue was washed with diethyl ether to afford 10-2A (608 mg, 129.57 mmol, 72percent yield) as an off-white solid.
Reference：
[1] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 6, p. 1233 - 1239
10
[ 675-20-7 ]
[ 24424-99-5 ]
[ 85908-96-9 ]
Yield
Reaction Conditions
Operation in experiment
91%
With dmap; triethylamine In dichloromethane at 20℃; for 3 h;
395] To a solution of piperidin-2-one (0.97 g, 9.78 mmol) in DCM (20 mL) were added Et3N (1.36 mL, 9.78 mmol), DMAP (0.12 g, 0.978 mmol) and B0C2O (3.20 g, 14.7 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/7) to give the title compound as pale yellow oil (1.78 g, 91percent). MS (ESI, pos. ion) m z: 144.2 [(M-C4)+H]+; 1H MR (600 MHz, CDCI3): δ (ppm) 3.65 (t, J= 6.1 Hz, 2H), 2.50 (t, J = 9.6, 7.2 Hz, 2H), 1.82 (m, 4H), 1.52 (s, 9H).
91%
With dmap; triethylamine In dichloromethane at 20℃; for 3 h;
Step 1) fert-butyl 2-oxopiperidine-l-carboxylate [0359] To a solution of piperidin-2-one (0.97 g, 9.78 mmol) in DCM (20 mL) were added Et3N (1.36 mL, 9.78 mmol), DMAP (0.12 g, 0.978 mmol) and B0C2O (3.20 g, 14.7 mmol). The reaction mixture was stirred at rt for 3 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/7) to give the title compound as pale yellow oil (1.78 g, 91percent). MS (ESI, pos. ion) m/z: 144.2 [(M-C4)+H]+; NMR (600 MHz, CDCb): δ (ppm) 3.65 (t, J= 6.1 Hz, 2H), 2.50 (t, J= 9.6, 7.2 Hz, 2H), 1.82 (m, 4H), 1.52 (s, 9H).
91%
With dmap; triethylamine In dichloromethane at 20℃; for 3 h;
Piperidin-2-one (0.97 g, 9.78 mmol) was dissolved in DCM (20 mL) and then Et3N (1.36 mL, 9.78 mmol), DMAP (0.12 g, 0.978 mmol) and Boc2O (3.20 g, 14.7 mmol) were sequentially added to the solution to obtain a reaction system. The resulting reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (EtOAc / PE (v / v) = 1/7) to give the title compound as a pale yellow oil (1.78 g, 91percent).
91%
With dmap; triethylamine In dichloromethane at 20℃; for 3 h;
Piperidin-2-one (0.97 g, 9.78 mmol) was dissolved in DCM (20 mL), and triethylamine (1.36 mL, 9.78 mmol), DMAP (0.12 g, 0.978 mmol) and Boc2O (3.20 g, 14.7 mmol) were added thereto and the resulting reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 1/7) to give a pale yellow oil (1.78 g, 91percent).
85%
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 48 h;
To a stirred solution of piperidin-2-one (5 g, 50.4 mmol, 1.0 equiv.), triethylamine (14.022 mL, 100.9 mmol, 2.0 equiv.) and N,N-4-dimethylaminopyridine (0.123 g, 1.0 mmol) in methylene chloride (100 mL) at 0° C. was added di-tert-butyl dicarbonate (16.512 g, 75.7 mmol, 1.5 equiv.). The mixture was slowly warmed to room temperature and stirred for 48 hrs. The reaction was quenched with water and the organic layer was washed sequentially with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (0-100percent ethyl acetate/hexanes) to afford the desired product as a yellow oil (8.5 g, 85percent). 1H NMR (300 MHz, CDCl3): δ 3.72-3.62 (m, 2H), 2.58-2.48 (m, 2H), 1.90-1.78 (m, 4H), 1.55 (s, 9H).
85%
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 48 h;
To a stirred solution ofpiperidin-2-one (5 g, 50.4 mmol, 1.0 equiv.),triethylamine (14.022 mL, 100.9 mmol, 2.0 equiv.)andN,N-4-dimethylaminopyridine (0.123 g, 1.0 mmol)in dichloromethane (100 mL)at 0 °Cwas addeddi-tert-butyl dicarbonate (16.512 g, 75.7 mmol, 1.5 equiv.).The mixture was slowly warmed to room temperature and stirred for 48 hrs. The reaction was quenched with water and the organic layer was washed sequentially with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonateand saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The residue was purified by silica gel column (0-100percent ethyl acetate/hexanes) to afford the desired product as a yellow oil (8.5 g, 85percent).1H NMR (300 MHz, CDCl3): δ 3.72-3.62 (m, 2H), 2.58-2.48 (m, 2H), 1.90-1.78 (m, 4H), 1.55 (s, 9H).
82%
With dmap In acetonitrile at 22℃; for 2 h;
In addition, this reaction can also be performed in a different reaction step. In a three necked round bottom flask fitted with: a stirring bar, a thermometer, and a bubler at 22° C., 1000 mg, (10 mmol) ö-Valerolactam was placed. Then a 0.7M solution of DMAP (60 g 0.4 mmol) in ACN (0.8 mE) was added. To the light-yellow solution (BOC)20 (3260 g 15 mmol) was portion wise added accompanied by gas evolution. After flall conversion (stirring at internal temperature 22° C. for 2 h) 10 mE 0.1M HC1 aq. solution were added and extracted with dichloromethane (3x20 mE). The organic phase was evaporated. Upon addition of 40 ml hexane and cooling to —30° C. and crystals where formed. Yield 82percent. Purity 98percent. The advantage of this reaction compared to the reaction mentioned above can be seen in that the reaction is performed at room temperature and that DMAP is easier to handle compared to BuEi. Furthermore,a higher degree of purity is achievable.
77%
With dmap; triethylamine In acetonitrile at 0 - 20℃; for 18 h;
To a solution of 5.00 g (50.4 mmol, 1.0 eq.) 2-piperidinone in 250 mL acetonitrile, 8.44 mL (6.12 g,60.5 mmol, 1.2 eq.) triethylamine and 616 mg (5.04 mmol, 0.1 eq.) DMAP are added and the mixture iscooled to 0 °C. After slow addition of 12.7 mL (12.1 g, 55.4 mmol, 1.1 eq.) di-tert-butyl dicarbonate,the reaction mixture is stirred for 18 hours at ambient temperature. The solvent is removed and the crudeproduct is purified via column chromatography (SiO2, 6.5 10 cm, pentane/EtOAc = 5/1 3/1 1/1)to obtain 7.71 g (77 percent) tert-butyl-2-oxopiperidine-1-carboxylate as yellow oil.
67.25%
With dmap; triethylamine In acetonitrile at 18℃; for 16 h; Inert atmosphere
10300] To a solution of compound 1 (31.00 g, 312.72 mmol) in CH3CN (500 mE) was added TEA (63.29 g, 625.44 mmol), 13oc20 (88.73 g, 406.54 mmol), DMAP (1.91 g, 15.64 mmol) in portions under N2. The mixture was stirred at 18° C. for 16 hours. TLC showed the reaction was completed. The mixture was concentrated in reduced pressure at 35° C. The residue was purified by silica gel chromatography (PE/EA30/1 to 5/1) to afford compound 2 (41.90 g, 210.29 mmol, 67.25percent yield) as yellow oil. LCMS:200 [M+1].
6.07 g
With dmap In acetonitrile at 0℃; for 24 h;
In 250mL eggplant-shaped flask were successively added piperidin-2-one (5g, 50mmol), di- tert -butyl dicarbonate (13.1g, 60mmol), acetonitrile, 100mL, ice-cooling to 0 , was slowly added portionwise 4- dimethylaminopyridine (1.22g, 10mmol, plus complete,The reaction temperature 24h, TLC the reaction was complete, solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1), to giveColorless oily liquid (6.07g, 30.5mmol).
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[12] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 8, p. 1815 - 1823
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11
[ 675-20-7 ]
[ 34619-03-9 ]
[ 85908-96-9 ]
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 8, p. 2610 - 2618
With phosphorus pentachloride; In chloroform; at 0℃; for 3h;Heating / reflux;
Part A. 8-Valerolactam (22.22 g, 222.89 mmol) was stirred inCHCl3 (500 mL) at0 C.PCl5 (140.0 g,68. 29 mmol) was added portionwise. The resulting slurry was stirred at reflux for 3 h until the solution became clear. The mixture was cooled in an ice bath andH20 was added carefully until the PC15 was quenched completely. The two layers were separated. The organic layer was washed withH20 (3x) and brine (2x), dried overMgSO4, filtered, and concentrated to dryness to give 3,3-dichloro-2-piperidinone (31.63 g, yield:85%). This solid (16.50 g, 98.80 mmol) was dissolved in DMF (20 mL), andLi2Co3 (21.93 g, 296.40 mmol, 3.0 eq) was added. The mixture was stirred at120 C for 1 day. The solvent was further concentrated, and 1N HCl was added to acidify the mixture. It was then extracted withCHCl3 (6x). The organic layers were washed with H2O, brine, dried overMgSO4, and concentrated to dryness to give almost pure 3-chloro-5,6-dihydro-2(1H)- pyridinone (11.13 g,87%).
77%
With phosphorus pentachloride; In chloroform; at 0 - 70℃; for 4h;
CHCl3 (2.89 dm3) was charged into a 5 dm3 three-neckedround-bottomed flask, fitted with a condenser, a mechanicalstirrer and a CaCl2 guard tube. PCl5 (1.071 kg,5.144 mol), followed by solution of 170 g d-valerolactam(1.715 mol) in 510 cm3 CHCl3, was gradually introduced into the reaction vessel while maintaining the temperature of the reaction mass at 0-5 C. The resulting mixture wasre fluxed at 65-70 C for 4 h. It was then allowed to cool to 0-5 C, slowly poured into 3.40 dm3 ice cold water and carefully rendered basic (pH 9-10) by addition of 50% aqueous NaOH solution at 0-5 C. The product was then extracted into dichloromethane (2 9 1.70 dm3). The organic layers were combined, washed with 1.70 dm3brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure at <50 C. The crude material obtained was stirred in 340 cm3 n-hexane at RT for15 min, filtered, washed with 100 cm3 n-hexane, and finally dried at RT for 4 h to obtain 10 (221 g, 77%, 98.4% purity by HPLC analysis) as a white solid.
58%
With phosphorus pentachloride; In dichloromethane; for 12h;
Phosphorus pentachloride (8.31 g, 39 mmol) was added to a solution of delta-valerolactam (1.287 g, 13 mmol) in chloroform (50 mL). The reaction solution was refluxed for 12 h and then cooled to room temperature. Then the mixture was poured into an ice-water mixture (50 mL), and the pH was adjusted to a value between 8 and 11 by adding NaOH aqueous solution (20% , w/w). The aqueous layer was extracted with chloroform/methanol (10/1) (3 times, 22ml for each time). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated and purified by column chromatography (petroleum ether/ethylacetate, 1/1) to give the title compound 14 as a white solid (1.265 g, 58%).
43.4%
With phosphorus pentachloride; In chloroform; for 2h;Reflux;
In the -5C lower, the 2-azahexacyclonone (30g, 303mmol) dissolved in chloroform (500 ml) in, by adding phosphorus pentachloride (150g, 757.5mmol), at -5 C lower stirring 10 minutes after the heating to reflux 2 hours. Cooling to room temperature, adding ice water (300 ml), stirring at room temperature 12 hours. By adding dichloromethane (100 ml × 2) extraction, combined with the phase, with water (50 ml × 2) and the saturated salt water (50 ml) to wash, dry anhydrous sodium sulfate. Filtering, distilling off the solvent under reduced pressure, obtaining light yellow solid (22g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.16667h;Reflux;
At -5C, 2-piperidone (30g, 303mmol) was dissolved in chloroform (500mL) and was added phosphorous pentachloride (150g, 757.5mmol) then stirred at -5C for 10 minutes and refluxed for 2 hours. Cooled to room temperature, ice water (300mL) was added and stirred at room temperature for 12 hours. It was extracted with dichloromethane (100mL x 2). The combined organic phases was successively washed with water (50mL × 2) and saturated brine (50mL), dried over anhydrous sodium sulfate, then filtered. The solvent was distilled off under reduced pressure to give a pale yellow solid (22g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.16667h;Reflux; Inert atmosphere;
In _5 C under nitrogen hexyl 2- cyclic ketone (30g, 303mmol) was dissolved in chloroform (a 500 mL) was added pentachloridePhosphate (150g, 757. 5mmol), stirred at -5 C for 10 minutes was heated at reflux for 2 hours. Cooled to room temperature, ice water (300mL), stirred at room temperature for 12 hours. Dichloromethane (100 mL x 2). The combined organic phases were washed with water (50 mL x 2) and saturated brine water (50mL), dried over anhydrous sodium sulfate. Filtered, and the solvent was evaporated under reduced pressure to give a pale yellow solid (22g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.16667h;Reflux;
2-azacyclohexanone (30g, 303mmol) dissolved in chloroform (500 ml) in, by adding phosphorus pentachloride (150g, 757.5mmol), at -5 C lower stirring 10 minutes after the heating to reflux 2 hours. Cooling to room temperature, adding ice water (300 ml), stirring at room temperature 12 hours. By adding dichloromethane (100 ml × 2) extraction, combined with the phase, with water (50 ml × 2) and the saturated salt water (50 ml) to wash, dry anhydrous sodium sulfate. Filtering, distilling off the solvent under reduced pressure, obtaining light yellow solid (22g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 14h;Reflux;
At -5 , the2- hexyl nitrogen cyclic ketone (30g, 303mmol) was dissolved in chloroform (a 500 mL) was added phosphorus pentachloride (150g, 757.5 mmol), stirred at -5 for 10 minutes was heated at reflux for 2 hours. Cooled to room temperature, ice water (300mL), stirred at room temperature for 12 hours. Dichloromethane (100mL × 2). The combined organic phases were washed with water (50mL × 2) and saturated brine water (50mL) was washed, dried over anhydrous sodium sulfate. Filtered, and the solvent was evaporated under reduced pressure to give a pale yellow solid (22g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.16h;
At at -5 C, the <strong>[675-20-7]2-Piperidone</strong>(30g, 303mmol) dissolved in chloroform (500ml), then added Phosphorus pentachloride(150g757. 5mmol) and after stirring the reaction for 10 min at -5 C the reaction was the heated under reflux for 2h. After cooling to room temperature, ice water (300 mL) was added, and the mixture was stirred at room temperature for 12 hours.After addition of dichloromethane (100 mLX2)The organic phases were combined,Followed by water(50 mL X2) and saturated brine(50 mL)Washed with water and dried over anhydrous sodium sulfate.Filtration and evaporation of the solvent under reduced pressure gave a light yellow solid (22 g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.16h;Reflux;
At -5 C, 2-piperidonene(30 g, 303 mmol) was dissolved in chloroform (500 mL)Phosphorus pentachloride (150 g, 757.5 mmol) was added, stirred at -5 C for 10 minutes, and heated to reflux for 2 hours.Cooled to room temperature, ice water (300 mL) was added, and the mixture was stirred at room temperature for 12 hours. The combined organic phase was washed successively with water (50 mL of X2) and saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a pale yellow solid (22 g, 43.4%).
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.33333h;
At -5 C, the 2-N-hexanone (30 g, 303 mmol) was dissolved in chloroform (500 mL), then added Phosphorus pentachloride (150 g, 757.5 mmol), and after stirring for 10min at -5 C the reaction was heated to reflux for 2h. Cooled to room temperature, ice (300 mL) was added and stirred at room temperature for 12 hours. Extraction was carried out by the addition of dichloromethane (100 mL x 2). The organic phases were combined, washed with water (50 mL of X2) and saturated brine(50 mL) and dried over anhydrous sodium sulfate. Filtration was carried out and the solvent was evaporated under reduced pressure to give a pale yellow solid (22 g, 43.4%)
43.4%
With phosphorus pentachloride; In chloroform; at -5℃; for 2.16667h;Reflux;
2-methylhexanone (30 g, 303 mmol) was dissolved in chloroform (500 mL) at -5 C, phosphorus pentachloride (150 g, 757.5 mmol) was added, and the mixture was stirred at -5 C for 10 minutes, hour.Cooled to room temperature, ice water (300 mL) was added and stirred at room temperature for 12 hours.Extraction was carried out by adding dichloromethane (100 mL x 2). The combined organic phases were washed successively with water (50 mL x 2) and saturated brine (50 mL) and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give a pale yellow solid (22 g, 43.4%).
With phosphorus pentachloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; chloroform; ethyl acetate;
Example 40 3,3-Dichloro-<strong>[675-20-7]piperidin-2-one</strong> (43). A solution of <strong>[675-20-7]piperidin-2-one</strong> (42, 25.0 g, 252.2 mmol) in CHCl3 (250 mL) was treated with PCl5 (158 g, 756.5 mmol, 3.0 equiv) at 0-5 C., and the resulting reaction mixture was stirred at 0-5 C. for 10 min before being warmed up to reflux for 2 h. When HPLC showed the reaction was complete, the reaction mixture was cooled down to 5-10 C. before being transferred into an ice water (500 mL) with caution. The resulting mixture was stirred at 0-5 C. for 1 h before being gradually warmed up to room temperature for 12 h. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (4*50 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (50 mL), dried over MgSO4, and concentrated in vacuo. The residual solids were treated with 30% EtOAc/hexane (50 mL) before being collected by filtration. The crude pale-yellow solids were dried in vacuo at 30-35 C. for 12 h to afford the desired 3,3-dichloro-<strong>[675-20-7]piperidin-2-one</strong> (43, 27.96 g, 42.36 g theoretical, 66%) as bright-yellow oil, which solidified upon standing at room temperature in vacuo. For 43, CIMS m/z 166/170 (M+-H, C5H7Cl2NO).
With phosphorus pentachloride; In chloroform;
Part A. To valerolactam (5.6 g, 55 mmol) in CHCl3 was added PCl5 (34.6 g, 166 mmol) and the reaction was heated to reflux 24 h. The reaction was cooled, quenched with H2O, extracted with CHCl3 and dried (MgSO4) to afford crude 3,3-dichloro-2-piperidinone.
With phosphorus pentachloride; In chloroform; for 4h;Heating / reflux;
2-piperidone (35.70 g, 360.2 mmol) was dissolved in chloroform (1 L). Phosphorus PENTACHLORIDE (300 g, 1.44 mol) was added, and the reaction was heated at reflux for 4hr. The reaction was cooled and poured over wet ice, extracted with chloroform (3X500 mL), washed with brine (1x250 ML), dried over MGSO4, and concentrated to afford the alpha-dichloro valerolactam intermediate. The di-chloro intermediate was dissolved in morpholine (300 ML) and refluxed for 1. 5HR. The reaction was concentrated, quenched with water (500 mL), extracted into ethyl acetate (3X500 mL), washed with brine (1x250 mL), dried over MgS04, concentrated, and purified by flash chromatography using 0-100% ethyl acetate/hexanes afforded 36.76 g (56%): 1H NMR (CDC13) 8 5.92 (bs, 1H), 5.56 (t, j=4. 6 Hz, 1H), 3.85-3. 80 (m, 4H), 3.33 (DT, J=7. 0 Hz, 3.3 Hz, 2H), 2. 89 (t, j=4. 8 Hz, 2H), 2.37 (DT, J=7. 0 Hz, 4.8 Hz, 2H) ppm.
With phosphorus pentachloride; In chloroform; at 0℃; for 3.25h;Reflux;
A solution of <strong>[675-20-7]piperidin-2-one</strong> (25.0 g, 252.2 mmol) in CH3Cl (250 mL) was treated with PCl5 (158.0 g, 765.5 mmol) at 0-5 C for 15 min before being refluxed for 3 h. Then the reaction mixture was cooled down to 25 C and transferred into an ice-water mixture (500 mL). The aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed with saturated saline solution (50 mL), dried over MgSO4 and concentrated in vacuo to yellow oil 2 which could be used in the next step without further purification.
With phosphorus pentachloride; In chloroform; at 0 - 66℃; for 12h;Reflux;
To the reaction flask by adding piperidine-2-one (20 g, 20.2 millimoles) and chloroform (500 ml). Furthermore, in the 0 to 5 C to the reaction under batch in the bottle by adding phosphorus pentachloride (168 g, 80.7 mmol). After the completion of the addition, the obtained mixture is heated to 66 C and the reaction to reflux 12 hours. After the completion of the reaction, the reaction mixture to cool to room temperature, then slowly poured into ice water mixture in (1.5 liter). The resulting mixture is extracted with methylene chloride. The resulting organic phase is concentrated to obtain pressure of 31.0 g of white solid, that is, 3,3-dichloro-piperidine-2-are, the crude, without purification directly used for the next reaction (yield: 91.3%).
With phosphorus pentachloride; In chloroform; for 5h;Reflux;
Step A: To a solution of <strong>[675-20-7]piperidin-2-one</strong> (30.0 g, 0.3 mol) in chloroform (1 L) was added PCl5(246.0 g, 1.2 mol). The mixture was refluxed for 5 hours. After cooled to room temperature, the mixture was poured into ice water slowly, extracted with dichloromethane twice. The combined organics were dried over anhydrous Na2SO4, concentrated to give 3,3-dichloro<strong>[675-20-7]piperidin-2-one</strong> (31 g, crude), which was used directly in next step.
With phosphorus pentachloride; In chloroform; for 24h;Reflux;
Part A. To valerolactam (5.6 g, 55 mmol) in CHCl3 was added PCl5 (34.6 g, 166 mmol) and the reaction was heated to reflux 24 h. The reaction was cooled, quenched with H2O, extracted with CHCl3 and dried (MgSO4) to afford crude 3,3-dichloro-2-piperidinone.
With phosphorus pentachloride; In chloroform; at 0 - 70℃; for 3h;
To a stirred solution of <strong>[675-20-7]piperidin-2-one</strong> (5 g, 50.50 mmol, 1 eq) in chloroform (200 mL)was added with PC15 (31.5 g, 151.5 mmol, 3 eq) at 0 - 5C portion-wise and the resulting mixture was allowed to stir at 70C for 3 h. Progress of reaction was monitored by TLC and LCMS.After completion, reaction mixture was diluted with dichloromethane (50 mL) and mixture was poured on ice-cold water. Organic layer was separated and aqueous layer was again extractedwith dichloromethane (3 x 100 mL). Combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded 3,3-dichloro<strong>[675-20-7]piperidin-2-one</strong> (10 g, crude)LCMS: 167 (M+1)
A solution of <strong>[675-20-7]piperidin-2-one</strong> (9.9 g, 100.0 mmol) in CH2Cl2 (200 mL) was treated with PCl5 (41.6 g, 200.0 mmol) at 0-5 C for 10 min. Then ZnI2 (1.0 g, 3.0 mmol) was added under N2 and warmed up to room temperature for 1 h. Then Br2 (32.0 g, 200.0 mmol) in CH2Cl2 (100 mL) was slowly added, the reaction mixture was stirred for 12 h and transferred into an ice-water mixture (500 mL). The aqueous layer was extracted with CH2Cl2 (5 x 30 mL). The combined organic extracts were washed with saturated saline solution (50 mL), dried over MgSO4, concentrated and purified by flash chromatography (Ethyl Acetate/Petroleum Ether = 1:4). The product was obtained as a light brown solid 5 (21.0 g, 82%).
82%
9.9 G of caprolactam was dissolved in 200 mL of dichloromethane in an ice bath, 41.6 g of phosphorus pentachloride was the portion wisecharged with , after adding, at 0 to 5c and reacting for 10 minutes, followed by addition of zinc iodide. 0 G, under the protection of nitrogen, andreacting at room temperature for 1 hour., followed by dropwise addition of bromine in dichloromethane (32 g of bromine was dissolved in 100 ml ofdichloromethane.) after dripping, stirred overnight, cooled to 0 to 5 degrees., the reaction is carefully poured into 500 mL of ice water, the extractedwith dichloromethane for 5 times, dried over anhydrous sodium sulfate and concentrated.: 1 (PE: EA) was added, solid was precipitated and filtered, 21.0 G of solid, which was used directly in the next reaction (82% yield). A 12.8 g of 3,3dibromocaprolactam dissolved in 70 ml of dry DMF., adding 4.0 g of lithium chloride, lithium carbonate, 7.0 g, heating to 130degrees for reaction for 8 hours, evaporating the DMF, through column chromatography to obtain a white solid, 6.8 g (77% yield).
74%
With phosphorus pentachloride; bromine; zinc(II) chloride; In dichloromethane; at 0 - 20℃; for 5h;
Weighed piperidone (1 · 0g, 0.01mol), anhydrous zinc chloride (55mg, 0.4mmol) was placed in 20ml of DCM, cooled to about 0 C slowly added phosphorus pentachloride (4.16) g, 0.02mol), Br2 (3.2g, 0.02mol) was added dropwise under stirring. After the addition, the reaction solution was naturally warmed to room temperature and continued to reflect for 5 hours. After the reaction was completed, saturated NaHCO3 was added to adjust the pH of the solution to 7- 8 and then extracted with DCM (20 mL*3), and the organic layer was dried over anhydrous Na2SO4.The product was removed by filtration under reduced pressure to remove the solvent (1·9 g, 74%).
58.6%
9.9 g (100 mmol) of 2-piperidone take part in1000ml bottle of eggplant,Add 200ml of dichloromethane to dissolve,Then, 41.6 g (200 mmol) of phosphorus pentachloride was added under ice water bath to stir the reaction for 10 min. Under a nitrogen atmosphere, 1 g of potassium iodide was added and the reaction was stirred at room temperature for 1 h.Then 32 g (200 mmol) dissolved in 100 ml of dichloromethaneBromine was slowly added to the reaction system and reacted at room temperature for 12 h.After the reaction was completed, the reaction solution was poured into 500 ml of ice water to terminate the reaction.It was then extracted five times with 50 ml of dichloromethane and the organic phases were combined.The organic phase was extracted once again with 50 ml of saturated brine.Next, the organic phase was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated.Finally, petroleum ether: ethyl acetate = 1:1 was passed through a silica gel column to obtain 3,3-dibromo-2-piperidone15 g (58.6 mmol) in a yield of 58.6%.
To a stirred solution of <strong>[675-20-7]piperidin-2-one</strong> (10 g, 101.01 mmol, 1 eq.) in chloroform (300 mL) was added PC15 (42 g, 202.02 mmol, 2 eq.) at 0-5 C for 10 minutes. To this suspension was added Zn12 (0.96 g, 3.03 mmol, 0.03 eq.) under nitrogen at 0-5 C and then allowed to stir atroom temperature for 1 h. To this reaction mixture was added a solution of Br2 (32.11 g, 202.02 mmol, 2 eq.) in chloroform (5 mL) dropwise and the reaction mixture was stirred overnight. Progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was diluted with ice-cold water and extracted with dichloromethane (3 x50 mL). Combined organic layer was washed with brine and dried over sodium sulphate. Removal of solvent under reducedpressure afforded 3,3-dibromo<strong>[675-20-7]piperidin-2-one</strong> (12 g, 46.17 %) as brown liquid which was used in the next step without purification.LCMS: 258 [M+1]
WX016-1 (20 g, 201.75 mmol, 1 eq) was dissolved in CHCl3 (200 mL) in a pre-dried 100 mL round bottom flask. After the reaction system was cooled to 0C, PCl5 (84.03 g, 403.51 mmol, 2 eq) was added thereto in portions. The system was reacted at 0C for 30 minutes. Afterwards, ZnCl2 (1.37 g, 10.09 mmol, 472.48 muL, 0.05 eq) and Br2 (64.48 g, 403.51 mmol, 20.80 mL, 2 eq) were added to the system. The temperature of the reaction was then raised to 0-25C and the reaction was carried out for 5 hours. Saturated sodium sulfite solution was slowly added to the reaction solution while stirring until pH = 8-9. The organic phase was collected after separation, and the aqueous phase was extracted with dichloromethane (3 100 mL). The organic phases were combined, washed with saturated brine (1 200 mL) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to give WX016-2.
With acetylhydroxamic acid; sulfuric acid; In acetonitrile; at 80℃; under 1292.9 Torr; for 0.133333h;Microwave irradiation;
General procedure: Acetophenone 1a (1.0 g, 8.3 mmol), acetohydroxamic acid (0.92 g, 12.5 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a 10 ml pressure tube and subjected to microwave heating (CEM discover, 360 W, 80 C, 25 psi) for 10 min. The crude product obtained was purified as mentioned above to afford acetanilide 2a (0.94 g, 86%) and it gave spectral data same as above.
With triethylamine; In toluene; for 4h;Inert atmosphere;
<strong>[675-20-7]2-Piperidone</strong> (19.8 g, 0.2 mol) and triethylamine (25 g, 0.25 mol) were dissolved in toluene (200 mL), then trimethylchlorosilane (23.9 g, 0.22 mol) was added slowly under N2. Then the mixture was stirred for 4 hours at 50 C and then cooled to 0 C. Next, a mixed solution of n-hexane and diethyl ether (V:V=1: 1, 200 mL) was added, filtered and the filtrate was evaporated in vacuo to give 1-(Trimethylsilyl) <strong>[675-20-7]piperidin-2-one</strong> (11) as a colorless oil (29.4 g, 86%).
85%
With triethylamine; In dichloromethane; at 20℃; for 4.5h;
General procedure: Into a 250 ml three-necked flask equipped with a magnetic stirrer, a condenser and a pressure-equalized dropping funnel, 2-pyrrolidinone (7.10 g, 94 mmol) was weighed out, then dichloromethane (100 ml) and triethylamine (14.5 ml, 103 mmol) were charged. Under vigorous stirring, trimethyl chlorosilane (13.0 ml, 101 mmol) in dichloromethane (20 ml) solution was added dropwise for 1.5 h at ambient temperature. After the completion of dropping, the mixture was further stirred for 3 h. The precipitated triethylammonium chloride salt was filtered out, the filtrate was evaporated to dryness, then extracted with hexane (50 ml). The undissolved solid residue was filtered out, the solvent was removed under reduced pressure and the raw product was distilled in vacuo. The preparation of the other lactams (TMSVL, TMSCL) and TMSPI were carried out in a similar way. In the case of DMSPI and TBDMSPI the corresponding chlorosilanes were used as reactants. TMSNI was synthesized by a silylation of the sodium naphthalimide (previously prepared from NaNH2 and naphthalimide) with a THF solution of Me3SiCl in excess upon stirring for 3 d at ambient temperature. Solid compounds were obtained by recrystallization from hot hexane.
1.5 g of 2-piperidone was dissolved in 75 mL of mesitylene, 248 muL of titanium tetrachloride was added thereto, and heated at 140C. A solution obtained by dissolving 4.02 g of aminoacetoaldehyde diethyl acetal to 45 mL of mesitylene was prepared, and was added dropwise to the previous mesitylene solution over 3 hours. The mixture was stirred at 140C for 70 hours, then cooled back to room temperature, and was extracted with a 2N aqueous solution of hydrochloric acid. The obtained aqueous layer was basified with a 5N aqueous solution of sodium hydroxide, and then was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the purification was carried out by distillation under reduced pressure (3mmHg, 120C), to obtain 375 mg of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-1] as a pale yellow oily product.
With manganese(II) triflate; 4,4'-diamino-2,2'-bipyridyl; dihydrogen peroxide; In acetone; at 20℃; for 1h;
5.59 mg (0.03 mmol) of 4,4'-diamino-2,2'-bipyridine (Ligand), 5.30 mg (0.015 mmol) of manganese (II) triflate (Mn(OTf) 2),1.5 mL of acetone was added to the reaction tube, and the reaction was stirred at 70 C for 10 min.Cool to room temperature and add 49.57 mg (0.5 mmol) of 2-piperidone.Then, 250 muL of 30% by mass of hydrogen peroxide was diluted with 0.5 mL of acetone and then added to the reaction tube through a flow injection pump for 60 minutes.After the addition, saturated sodium sulfite was added to the reaction solution to quench the remaining hydrogen peroxide.Extraction with ethyl acetate gave 1,2-dipiperidone in a yield of 98%.
95%
With potassium peroxymonosulphate; water; potassium bromide; In dichloromethane; at 20℃; for 7h;Sealed tube; Irradiation;
General procedure: N-Propylbenzamide (A1) (40.8 mg, 0.25 mmol, 1.0 equiv), Oxone(307.8 mg, 0.50 mmol, 2.0 equiv), KBr (8.9 mg, 0.075 mmol, 0.3equiv), H2O (198.2 mg, 44 equiv, 0.2 mL) and CH2Cl2 (1.5 mL) wereadded to a 15 mL sealed tube containing a magnetic stir bar. The reaction mixture was stirred at room temperature for 7 hours under irradiation with an 8 W white LED. After completion of the reaction, saturated Na2SO3 (5.0 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organics were washed with brine(10 mL), dried over Mg2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/PE,1:6) to afford N-propionylbenzamide (B1). 3b White solid; yield: 37.7 mg (85%); mp 93-94 C (Lit. 3b 93-94 C).1 H NMR (400 MHz, CDCl 3 ): delta = 8.54 (br s, 1 H), 7.84 (d, J = 7.2 Hz, 2 H),7.61 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 2 H), 3.04 (q, J = 7.2 Hz, 2 H),1.23 (t, J = 7.6 Hz, 3 H).13 C NMR (100 MHz, CDCl 3 ): delta = 177.8, 166.0, 133.3, 133.0, 129.1,128.0, 31.5, 8.4.
With sodium hydride; In tetrahydrofuran;Inert atmosphere;
To the solution of δ-valerolactam (4.000 g, 40 mmol) in 50 mL of THF was added NaH (1.008 g, 42 mmol) and the mixture was stirred for about 30 min. Benzyl bromide (7.2 mL, 60 mmol) was added to the mixture and stirring was continued for overnight. The reaction was treated with 8 mL of saturated NH4Cl solution and the aq layer was extracted by EtOAC. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by flash column using cyclohexane-TBME (1:1 v/v mixture) as eluent to afford 2 (4.757g, 63%).
In water; N,N-dimethyl-formamide; mineral oil;
Reference Example 14 1-Benzyl-7-bromo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthylidin-5-ylamine hydrochloride To a suspension of sodium hydride (60% in mineral oil; 440 mg) in N,N-dimethylformamide (10 ml), 2-piperidone (991 mg) was added and stirred at room temperature for 15 minutes, followed by addition of benzyl bromide (1.31 ml). After stirring at room temperature for 4 hours, water was added to the reaction mixture, which was then extracted with diethyl ether. The extracted solution was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane/ethyl acetate = 1/1) to give 1-benzyl-2-piperidone (1.30 g).
62.1 Synthesis of 1-benzyl-2-oxo-piperidine Prepare by the method of Example 53.1 using 2-piperidinone and benzyl bromide to give the title compound: Rf=0.77 (silica gel, 1/1 ethyl acetate/hexane).
With dmap; triethylamine; In dichloromethane; at 0℃;Inert atmosphere;
General procedure: delta- or gamma-Lactam (10 mg, 1.0 equiv) was dissolved inmethylene chloride and added with acyl chloride (1.2 equiv), triethylamine (TEA, 1.5 equiv) and dimethylaminopyridine (DMAP, 5 mol%). The mixture was kept at 0 C for 6 hours or until completion of reaction. The reaction mixture was quenched with saturated sodium bicarbonate and washed successively with water and brine and dried with anhydrous sodium sulfate. Column chromatography was performed with silica gel (230-400 Mesh) using hexanes: ethyl acetate solvent system to isolate and purify the products.
With hydrogen; In tetrahydrofuran; at 160℃; under 75007.5 Torr;
The hydrogenolysis of 2-piperidone to piperidine, as shown in the above equation, was chosen as a benchmark reaction to investigate the catalytic activity and leaching behavior of catalyst III-b in a variety of solvents and under various conditions. (0077) <strong>[675-20-7]2-Piperidone</strong> was subjected to hydrogenolysis in seven experiments according to the general procedure above. The conditions for Runs 1-4 were as follows: 0.25 mol % catalyst loading (0.06 mmol/g on amorphous silica); 1.0 mmol substrate; 1.0 mL solvent; 160 C.; and 100 bar H2 at room temperature. The conditions for Runs 5-7 were the same as Runs 1-4, except that 0.50 mol % catalyst loading was used. The results are shown in Table 1. As seen from Table 1, THF and toluene were the best solvents for this transformation, having the best conversions (up to 95%) and the lowest leaching rates (between 0.24 and 0.99% total Ru leaching). Almost full conversion was observed at 160 C. using 0.5 mol % of catalyst III-b (Run 7). Lower temperatures drastically decreased the yields. Surprisingly, lower temperatures also resulted in more leaching. (0079) Without wishing to be bound by theory, this increase in the leaching rate at lower temperature can be explained by the increased concentration of the intermediate linear amino alcohol, according to the presented reaction mechanism in this transformation. To test this theory, additional runs were performed with excess intermediate. The data showed that adding excess intermediate resulted in much higher leaching rates. In contrast, adding excess water, similar to what would be made by complete hydrogenolysis of the substrate, did not result in increased leaching (SI, 4).
86%
Piperidone-2 (5 g, 50 mmol) is admixed with dimethyl sulphate (5 ml, 50 mmol) and stirred under argon for 3 hours at 80 C., and the product is then taken up in 10 ml of absolute methanol. An autoclave is charged with 5% Pt/C (0.98 g, 0.5 mol %), flushed with argon and filled with the reaction solution in methanol. 40 bar of hydrogen are then injected in, and the mixture is stirred at 25 C. and a constant pressure until hydrogen absorption is no longer evident (5 h). After separation off from the catalyst, the filtrate is concentrated on a rotary evaporator, the residue is dissolved in 20 ml of water and washed with diethyl ether, the aqueous phase is rendered basic with 2N NaOH solution and etherified out. The organic phase is dried over K2CO3; after evaporating off the ether virtually clean piperidine is obtained. (0177) The yield can be found in Table 4.
78%Spectr.
With sodium 2-methyl-2-adamantoxide; dichlorobis(dicyclohexylphosphinomethylpyridine)-ruthenium (II); hydrogen; sodium hydride; In toluene; mineral oil; at 160℃; under 60006.0 Torr; for 48h;Inert atmosphere; Autoclave;
General procedure: Under a continuous Ar flow, 2-methyl-2-adamantanol (16.6 mg, 0.1 mmol), NaH (60% oil dispersion, 4.0 mg, 0.1 mmol), anhydrous toluene (1.5 mL) and a magnetic stirring bar were placed in a dried Teflon tube (21 mL capacity). The Teflon tube was stoppered with a rubber septum, and the mixture was stirred at room temperature for 2 h under Ar. After removing the septum, under a continuous Ar flow, to the mixture was added RUPCY (7.50 mg, 0.01 mmol) and N-benzylbenzamide (105.6 mg, 0.5 mmol). The Teflon tube was quickly inserted into an autoclave and the inside of the autoclave was purged several times with hydrogen gas (>5 MPa). The autoclave was pressurized with an 8 MPa of hydrogen gas at 25C, and heated at 160C for 24 h under stirring (800 rpm). The autoclave was cooled to room temperature in an ice-water (0C) bath,and the reaction mixture was quenched with NH4Cl (5.3 mg, 0.1 mmol). The organic phase was removed in vacuo (ca. 100 mmHg, 40 C). The residue was diluted with CDCl3, and analyzed by 1H NMR. The yields of benzyl alcohol (92%) and benzylamine (92%) were calculated based on the integral ratio among the signals of these compounds with respect to an internal standard (1,1,2,2-tetrachloroethane). Afterward, the reaction mixture was purified by column chromatography on silica gel (silica gel (ca. 100 g) was pretreated with Et3N (small amount)-Et2O/hexane (vol%: 2/3), eluent; Et2O/hexane = 2/3, then EtOAc/Et3N = 100/1) to give N-benzylbenzamide (7.7 mg, 0.036 mmol, 7%), benzyl alcohol (47.4 mg, 0.438 mmol, 88%) and benzylamine (44.1 mg, 0.4187 mmol, 82%).
With methanesulfonic acid; [Ru(1,1,1-tris(di(3,5-dimethoxyphenyl)phosphino-methyl)ethane)(trimethylenemethane)]; hydrogen; In tetrahydrofuran; at 160℃; under 75007.5 Torr; for 16h;
delta-Valerolactam was subjected to hydrogenolysis under the same reaction conditions (0.5 mol % [Cat.], 16 h reaction time, 160 C., 2 mL THF, 100 bar H2) using three different catalysts, each with and without an acid, to form piperidine. The catalysts were [Ru(triphos-xyl)TMM], [Ru(triphos-(CF3)2)TMM], and [Ru(triphos-(OMe)2)TMM]. The acid was methanesulfonic acid. (0076) The results are shown in FIG. 2.
With potassium phosphate; N,N`-dimethylethylenediamine;copper(l) iodide; In toluene; for 48h;Inert atmosphere; Reflux;
Example 5. Synthesis of a compound of formula (II): l-(4- methoxyphenyl)-6-[4-(2-oxo-piperidinyl)phenyl]-7-oxo-4,5,6,7-tetrahydro- l//-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl esterII IICompound II, prepared as in Example 4 (35.90 g, 69.40 mmol) is suspended in 250 ml of toluene in a 1L 4-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere, delta-valerolactam (13.74 g, 138.60 mmol), K3PO4 (30.25 g, 142.50 mmol) and Cul (2.54 g, 13.34 mmol) are then added in sequence. The suspension obtained is degassed 3 times at room temperature; N,N'-dimethylethylenediamine (1.65 ml, 26.78 mmol) is then added and the mixture is heated to reflux temperature. After 48 h the end-of-reaction mixture is filtered through a Buchner funnel, and the filter is washed with 200 ml of toluene. The toluene phase is washed with a solution of Na2S2O3 (50 g in 160 ml of H2O, 2x80 ml), 15% NH3 (2x80 ml) and a saturated solution of NaCl (1x80 ml). The organic phase is anhydrified on (Na2SO4), filtered and evaporated under low pressure. A solid product is obtained (37 g), which is crystallised by AcOEt. After crystallisation the product is obtained as a pure white solid (22.7 g, yield 67%).1H NMR (300 MHz, DMSO-dtf): 67.47 (2H, dd, J0=8.7 Hz, Ar-H), 7.32 (2H, dd, Jo=9.0 Hz, Ar-H), 7.28 (2H, dd, J0=8.7 Hz, Ar-H), 6.90 (2H, dd, Jo=9.0 Hz, Ar-H), 4.32 (2H, q, J=6.9 Hz, COOCEbCH^, 4.06 (2H, t, J=6.6 Hz, CH2CH2N), 3.79 (3H, s, Ar-OCH3), 3.57 (2H, m, N(¾CH2CH2CH2CO) 3.19 (2H, t, J=6.6 Hz, ¾CH2N), 2.36 (2H, m, NCH2CH2CH2CH2CO), 1.83 (4H, m, NCH2CH2CH2CH2CO), 1.31 (3H, t, J=6.9 Hz, COOCH2CH3).
29%
With potassium carbonate;copper(l) iodide; 1,10-Phenanthroline; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
Step 6; Ethyl l-(4-methoxyphenyl)-7-oxo-6-r4-(2-oxo-l-piperidin-l-yl)phenyl)- 4.5.6.7-tetrahydro-lH-pyrazole-|"3.4-clpyridine-3-carboxylate:; A mixture of ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3,4c] pyridine-3-carboxylate (8.0 g, 15.47 mmol), delta-valerolactam (2.14 g, 21.61 mmol), potassium carbonate (2.52 g, 18.23 mmol) and dimethylsulfoxide (80 mL) was degassed with nitrogen for about 30 minutes. Cuprous iodide (0.530 g, 2.78 mmol) and 1,10-phenanthroline (0.150 g, catalytic) were then added to the mixture. The mixture was heated at about 130 0C for about 24 hours, cooled to ambient temperature, and water (150 mL) was added. Standard extractive work up with ethyl acetate provided a crude residue which was purified by silica gel column chromatography (4% methanol in chloroform) to give the title compound as an off- white solid (2.2 g, yield = 29%). mp: 150-153 0C; 1H NMR (400 MHz, CDCl3) delta 1.43 (t, J= 7.2 Hz, 3H), 1.92-1.94 (m, 4H), 2.50-2.60 (m, 2H), 3.31 (t, J= 6.4 Hz, 2H), 3.58-3.59 (m, 2H), 3.8 (s, 3H), 4.12 (t, J= 6.8 Hz, 2H), 4.46 (q, J= 6.6 Hz, 2H), 6.90 (d, J= 9.2 Hz, 2H), 7.25 (d, J= 9.6 Hz, 2H) 7.34 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.8 Hz, 2H); IR (KBr) upsilon 3454, 2982, 2934, 2876, 1711, 1676, 1645, 1513, 1254, 1146, 1024, 838 cm"1; MS: 487 (M - 1).
28%
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 140℃; for 24h;
Part A. A mixture of 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (5 g, 9.7 mmol), K2CO3 (1.5 g, 110 mmol), piperidine-2-one (1.2 g, 11.6 mmol), CuI (228 mg, 1.2 mmol), and DMSO (10 mL) was heated at 140 C. for 24 h. The solution was cooled to rt, diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and evaporated. Purification of the residue by column chromatography provided the corresponding aryl lactam (1.3 g, 28%): ESI MS m/z 489 (M+H)+.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; at 110℃; for 6h;Inert atmosphere; Sealed tube;
The preparation was carried out in an inert atmosphere (argon). Ethyl 6-(4-iodophenyl)-l-(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (536 mg; 1.04 mmol) was dissolved in 5 ml of cyclopentyl methyl ether in a 10 ml sealable pressure container. Piperidin-2-one (128 mg; 1.30 mmol), Cul (10 mg; 0.052 mmol), K3PO4 (440 mg; 2,1 mmol) and N,N'-dimethylethylenediamine (37 mg; 0.42 mmol) were added. A stirrer was inserted in the container and it was closed under an inert atmosphere. Being stirred by a magnetic stirrer the mixture was heated up in an oil bath to 110 C for 6 h. After cooling the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. The filtrate was concentrated and the crude product was obtained in the yield of 84%.
40 g
Example 7Preparation of ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1 -piperidinyl)phenyl]4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c]pyridine-3-carboxylatePiperidin-2-one (95.5 g) was added to toluene (2000 ml) and the mixture was heated to reflux while removing the collected water through Dean-Stark apparatus under nitrogen atmosphere. The reaction mass was cooled to room temperature and then stirred for 15 minutes under nitrogen atmosphere at the same temperature, followed by the addition of ethyl 6-(4-iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 F1-pyrazolo[3 ,4-cjpyridine-3-carboxylate (100 g). The resulting mixture was stirred for 15 minutes under nitrogen atmosphere, followed by the addition of potassium carbonate (28.5 g) and then stirring for 15 minutes under nitrogen atmosphere. Cuprous iodide (14.6 g) and 8- hydroxyquinoline (11.2 g) were added to the reaction mass and then heated to reflux under nitrogen atmosphere, followed by portion-wise addition of potassium carbonate (28.5 g x 3) for every 5 hours. After reaction completion, the reaction mass was filtered and thenwashed with toluene (200 ml x 2). The resulting filtrate was washed with 30% aqueous hypo solution (2 x 100 ml). Aqueous ammonia (100 ml) was added to the resulting toluene layer and then stirred for 3 hours at room temperature. The separated solid was filtered, washed with toluene (100 ml) and then dried the material at 70C for 5 hours to produce 40 g of ethyl 1 -(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo- 1 -piperidinyl)phenyl]-4,5 ,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Purity by HPLC: 99%; Melting range: 148.8C - 150C).
With ammonium hydroxide; caesium carbonate; In ethyl acetate; toluene;
Part B. Soluble copper(I)-catalyzed Ullmann coupling reaction. A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 2.2 g, 5.73 mmol), piperidin-2-one (42, 851 mg, 8.59 mmol, 1.5 equiv), and Cs2CO3 (3.73 g, 11.46 mmol, 2.0 equiv) in toluene (15 mL) was treated with Cu(PPh3)3Br (1.065 g, 1.146 mmol, 20% equiv) at room temperature under N2, and the resulting reaction mixture was degassed three times under a steady stream of nitrogen. The reaction mixture was warmed up to reflux for 6 h. When HPLC showed the Ullmann coupling reaction was complete, the reaction mixture was cooled down to 5-10 C. before being quenched with 14% of ammonium hydroxide aqueous solution (20 mL) and EtOAc (30 mL) at 5-10 C. The mixture was stirred for an additional 4 h at 25 C. The two layers were then separated, and the aqueous layer, was extracted with EtOAc (3*20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 1.568 g, 2.036 g theoretical, 77%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 63, CIMS m/z 356 (M++H, C2OH25N3O3).
To a 2000 L glass-lined reactor, under the protection of nitrogen, MTBE (633 kg) and valerolactam (34.9 kg, 350 mol) were charged by vacuum. After initiating stirring, a 33% aqueous solution of tetrabutylammonium hydrogen sulfate (8.35 kg) was added. The mixture was cooled to 20-30 C and then a 50% aqueous solution of sodium hydroxide (270 kg) was added to the mixture at a rate of 10-15 L/minute at this temperature. After the addition, the mixture was maintained at the same temperature for 30 minutes followed by the addition of 3- chloro-4-fluoro-benzylbromide (62.9 kg, 280 mol) at a rate of 2-3 kg/minute at 20-30 C. After 5-10 hours, water (283 kg) was added to the reaction mixture at a rate of 30-40 kg/minute at 20- 30 C to quench the reaction. The mixture was stirred for 30 minutes and then the water phase was separated out. The organic phase was washed with 25% aqueous brine solution (226 kg), and the organic phase was dried with anhydrous sodium sulfate (30 kg) under stirring. The dried mixture was filtered by nutsche filter and the filter cake was rinsed with MTBE (50 kg). The combined filtrate was concentrated in vacuo (T< 35 C, P< -0.08 MPa) until the mixture volume remained at about 350-500 L. Petroleum ether was added (138.4 kg) to the mixture and concentrated continuously. After the mixture volume remained at about 350-500 L, another 138 Kg of petroleum ether was added to the mixture and then concentrated in vacuo. The mixture was cooled to 0-5 C, stirred for 2-3 hours, and then filtered. The filter cake was dried by rotary conical dryer below 35 C to provide 67.7 kg of l-(3-chloro-4-fluorobenzyl)piperidin-2-one (99% yield).
Valerolactam (60 g) was dissolved in MTBE (1.5L) at room temperature. To this solution was added BU4NSO4 (4.9 g) as a phase transfer catalyst. The cloudy solution was stirred at room temperature for 5 minutes. Then, NaOH (50 wt%;300 mL) was slowly added as to keep the internal temperature below 3O0C. 3-Chloro-4-fluorobenzyl bromide (108.3 g) was then added slowly to this biphasic mixture, again as to keep the internal temperature under control. The reaction was then aged for 4 hours at room temperature. At this time LC showed the reaction to be complete. Water (500 mL) was then added. After phase cut, the organic layer was washed with brine (300 mL), dried under MgSO4 followed by solvent switch to heptane (400 mL). The slurry obtained was stirred at room temperature. for 1 hour and then filtered to afford the title product.
To a cold (O C) solution of valerolactam (153.30 g, 1.54 mol) in mixture of anhydrous l-methyl-2-pyrrolidinone (3.5 L) and THF (350 mL), sodium hydride (67.7 g, 1.69 mol, 60% dispersion in oil) was added over a period of 5 minutes. The reaction mixture was stirred for 30 minutes, and a solution of 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) in l-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0 C. The reaction mixture was stirred at 0 0C for 1 hour, and was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with distilled water (5 L), and extracted with dichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts were combined, washed with <n="20"/>water (3X; 4 L each time). The residual oil was dissolved in ethyl acetate (4 L), and extracted with water (3X; 2 L each time). The organic layer was separated, concentrated under vacuum to give the title product that solidified upon standing. lH NMR (400 MHz, CDCI3) delta 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, IH), 4.56 (s, 2H), 3.19 (t, J=4.9 Hz, 2H), 2.46 (t, J= 6.4 Hz, 2H), 1.8-1.75 (m, 4H).
Step 1: 1-(3-Chloro-4-fluorobenzyl)piperidin-2-one To a cold (0 C.) solution of valerolactam (153.30 g, 1.54 mol) in mixture of anhydrous 1-methyl-2-pyrrolidinone (3.5 L) and THF (350 mL), sodium hydride (67.7 g, 1.69 mol, 60% dispersion in oil) was added over a period of 5 minutes. The reaction mixture was stirred for 30 minutes, and a solution of 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) in 1-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0 C. The reaction mixture was stirred at 0 C. for 1 hour, and was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with distilled water (5 L), and extracted with dichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts were combined, washed with water (3*; 4 L each time). The residual oil was dissolved in ethyl acetate (4 L), and extracted with water (3*; 2 L each time). The organic layer was separated, concentrated under vacuum to give the title product that solidified upon standing. 1H NMR (400 MHz, CDCl3) delta 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, 1H), 4.56 (s, 2H), 3.19 (t, J=4.9 Hz, 2H), 2.46 (t, J=6.4 Hz, 2H), 1.8-1.75 (m, 4H).
To a solution of 133a (3.25 g, 32.80 mmol) in THF/DMF (25/25 ml) was added NaH (60percent, 1.95 g, 49.25 mmol) at 0 °C and stirred for 10 min, followed with addition of 4-fluoro alpha-methyl benzyl bromide (10.00 g, 49.25 mmol). The resulting mixture was stirred overnight, then quenched with saturated aqueous NH4CI, extracted with EtOAc (3 X). The combination of organic layers was washed with brine, dried (Na2SO4), concentrated and purified by flash chromatography to afford product 133b as colorless oil (4.1 g, 56.6percent).
With Rh(trop2N)(PPh3); methacrylic acid methyl ester In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;
94%
With dichloro(benzene)ruthenium(II) dimer; sodium hydride; acetonitrile; 1,3-di(propan-2-yl)-1H-imidazol-3-ium bromide In toluene for 36h; Inert atmosphere; Reflux;
94%
With sodium hydride In toluene for 36h; Inert atmosphere; Reflux;
B.9
A range of amides were synthesized with good to excellent isolated yields under our systems (Fig. 4). Excellent yields of amides were obtained from the reaction of sterically unhindered alcohols and amines for both reaction conditions (entries 1-5). The amidation of 1- hexanol with 2-aminoheptane yielded 45% using [Ru(p-cymene)Cl2]2, while [Ru(benzene)Cl2]2 reached a better yield of 60% of the corresponding amide (entry 6). Reaction of 2-methylbutanol with benzylamine afforded 70-77% yield of corresponding amide (entry 7), while neopentyl alcohol with benzylamine gave just 19% yield of the corresponding amide (entry 8). These results indicate that the ruthenium-catalyzed direct amide formation is sensitive to steric hindrance as reported by others (Gunanathan, C, et al., Science (2007) 317, 790; Watson, AJA, et al., Org. Lett. (2009) 11, 2667; Nordstram, LU, et al., J. Am. Chem. Soc. (2008) 130, 17672). Intramolecular amidation was also carried out by using 5- aminopentanol with excellent yield (entry 9). The use of 5-hexen-l-ol gave the hexanamide with 100% reduction of double bond (entry 10) as observed by Madsen's group as well (Nordstram et al., 2008, supra).[0063] In the case of cyclic secondary amines such as piperidine (entry 1 1) and morpholine (entry 12), [Ru(benzene)Cl2]2 (80%, piperidine, and 90%, morpholine) affords better yield than [Ru(p-cymene)Cl2]2 (64%, piperidine, and 63%, morpholine). The Williams group reported that [Ru(p-cymene)Cl2]2 and a bis(diphenylphosphino) butane-based catalytic system showed moderate catalytic activity in the morpholine case (Watson, et al., 2009, supra). The improved activity of our catalytic system is probably due to the more electron- donating N-heterocyclic carbene ligand system.[0064] In the case of non-cyclic secondary amines such as N-benzylmethylamine, our system showed an improvement over Madsen's Ru(COD)Cl2 catalytic system under the same conditions (entry 13, vs. 40% with Madsen's catalyst system, Nordstram et al., 2008, supra). However, with sterically hindered secondary amines such as dibenzylamine, the reaction did not proceed at all (entry 14). Also, the less basic aniline was less reactive even at 163 °C in mesitylene (entry 15). These limitation has also been observed with other ruthenium catalyst systems demonstrating challenges in this area (Gunanathan et al., 2007, supra; Watson et al, Nordstram et al., 2008, supra). Although catalytic systems according to the invention showed comparable or a slightly improved activity compared with Madsen's system under basic conditions, the turnover numbers (TONs) are less than those of the Milstein catalyst under neutral conditions (entry 16, vs. 960 TONs with Milstein's system). [Ru(p-cymene)Cl2]2 exhibited higher TONs than [Ru(benzene)Cl2]2 (55 vs. 23) presumably due to the better stability from the stronger p-coordination of p-cymene than benzene. Further investigations on electronic and steric effects of related ligands will be necessary to develop more improved catalytic systems.; General Procedure for Amide Synthesis; [Ru(p-cymene)Cl2]2 (A, 15.3 mg, 0.025 mmol) or [Ru (benzene)Cl2]2 (B; 12.5 mg, 0.025 mmol), 1,3-diisopropylimidazolium bromide (11.7 mg, 0.05 mmol), NaH (3.6 mg, 0.15 mmol) and pyridine (A, 4 mL, 0.05 mmol) or acetonitrile (B, 2.6 mL, 0.05 mmol), were placed in an oven-dried Schlenk tube inside the glove box; toluene (0.6 mL) was added to the mixture there. The Schlenk tube was taken out and heated to reflux in an oil bath under an argon atmosphere. The flask was removed from the oil bath after 20 min and the alcohol (1 mmol) and the amine (1.1 mmol) were added. The mixture was heated to reflux under an argon atmosphere for 36 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum and the residue was purified by silica gel flash column chromatography to afford the amide. All the amides were identified by spectral comparison with literature data or with analogous literature data.; Piperidin-2-one [0078] Purified by silica gel column chromatography (CH2Cl2:MeOH 19:1, Rf=0.30) to afford a white solid. Isolated yields: conditions A: 92%, conditions B: 94%.1H NMR (CDCI3, 400 MHz): δ = 7.52 (bs, 1 H), 3.19-3.16 (m, 2H), 2.21 (t, 2H, J=6.4 Hz), 1.72-1.60 (m, 4H);13C NMR (CDCI3, 100ΜΗζ): δ = 172.9, 42.0, 31.4, 22.1, 20.8;HR-MS (ESI): m/z=100.0761 [MH+], calcd. for C5H10NO: 100.0762.
92%
With dihydridotetrakis(triphenylphosphine)ruthenium; sodium hydride; acetonitrile; 1,3-di(propan-2-yl)-1H-imidazol-3-ium bromide In toluene for 24h; Inert atmosphere; Reflux;
90%
With C15H22Cl2N2Ru; potassium <i>tert</i>-butylate In toluene for 24h; Inert atmosphere; Reflux;
88%
With dichloro(η6-p-cymene)(1,3-dimethylimidazole-2-ylidene)ruthenium; potassium <i>tert</i>-butylate In toluene for 24h; Inert atmosphere; Reflux;
87%
With C33H30N2Ru In toluene at 120℃; for 15h;
86%
With [RuCl2(cod)]n; 1-ethyl-3-methyl-1H-benzo[d]imidazol-3-ium iodide; caesium carbonate In toluene for 36h; Inert atmosphere; Glovebox; Reflux; Schlenk technique; Green chemistry;
3.2. General Procedure for the Amide Synthesis
General procedure: Inside an argon -filled glove box , {Ru(cod)Cl2]n(3.5 mg ,0.0125 mmol),L4(18.0 mg , 0.0625 mmol),Cs2CO3 (28.6 mg, 0.0875 mmol), and dry toluene (1.50 mL) were added to an oven-dried 25-mLSchlenk flask. The tube was taken out of the glove box and heated to reflux under argon for 2 h. Then,an alcohol (5.00 mmol) and an amine (5.50 mmol) were added, and the mixture was stirred at arefluxing temperature for 36 h. The procedures for calculating the NMR yields were as follows: whenthe reaction was complete, 1,3,5-trimethoxybenzene (0.5 mmol, 84.0 mg) and CHCl3 (1.0 mL) wereadded to the reaction mixture. Afterward, to an NMR tube was added 0.1 mL of the above solution 0.4 mL of CDCl3. TheNMRyields were obtained based on the exact amount of 1,3,5-trimethoxybenzene.In order to obtain the isolated yields of the amides, the reaction mixture was cooled down to roomtemperature, and the solvent was removed under reduced pressure. Finally, the residue was purifiedby silica-gel flash column chromatography to afford the amides.
76%
With [RhCl2(p-cymene)]2; 1-ethyl-3-methyl-1H-benzo[d]imidazol-3-ium iodide; sodium hydride In toluene; mineral oil for 36h; Schlenk technique; Inert atmosphere; Reflux;
75%
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; 1,3-dimethylbenzimidazolium Iodide; sodium hydride In toluene at 110℃; for 24h; Schlenk technique; Glovebox; Inert atmosphere; Reflux;
70%
With C21H26N2O3Ru In toluene for 24h; Schlenk technique; Inert atmosphere; Glovebox; Reflux;
64%
With [bis({2‐[bis(propan‐2‐yl)phosphanyl]ethyl})amine](borohydride)(carbonyl)(hydride)iron(II); potassium carbonate In tert-Amyl alcohol at 150℃; for 5h; Inert atmosphere; Green chemistry;
63%
With 3-methyl-butan-2-one; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; caesium carbonate; 1,4-di(diphenylphosphino)-butane In <i>tert</i>-butyl alcohol at 125℃; for 24h; Schlenk technique; Inert atmosphere;
Representative Procedure for Formation of Amides from Alcohols
General procedure: To an oven-dried, nitrogen purged Schlenk tube containing [Ru(p-cymene)Cl2]2(46.9 mg, 0.075 mmol), dppb (64.0 mg, 0.15 mmol) and Cs2CO3(97.7 mg, 0.30 mmol) was added alcohol (3 mmol), amine (0.33 mmol),3-methyl-2-butanone (0.8 ml, 7.5 mmol) and tBuOH(3 ml) and the reaction heated at reflux for 24 h. On completion, the reaction was allowed to cool to room temperature before the solvent was removed invacuo. The crude product was purified by column chromatography (diethyl ether/petroleum ether (b.p. 40-60 °C) as eluent) before recyrstallization from(dichloromethane/hexane), to afford the corresponding amide in good yield.
32.5%
With ethanol; Au NCs/TiO2 for 17h; Inert atmosphere; UV-irradiation;
100 %Chromat.
In toluene at 120℃; for 3h;
44
5.9 mg (0.01 mmol) of the ruthenium complex 1 which has been produced in theExample 1 was added to a 30 mL Schlenk flask in which boiling chips are added.Subsequently, 10 mL of toluene was added thereto and the mixture was then reacted for 3 hours under stirring with heating in an oil bath which is set at 120 degrees C. As a result of analysis of the reaction solution, it was found that 100% of δ-valerolactam was produced.
With dodecacarbonyl-triangulo-triruthenium; 1-phenyl-propan-1-one; N–phenyl–2–(dicyclohexylphosphino)pyrrole In cyclohexane at 140℃; for 21h; Inert atmosphere; Schlenk technique; Autoclave;
99 %Spectr.
With C21H35BrMnN2O2P; potassium hydride In toluene for 18h; Reflux; Inert atmosphere;
20
A solution of methylcyclohexane (2mL), complex 6B (5mol%), KH (10mol%), benzylamine (1 mmol) and 1-hexanol (1 mmol) was refluxed for 60 hours, 70% conversion of benzylamine was observed, rendering a mixture consisting of N-benzylhexanamide (A) in 40% yield and N-hexylidenebenzenemethanamine (B) in 28% yield (Table 16, Entry 1), with the rest of the alcohol being converted to hexyl hexanoate. Under the same conditions, when 1-hexanol reacts with 1-hexylamine, the corresponding imine was obtained in 99% yield (Entry 2). Refiuxing of 1- hexanol, benzylamine and toluene in presence of complex 6B (5mol%) and KH (10%) provided only the imine B in 80% yield (Entry 3), with the rest of the alcohol being converted to hexyl hexanoate. [00389] Once having performed the synthesis of lactones from diols (Table 14, entries 2-4), this domino sequence was applied to the synthesis of other biologically relevant compounds. The similarity of their structures led us to focus on analogous lactams. When a toluene solution of 1 mmol of 4-amino-l-butanol and 5mol% of complex 6B in presence of KH (10%) was refluxed under argon atmosphere, γ-butyrolactone was formed in 68% yield after 18 hours (Table 18, Entry 4). Under analogous conditions, intramolecular amidation was also carried out by using 5-amino-l- pentanol with full conversion to δ-valero lactam after 18 h (Entry 5).
[4-(4-chlorophenylsulfanyl)phenyl]-(3,4,5,6-tetrahydropyridin-2-yl)amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49.3%
Stage #1: piperidin-2-one With trichlorophosphate In benzene at 20℃; for 4h;
Stage #2: 4-(4-chlorophenylthio)aniline In benzene for 18h; Heating / reflux;
4
Example 4: [4- (4-Chloro-phenylsulfanyl)-phenyl]- (3,4, 5, 6-tetrahydro-pyridin-2-yl)- amine To a solution of 0.555 g delta valerolactam in 10 mL of benzene was added 0.383 g of POCL3. The mixture was stirred under nitrogen at RT for 4 hours. 4- (4-CHLORO- phenylsulfanyl) -benzylamine (0.624 g) was then added and the mixture was allowed to stir at RT for 17 hours. The reaction mix was then brought to reflux for 1 hour and cooled to RT. The reaction mix was quenched with water, basified with ammonium hydroxide solution, and extracted thoroughly with ethyl acetate. The combined organic layers were evaporated in vacuo, and the resulting solid was eluted on neutral alumina (MeOH: dichloromethane 10%: 90%). The resulting product was recrystallized from ethyl acetate to yield 0.408 g (49.3%) of [4- (4-CHLORO-PHENYLSULFANYL)-PHENYL]- (3, 4,5, 6- tetrahydro-pyridin-2-yl)-amine hydrochloride salt as a white solid. Mp: 148-152°C. MS M+H: 317.
With 2,2,6,6-tetramethylpiperidin-1-ol; 2,6-di(t-butyl)-4-phenylphenol; caesium carbonate; In dimethyl sulfoxide; for 16h;Irradiation;
The benzyl protected 2-piperidone (0.30 mmol), phenol catalyst 2,6-di-tert-butyl-4-phenylphenol (5.0% of the molar amount of the substrate), Hydrogen source 1-hydroxy-2,2,6,6-tetramethylpiperidine (TEMPOH, 0.36 mmol) and base cesium carbonate (0.60 mmol) are dissolved in the solvent dimethyl sulfoxide (3.0 ml),After the addition, the reactant was irradiated under 415nm light for 16 hours,The reaction was quenched by adding water, and the aqueous phase was extracted three times with ethyl acetate (15 ml×3),Collect the combined organic phase, water,Wash with saturated brine, dry with anhydrous sodium sulfate, concentrate and column chromatography to obtain 2-piperidone (93% yield).
Under argon, 243 mg (2.45 mmol) of piperidin-2-one in 12 ml of DMF are admixed at 0 C. with 330 mg (2.95 mmol) of potassium tert-butoxide, and the mixture is stirred at room temperature for 30 min. 500 mg (2.70 mmol) of example 89A in 30 ml of DMF are added and the mixture is stirred at RT. After 18 h, it is added to 150 ml of saturated aqueous ammonium chloride solution and then extracted three times with 100 ml each time of ethyl acetate. The combined organic phases are washed with 200 ml of water and then dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (1:5 cyclohexane/ethyl acetate). This affords 256 mg (39% of theory) of the desired compound. 1H NMR (400 MHz, DMSO-d6, delta/ppm): 7.89-7.81 (m, 2H), 7.50-7.42 (m, 1H), 4.18 (q, 2H), 3.47 (t, 2H), 2.38 (t, 2H), 1.92-1.78 (m, 4H), 1.33 (t, 3H). HPLC (Method 1): Rt=3.93 min. MS (DCI, m/z): 265 (M+H)+.
With copper(I) oxide; potassium phosphate; tetra-n-propylammonium bromide In water at 130℃; for 24h;
General procedure for N-arylation of amides
The N-nucleophile (2.21 mmol), Cu2O (Sigma-Aldrich, 99.99% purity, 0.147-0.294 mmol), K3PO4(2.94 mmol), the aryl halide (1.47 mmol), phase transfer catalyst (0.147-0.294 mmol) and water(0.40 mL) were added to a reaction vial and a screw cap was fitted to it. The reaction mixture wasstirred under air in a closed system at 130°C for 24 h, then the heterogeneous mixture was cooledto RT and diluted with dichloromethane. The resulting solution was directly filtered through apad of Celite. The combined organic extracts were dried with anhydrous Na2SO4 and the solventwas removed under reduced pressure. The crude product was purified by silica-gel columnchromatography to afford the N-arylated product. The identity and purity of all products wasconfirmed by 1H and 13C NMR spectroscopic analysis.
General procedure: Amide (25 mmol) was dissolved in dry toluene (100 mL) and POCl3 (1.93 g, 12.5 mmol) was added dropwise at 0 C. The reaction solution was kept at the ice-bath with stirring for 2 h. After that aniline (12.5 mmol) was added in one portion and the result mixture was refluxed under stirring for 4 h. The organic layer was removed and the residue was dissolved in 50 mL of water. The mixture was stirred with coal for 30 min and after filtration 2 M NaOH was added to a pH=10. Precipitate was filtered, dried, and crystallized from a mixture of EtOAc/hexane (1:1).
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene;Inert atmosphere; Reflux;
General procedure: An oven-dried, two-neck round bottom flask fitted with a condenser was charged with CuI (0.05 mmol) and K2CO3 (2.0 mmol) under nitrogen atmosphere. N, N'-dimethylethylenediamine (0.10 mmol), 4-haloaniline derivative (4a-4c) (1.0 mmol), piperidin-2-one (5a) or morpholin-3-one (5b) (1.5 mmol), and anhydrous toluene (1 mL) were added. The reaction mixture was stirred and refluxed overnight. The resulting mixture was allowed to reach RT and filtered through Celite, which was further washed with methanol (10 mL). The organic filtrate was concentrated in vacuo and the residue was purified by flash chromatography using gradient mobile phase of EtOAc/hexanes to afford the corresponding para-amidated aniline derivatives (8a-8g) as solid products in 65-90% yield. The full spectral characterization of these products is provided as Supplementary Information.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 90℃; for 20h;Inert atmosphere; Sealed tube;
The preparation was carried out in an inert atmosphere (argon). Ethyl 6-(4-iodophenyl)-1-(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahycho-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.538 g; 1.04 mmol) was dissolved in 1 ml of DMF in a sealable pressure container fitted with a magnetic stirrer; piperidin-2-one (0.15 g; 1.5 mmol), Cul (18.4 mg; 0.096 mmol), K3PO4 (0.457 g; 2.15 mmol) and N,N'-dimemylethylenediamine (15 mu; 0.136 mmol) were added. Being intensively stirred, the mixture was heated in an oil bath to 90C for 20 hours. The conversion was monitored with HPLC. After the above mentioned period the reaction mixture contained 36% of the product 30.3% of the acid V and 2.5% of the starting compound. After cooling the reaction mixture was diluted with water and the product was extracted with ethyl acetate. After concentration the product was obtained in the yield of 0.237 g, i.e. 48.6%, with the HPLC content of the desired substance of 68%.
methyl 3-methoxy-4-((2-oxopiperidin-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of 2-piperidinone (2.2 g, 22 mmol) in DMF (30 mL) was added to a stirred slurry of NaH (0.90 g, 60percent dispersion in mineral oil, 23 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (5.0 g, 19 mmol) in DMF (30 mL) was added. The resulting mixture was stirred at 0 °C for 4 h and was then slowly allowed to warm to ambient temperature. The mixture was stirred for 1 h. The mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution was added and the mixture was extracted using EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS04, filtered, and concentrated. Purification of the concentrate by silica gel chromatography (100? 90percent CH2CI2/ MeOH) gave the title compound. LC-MS m/z = 278.3 [M+l].
With copper(l) iodide; dimethylaminoacetic acid; potassium carbonate In N,N-dimethyl-formamide at 110℃; for 26h; Schlenk technique; Inert atmosphere;
3.3. General Procedure for the Coupling of Aryl Bromides with Amides Using Copper/N,N-DimethylglycineCatalytic System
General procedure: A Schlenk tube was charged with amide (1.2 mmol), aryl halide (1 mmol), CuI (0.05 or 0.1 mmol), N,N-dimethylglycine (0.1 or 0.2 mmol), and potassium carbonate (2 mmol). The tube was evacuated and backfilled with argon at room temperature. DMF (0.5 mL) was added under argon via syringe. The Schlenk tube was immersed in a preheated oil bath and the reaction mixture was stirred for the specified time at the indicated temperature. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:8 to 1:2 ethyl acetate/petroleum ether) to give the the desired N-aryl amides.
1.s Synthesis of Compound (No. 37)
First step In a 300-mL Erlenmeyer flask, isobutyraldehyde (T-1) (24.50 g, 0.34 mol) and 130 g of water were put, and the resulting mixture was cooled to 4° C. Benzylamine hydrochloride (31.60 g, 0.22 mol) was added thereto, and the resulting mixture was stirred for 30 minutes, and then acetonedicarboxylic acid (24.80 g, 0.17 mol) and a sodium acetate aqueous solution (sodium acetate (6.4 g, 0.078 mol), water 50 g) were added thereto. The resulting reaction mixture was slowly heated to room temperature, and stirred at room temperature for 30 hours. Deposited crystals were obtained by filtration to obtain piperidinone form (T-2) (12.25 g, yield 26.4%).
With bromotris(triphenylphosphine)copper(I); In 5,5-dimethyl-1,3-cyclohexadiene;Dean-Stark; Reflux;
Example-5 Preparation of 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (75 g, 0.194 moles), 2-piperidone (48 g, 0.485 moles) and tripotassium phosphate (103 g, 0.485 moles) in xylene (750 ml) was treated with Cu(PPh3)3Br (54.5 g, 0.058 moles) at room temperature and heated to reflux by using a dean stark water separator for 8-10 hrs. After completion, the reaction mass was cooled to 0-5 C. Aqueous ammonia (750 ml) and ethyl acetate (1125 ml) were added to the reaction mixture and stirred for 2-3 hrs. The resultant solid was filtered and washed with ethyl acetate (20 ml) to get a solid, which was dissolved in methylene dichloride (375 ml) at 35-40 C. and treated with activated carbon. The resultant solution was filtered through a hyflow bed and distilled under vacuum to get an residue; followed by addition of methanol (90 ml) and the reaction mass was cooled to 0-5 C., stirred for 1 hr at the same temperature and filtered to get a solid material. The obtained solid was washed with methanol to get 59 g (84%) of the title compound with >99% purity.
84%
With potassium phosphate; bromotris(triphenylphosphine)copper(I); In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; Dean-Stark;
A suspension of l-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-lH-pyridin-2-one (75 g, 0.194 moles), 2-piperidone (48 g, 0.485 moles) and tripotassium phosphate (103 g, 0.485 moles) in xylene (750 ml) was treated with Cu(PPh3)3Br (54.5 g , 0.058 moles) at room temperature and heated to reflux by using a dean stark water separator for 8-10 hrs. After completion, the reaction mass was cooled to 0-5C. Aqueous ammonia (750 ml) and ethyl acetate (1125 ml) were added to the reaction mixture and stirred for 2-3 hrs. The resultant solid was filtered and washed with ethyl acetate (20 ml) to get a solid, which was dissolved in methylene dichloride (375 ml) at 35-40C and treated with activated carbon. The resultant solution was filtered through a hyflow bed and distilled under vacuum to get an residue; followed by addition of methanol (90 ml) and the reaction mass was cooled to 0-5C, stirred for 1 hr at the same temperature and filtered to get a solid material. The obtained solid was washed with methanol to get 59 g (84%) of the title compound with > 99% purity.
35 g
Example-8 Preparation of 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydro pyridin-2(1H)-one (Formula-8) A mixture of 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one compound of formula-7 (50 g), piperidin-2-one (32.25 g) and o-xylene (75 ml) was stirred for 10 minutes at 25-30 C. Potassium carbonate (27.0 g), followed by copper iodide (7.43 g) were added to the reaction mixture. The reaction mixture was heated to 140-145 C. under azeotropic distillation condition and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 35-40 C., water (175 ml) was slowly added to the reaction mixture at 35-40 C. Cooled the reaction mixture to 10-15 C. and ammonia (125 ml) was added to the reaction mixture at 10-15 C. The temperature of the reaction mixture was raised to 25-30 C. and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and then dried to get title compound. Yield: 35 gm; MR: 195-200 C.; HPLC purity: 95%.
1,2,3,4-Tetrahydro-10-cyanopyrido<1,2-a>indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane; In toluene; at 110℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: General procedure for indole synthesis by Cu-catalyzed amidation reaction. A dried re-sealable vialwith a Teflon stir bar was charged with amide (3.0 equiv, 1.5 mmol), CuI (5 mol%, 0.025 mmol), K3PO4(2.0 equiv, 1.0 mmol). The vial was sealed with a rubber septum and evacuated and refilled with argonthree times through a syringe needle. Under an argon atmosphere, toluene (0.5 mL),trans-1,2-diaminocyclohexane (20 mol%, 0.1 mmol) and aryl halide (0.50 mmol) were each added viasyringe. The rubber septum was then removed and quickly replaced with a Teflon screw cap and thereaction mixture was stirred at 110 C for 24 h. The resulting suspension was allowed to reach roomtemperature and filtered through a pad of silica gel eluting with AcOEt (10 mL). The filtrate wasconcentrated and the residue was purified by flash chromatography to afford a pure product.
Stage #1: piperidin-2-one; Dimethyl-p-toluidine With Cl4Fe(1-)*C24H30N3(1+) In ethyl acetate for 0.25h;
Stage #2: With tert.-butylhydroperoxide In water; ethyl acetate at 40℃; for 8h;
Typical procedure of amidation reaction
General procedure: A 15 mL round-bottom flask was charged with a stirring bar, 2.0 mL ethyl acetate, N,N-dimethylaniline derivative (0.9 mmol), amide (0.5 mmol) and complex 2 (27.9 mg, 0.05 mmol) were added. After stirring 15 min, TBHP (0.75 mmol, 108 mL) was added without extrusion of the air. The mixture was stirred for 8 h at 40 oC. After cooling to room temperature, 10 mL ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using ethyl acetate/pet ether (60-90 oC) as eluent to give the desired product.
58%
With ferrocene; tetrabutyl ammonium fluoride; acetic acid In acetonitrile at 60℃; for 3h; Electrochemical reaction; Inert atmosphere;
With hydrogenchloride; In water; at 20 - 55℃; for 20h;Inert atmosphere;
To a stirred solution of piperidin-2-one 10-lA (500 mg, 5.05 mmol) in MeOH (10 mL) was passed HCl gas. The reaction mixture was stirred at RT for 4 hr under N2 atmosphere. Then reaction mixture warmed to 55 C and stirring continued for 16 hr. Reaction solvents were evaporated under reduced pressure and the crude residue was washed with diethyl ether to afford 10-2A (608 mg, 129.57 mmol, 72% yield) as an off-white solid.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 48h;Inert atmosphere;
General procedure: A mixture of CuI (0.10 g, 0.50 mmol), lactam (12 mmol), K3PO4 (4.4 g,20 mmol), halide (10 mmol), and DMEDA (0.11 mL, 1.0 mmol) in dioxane (5 mL) was degassed and heated under argon at 110 C. After filtration over Celite (washing using EtOAc) and removal of the solvents, the crude product was purified by chromatography (silica gel).
methyl 2-methyl-5-(2-oxopiperidin-1-yl)thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; for 12h;Reflux;
General procedure: A mixture of 11 (500mg, 2.13mmol), 2-pyrrolidone (210mg, 2.47mmol), CuI (20.0mg, 0.105mmol), N,N?-dimethylethylenediamine (18.5mg, 0.210mmol), and K2CO3 (580mg, 4.20mmol) in toluene (2.50mL) was refluxed for 12h. After cooling to room temperature, the reaction mixture was diluted with AcOEt and filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 and brine and dried over Na2SO4. After filtration, the solvent was concentrated under reduced pressure and the residue was triturated with 50% (v/v) solution of AcOEt/n-hexane to give 166mg (33%) of 27a as a white solid:
1-(4-chlorophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one[ No CAS ]
[ 545445-44-1 ]
Yield
Reaction Conditions
Operation in experiment
93.1%
With bis-triphenylphosphine-palladium(II) chloride; sodium hydride; In dimethyl sulfoxide; at 20℃; for 2h;
Compound VI (58.6 g, 0.2 mol), 2-piperidone (29.7 g, 0.3 mol), bistriphenylphosphine palladium dichloride (7.0 g, 0.01 mol), sodium hydride (97.7 g, 0.3 mol) 2000 mL of dimethyl sulfoxide was added to the reaction flask, and the reaction was carried out at room temperature. After TLC monitoring, the reaction was stopped after 2 hours, and 2000 mL of ice water and 1000 mL of ethyl acetate were added to the reaction solution, and the mixture was washed twice with ice water. dried over anhydrous sodium sulfate, vacuum filtration, recrystallized from ethyl acetate to give a white solid 66.1 g, yield 93.1%, HPLC purity of 99.6%.
There is stirring,thermometer,Reflux condenser,In a 500 ml four-necked flask with an air duct and a 30 wt% sodium hydroxide aqueous solution absorption device,Add 150 grams of trichloroethane,49.5 g (0.5 mole) of 2-piperidone (II),0.9 g triphenyl phosphite,Heat and keep between 70-75 ,Slowly introduce 115.0 grams (1.62 moles) of chlorine,Access is completed in about 3-4 hours,Thereafter, the reaction was stirred at 70-75 C for 3 hours,Cool to 20-25 Add 170.0 grams (1.7 moles) of 40wt% aqueous sodium hydroxide solution, Stir the reaction at 40-45 for 3 hours,Cool to 20-25 The pH value of the 30wt% hydrochloric acid acidification system is 3.0-4.0,The layers were separated, and the aqueous layer was extracted three times with trichloroethane,50g each time, combine the organic phases, distill the solvent to recover,Drying to obtain 60.4 g of 3-chloro-2-hydroxypyridine solid (IV),The yield was 93.3% and the gas phase purity was 99.6%.
91.6%
To a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser, air duct, and 30 wt% sodium hydroxide aqueous solution absorption device, add 150 g of 1,2-dichloroethane, 49.5 g (0.5 mole) of 2- Piperidone (II), 0.6 g of triethyl phosphite, heat and keep between 40-50 C, slowly pass in 78.0 g (1.1 mol) of chlorine gas. After about 3-4 hours, the introduction is complete, after which 45-50 The reaction was stirred at for 3 hours, cooled to 20-25 C, and the remaining chlorine and hydrogen chloride were blown out by blowing nitrogen for 7 hours. 70.0 g (0.7 mol) of 40 wt% sodium hydroxide aqueous solution was added, and the reaction was stirred at 40-45 C for 3 hours, and cooled to 20 -25 C, add 74.0 g (0.65 mol) of 30% by weight hydrogen peroxide, stir the reaction at 30-35 C for 3 hours, cool to 20-25 C, 30% by weight hydrochloric acid acidification system pH 3.0-4.0, separate the layers, use 1 for the water layer , 2-dichloroethane extraction 3 times, 50 grams each time, combined organic phases, solvent was recovered by distillation, and dried to obtain 59.3 grams of 2-hydroxy-3-chloropyridine (V), yield 91.6%, gas phase purity 99.5% .
With dmap; triethylamine In dichloromethane at 0℃; Inert atmosphere;
2.1. General Procedure for the Synthesis of N-Acylated Lactam Derivatives
General procedure: δ- or γ-Lactam (10 mg, 1.0 equiv) was dissolved inmethylene chloride and added with acyl chloride (1.2 equiv), triethylamine (TEA, 1.5 equiv) and dimethylaminopyridine (DMAP, 5 mol%). The mixture was kept at 0 °C for 6 hours or until completion of reaction. The reaction mixture was quenched with saturated sodium bicarbonate and washed successively with water and brine and dried with anhydrous sodium sulfate. Column chromatography was performed with silica gel (230-400 Mesh) using hexanes: ethyl acetate solvent system to isolate and purify the products.
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