* 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] Chemistry - A European Journal, 2015, vol. 21, # 36, p. 12797 - 12803
2
[ 109384-19-2 ]
[ 301673-14-3 ]
Yield
Reaction Conditions
Operation in experiment
93%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 18 h;
To a solution of N-Boc-4-hydroxypiperdine (10.0 g, 49.7 mmol) in dichloromethane (200 mL) was added triphenylphosphine (16.9 g, 64.6 mmol) and imidazole (5.07 g, 74.5 mmol). The resulting slurry was cooled to 0° C. in an ice bath. Iodine (15.1 g, 59.6 mmol) was added in small portions. The solution was then stirred for 18 hr at ambient temperature. Afterward, the solution was diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated aqueous NaCl, and then dried over sodium sulfate. Concentration in vacuo followed by trituration with hexane removed the excess triphenylphosphine and triphenylphosphine oxide. The filtrate was concentrated in vacuo to provide the iodo intermediate as a colorless oil (14.4 g, 93percent yield).
90%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 15℃; for 16 h; Inert atmosphere
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (30.0 g, 149 mmol, CAS 109384-19-2), imidazole (13.1 g, 193 mmol) and PPh3 (46.9 g, 178 mmol) in DCM (500 mL) was added iodine (45.4 g, 178 mmol) in portions at 0 °C and the reaction mixture was stirred at 25 °C for 16 hrs under nitrogen. On completion, the reaction mixture was filtered and the filtrate was washed with Na2SO3solution until the organic layer was colorless. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 20:1) to give the title compound (42.0 g, 90percent yield) as a white solid.1H NMR (400MHz, CDCl3) δ = 4.48 - 4.42 (m, 1H), 3.64 - 3.56(m, 2H), 3.32 - 3.58 (m, 2H), 2.08 - 1.97 (m, 4H), 1.46 (s, 9H).
84%
With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 18 - 20℃; for 6 h; Cooling with ice
A solution of N-Boc-4-hydroxypiperidine (246 g, 1.224 mol), imidazole (100 g, 1.469 mol, 1.2 eq.) and triphenylphosphine (385 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was cooled using an ice bath. Then a solution of iodine (373 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was added slowly over a period of lh keeping the internal temperature below 18 °C. The resulting mixture was allowed to stir at room temperature for 5 h and the mixture was diluted with ethyl acetate (2 L), brine (1 L) and water (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 L x 2). The organic layers were combined, washed with 15percent aqueous sodium sulfite (1 L), brine (1 L), dried and concentrated. The resulting residue was stirred with hexanes (2 L) and the solid was removed by filtration. The solid was stirred with hexanes (2 L x 2) and filtered. The filtrate was concentrated to give 363 g of crude oil which was purified by column chromatography (eluting with hexanes/ethyl acetate = 50: 1 to 20: 1) to afford 319 g tert-butyl 4-iodopiperidine- 1 -carboxylate Yield: 84percent.
76%
With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 17 h;
Intermediate 291 , 1 -Dimethylethyl 4-iodo- 1 -piperidinecarboxylateTo a solution of 1,1 -dimethylethyl 4-hydroxy-l -piperidinecarboxylate (5.35 g, 26.6 mmol), imidazole (2.18 g, 32.0 mmol), and triphenylphosphine (8.45 g, 32.2 mmol) in THF (13 mL) at 0 0C under N2 was added a solution of I2 (8.11 g, 32.0 mmol) in THF (13 mL) dropwise. The mixture was allowed to warm to room temperature and stirred under N2 for 17 h, then quenched with 10percent aq NaHSO3 (10 mL), concentrated to remove most of the THF, poured into H2O, and extracted with hexanes (2x). The extracts were washed with H2O, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of hexanes to 20percent EtOAc in hexanes to give the title compound as a white solid (6.32 g, 76percent). LC-MS (ES) m/z = 256 [M-C4H9+H]+.
70%
With 1H-imidazole; iodine; triphenylphosphine In acetonitrile at 20℃; for 24 h;
2.15 g of triphenylphosphine(8.2 mmole) and 2.08 g of iodine (8.2 mmole) are dissolved in 30 ml of acetonitrile. The reaction mixture is stirred for 10 minutes at ambient temperature then 918 mg of imidazole (13.5 mmol) is added and stirring is maintained for another 10 minutes at ambient temperature. Then 1 g (5 mmol) of tert-butyl 4-hydroxy-1-piperidinecarboxylate of the preceding stage is added and stirring is maintained for 24 hours at ambient temperature. The reaction is treated by adding an aqueous solution of sodium thiosulphate and the acetonitrile is evaporated off under reduced pressure (2 kPa), followed by taking up in ethyl acetate, extracting and washing with an aqueous solution of sodium thiosulphate. The organic phases are dried over MgSO4, filtered and the ethyl acetate is evaporated off under reduced pressure (2 kPa). After chromatography on Silicagel eluding with dichloromethane then dichloromethane/methanol 90:10, 1.1 g (yield=70percent) of a colourless oil is recovered. TLC: Rf=0.8 (silicagel, eluent: CH2Cl2/MeOH 90:10 1H-NMR (CDCl3): δ 1.47 (s, 9H, tBu); 2.03 (m, 4H, -C2-CH1-C2-); 3.30 and 3.60 (2m, 4H, -C-N-C2-); 4.46 (m, 1H-C1-);
66%
With 1H-imidazole; iodine; triphenylphosphine In acetonitrile at 0 - 20℃; for 120 h;
STEP B: Imidazole (1.196 g, 17.57 mmol), triphenylphospine (3.72 g, 14.19 mmol) and iodine (3.60 g, 14.19 mmol) are added at 0°C to the solution of N-Boc-4-hydroxypiperidine (2.72 g, 13.51 mmol) in CH3CN (113 mL). The reaction is stirred at 0°C for 30 min and then for 5 days at RT. The organic solvent is removed at reduced pressure and the residue is dissolved in DCM. The organic phase is washed with a solution of tiosulfate and then with brine. The organic phase is dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent petroleum ether/EtOAc from 100/0 to 95/5) to yield the title compound (2.76 g, 8.87 mmol, Yield: 66percent) as light yellow oil..1H-NMR (DMSO-d6) δ (ppm): 4.60 (tt, J=8.5, 4.1 Hz, 1 H); 3.39-3.53 (m, 2 H); 3.08-3.24 (m, 2 H); 1.96-2.12 (m, 2 H); 1.79-1.96 (m, 2 H); 1.40 (s, 9 H)
1000 g
With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 2 - 20℃; Large scale
Example 2: A mixture of raw material 1(1000 g, 4.96πο1), triphenylphosphine (1560 g, 5.96πο1) and imidazole (4050 g, 5.96πο1) were dissolved in anhydrous tetrahydrofuran (4000 ml) At a temperature of 2-3 ° C, and then iodine (1510 g, 5.96 mol) was dissolved in anhydrous tetrahydrofuran and the reaction solution was added dropwise. The dropping temperature was not more than 12 ° C. After the addition was complete, the room temperature was restored and stirred overnight. The product Rf was about 0.5 in terms of petroleum ether: ethyl acetate (volume ratio) = 5: 1. After the reaction was tested, 10percent by mass of NaHS03 (800 mL) was added to 8°C. Spin the solution, then add n-hexane (4000mL), suction filter, first pour the upper overnight, and then filter out the bottom of the solid, filter with a large number of n-hexane washing. The upper layer of the night with lmol / L hydrochloric acid to wash to neutral, and then water, saturated NaCl were washed, sodium sulfate drying, filtration, spin to get crude. The crude product was dissolved in 3017 mL of ethanol and then cooled to -5 ° C. 2700 mL of water was added three times with stirring over 20 minutes while maintaining a temperature of about -5 ° C, with a large amount of solid precipitated. After adding water, stirring was continued for 1 hour, and the mixture was filtered to obtain a white solid.
Reference：
[1] Patent: US2005/9838, 2005, A1, . Location in patent: Page 143
[2] Patent: WO2018/106636, 2018, A1, . Location in patent: Paragraph 00283
[3] Patent: WO2011/143366, 2011, A1, . Location in patent: Page/Page column 45
[4] Journal of Organic Chemistry, 2004, vol. 69, # 15, p. 5120 - 5123
[5] Synlett, 1998, # 4, p. 379 - 380
[6] Patent: WO2008/147831, 2008, A1, . Location in patent: Page/Page column 46
[7] Angewandte Chemie - International Edition, 2013, vol. 52, # 47, p. 12409 - 12413[8] Angew. Chem., 2013, vol. 125, # 47, p. 12635 - 12639,5
[9] Patent: US2006/52398, 2006, A1, . Location in patent: Page/Page column 62
[10] Patent: WO2013/64919, 2013, A1, . Location in patent: Page/Page column 30; 31
[11] Journal of the American Chemical Society, 2018, vol. 140, # 1, p. 155 - 158
[12] Organic Letters, 2014, vol. 16, # 23, p. 6160 - 6163
[13] Chemistry - A European Journal, 2015, vol. 21, # 36, p. 12797 - 12803
[14] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1517 - 1521
[15] Patent: WO2010/54279, 2010, A1, . Location in patent: Page/Page column 127
[16] Patent: WO2011/143495, 2011, A1, . Location in patent: Page/Page column 90-91
[17] Angewandte Chemie - International Edition, 2013, vol. 52, # 3, p. 933 - 937[18] Angew. Chem., 2012, vol. 125, # 3, p. 967 - 971,5
[19] Patent: WO2015/84606, 2015, A1, . Location in patent: Page/Page column 95; 96
[20] Patent: CN103130708, 2016, B, . Location in patent: Paragraph 0015; 0017
[21] Organic Letters, 2017, vol. 19, # 23, p. 6412 - 6415
[22] Organic Letters, 2018, vol. 20, # 15, p. 4677 - 4680
3
[ 288-32-4 ]
[ 109384-19-2 ]
[ 301673-14-3 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With iodine; triphenylphosphine In acetonitrile at 20℃; for 0.166667 h; Stage #2: at 20℃; for 0.166667 h;
2) Synthesis of N-t.butoxycarbonyl-4-iodo-1-piperidine 2.15 g of triphenylphosphine (8.2 mmole) and 2.08 g of iodine (8.2 mmole) are dissolved in 30 ml of acetonitrile. The reaction medium is left under stirring for 10 minutes at ambient temperature then 918 mg of imidazole (13.5 mmol) is added and stirring is maintained for another 10 minutes at ambient temperature. Then 1 g (5 mmol) of N-t.butoxycarbonyl-4-hydroxy-1-piperidine is added and stirring is maintained for 24 hours at ambient temperature. The reaction is treated by adding an aqueous solution of sodium thiosulphate and the acetonitrile is evaporated off under reduced pressure (2 kPa), followed by taking up in ethyl acetate, extracting and washing with an aqueous solution of sodium thiosulphate. The organic phases are dried over MgSO4, filtered and the ethyl acetate is evaporated off under reduced pressure (2 kPa), followed by chromatography on silica gel eluding with dichloromethane then dichloromethane/methanol 90:10. 1.1 g (Yield=70percent) of colourless oil is recovered. TLC: Rf=0.8 (silica gel, eluent: CH2Cl2/MeOH 90:10 1H-NMR (CDCl3): δ 1.47 (s, 9H, tBu); 2.03 (m, 4H, -C-CHI-C2-); 3.30 and 3.60 (2m, 4H, -C-N-C-); 4.46 (m, 1H -CI-)
With 1,3-Diiodo-5,5-dimethyl-2,4-imidazolidinedione In chlorobenzene for 1 h; Reflux; Fluorescent lighting
EXAMPLE 3; Radical iodo-de-caboxylation induced by TV-iodo amides/V-iodo amideR-COOH *- R-lGeneral procedure[00111] Procedure: A mixture of R-COOH (1 mmol), N-iodo amide (1-4 equiv), and solvent (3-6 mL) was refluxed (Δ) for 1-24 h in the dark (NL) or under irradiation with 500 W tungsten lamp (TL) or under fluorescent room lighting (FL).[00112] Treatment: The reaction mixture was cooled to rt, and washed with aq NaHS03 and NaHC03 to destroy excess of iodination agent and dissolve unreacted carboxylic acid. The organic solution was dried (Na2S04), filtered through short silica or alumina pad and concentrated in vacuo to give iodide R-I. 100113J Purification: Optionally, the iodide R-I was further purified by crystallization (if the iodide is crystalline compound), or rectification (if the iodide is liquid compound). Analytical sample of the product was purified by column chromatography./V-iodoamideAlk-COOH *- Alk-I[00114] A mixture of Alk-COOH (1 mmol), N-iodo amide (1-3 equiv), and solvent (4 mL) was refluxed (Δ) in the dark (NL) or under irradiation with 500 W tungsten lamp (TL), or under fluorescent room lighting (FL).
Reference：
[1] Patent: WO2011/154953, 2011, A1, . Location in patent: Page/Page column 28-30
[2] Advanced Synthesis and Catalysis, 2011, vol. 353, # 9, p. 1438 - 1442
5
[ 5382-16-1 ]
[ 301673-14-3 ]
Reference：
[1] Synlett, 1998, # 4, p. 379 - 380
[2] Patent: WO2013/64919, 2013, A1,
[3] Organic Letters, 2014, vol. 16, # 23, p. 6160 - 6163
[4] Chemistry - A European Journal, 2015, vol. 21, # 36, p. 12797 - 12803
[5] Journal of the American Chemical Society, 2018, vol. 140, # 1, p. 155 - 158
6
[ 24424-99-5 ]
[ 301673-14-3 ]
Reference：
[1] Synlett, 1998, # 4, p. 379 - 380
[2] Patent: WO2013/64919, 2013, A1,
[3] Organic Letters, 2014, vol. 16, # 23, p. 6160 - 6163
[4] Chemistry - A European Journal, 2015, vol. 21, # 36, p. 12797 - 12803
[5] Journal of the American Chemical Society, 2018, vol. 140, # 1, p. 155 - 158
7
[ 586-76-5 ]
[ 301673-14-3 ]
[ 149353-75-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 6088 - 6092
8
[ 301673-14-3 ]
[ 149353-75-3 ]
Reference：
[1] Patent: WO2015/84606, 2015, A1,
9
[ 585-76-2 ]
[ 301673-14-3 ]
[ 828243-30-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 6088 - 6092
10
[ 301673-14-3 ]
[ 88-65-3 ]
[ 170838-26-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 6088 - 6092
Zinc powder (10.50g, 160.60mmol) was added to 2M hydrochloric acid (25mL) and the resulting suspension was stirred for 20 minutes. It was then filtered and washed with water (10mL), ethanol (10mL), diethyl ether (10mL) and dried in a vacuum oven for 24 hours. The dried zinc was suspended in N, N-dimethylformamide (50mL) and 1,2-dibromoethane (277nL, 3.21 mmol) was added. The resulting suspension was warmed to 65 C for 5 minutes and then allowed to cool to room temperature, after which time trimethylsilyl chloride (406|aL, 3.2mmol) was added. The reaction was stirred at room temperature for 45 minutes and then a solution of <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (Synlett, 4, 379, 1998) (10g, 32.1 mmol) and hydroquinone (177mg, 0.05mmol) in N, N-dimethylformamide (50mL) was slowly added, followed by warming to 150 C for 30 minutes. 2-bromopyridine (3.06ml_, 32.10mmol) in N, N-dimethylformamide (20mL) was then added, followed by 5mol% of Pd2(dba)3 (1.44g, 1.57mmol), 10 mol% P-(2-furyl)3 (747mg, 3.22mmol) and the reaction was heated at 65 C for 24 hours. The reaction mixture was filtered through Celite and diluted with water (500ml_). It was then extracted with diethyl ether (2x250ml). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using diethyl ethenpentane (50:50-100:0) as eluent afforded the product as a yellow oil, 1.9g (23%).1H NMR (400 MHz, CDCI3): 5 1.45 (9H, s), 1.72 (2H, m), 1.93 (2H, m), 2.70-2.95 (3H, m), 4.26 (2H, m), 7.07-7.20 (2H, m), 7.63 (1H, m), 8.54 (1H, dd).
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 18h;
To a solution of N-Boc-4-hydroxypiperdine (10.0 g, 49.7 mmol) in dichloromethane (200 mL) was added triphenylphosphine (16.9 g, 64.6 mmol) and imidazole (5.07 g, 74.5 mmol). The resulting slurry was cooled to 0 C. in an ice bath. Iodine (15.1 g, 59.6 mmol) was added in small portions. The solution was then stirred for 18 hr at ambient temperature. Afterward, the solution was diluted with water and extracted with diethyl ether. The organic layer was washed with water and saturated aqueous NaCl, and then dried over sodium sulfate. Concentration in vacuo followed by trituration with hexane removed the excess triphenylphosphine and triphenylphosphine oxide. The filtrate was concentrated in vacuo to provide the iodo intermediate as a colorless oil (14.4 g, 93% yield).
90%
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 15℃; for 16h;Inert atmosphere;
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (30.0 g, 149 mmol, CAS 109384-19-2), imidazole (13.1 g, 193 mmol) and PPh3 (46.9 g, 178 mmol) in DCM (500 mL) was added iodine (45.4 g, 178 mmol) in portions at 0 C and the reaction mixture was stirred at 25 C for 16 hrs under nitrogen. On completion, the reaction mixture was filtered and the filtrate was washed with Na2SO3solution until the organic layer was colorless. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 20:1) to give the title compound (42.0 g, 90% yield) as a white solid.1H NMR (400MHz, CDCl3) delta = 4.48 - 4.42 (m, 1H), 3.64 - 3.56(m, 2H), 3.32 - 3.58 (m, 2H), 2.08 - 1.97 (m, 4H), 1.46 (s, 9H).
84%
With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 18 - 20℃; for 6h;Cooling with ice;
A solution of N-Boc-4-hydroxypiperidine (246 g, 1.224 mol), imidazole (100 g, 1.469 mol, 1.2 eq.) and triphenylphosphine (385 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was cooled using an ice bath. Then a solution of iodine (373 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was added slowly over a period of lh keeping the internal temperature below 18 C. The resulting mixture was allowed to stir at room temperature for 5 h and the mixture was diluted with ethyl acetate (2 L), brine (1 L) and water (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 L x 2). The organic layers were combined, washed with 15% aqueous sodium sulfite (1 L), brine (1 L), dried and concentrated. The resulting residue was stirred with hexanes (2 L) and the solid was removed by filtration. The solid was stirred with hexanes (2 L x 2) and filtered. The filtrate was concentrated to give 363 g of crude oil which was purified by column chromatography (eluting with hexanes/ethyl acetate = 50: 1 to 20: 1) to afford 319 g tert-butyl 4-iodopiperidine- 1 -carboxylate Yield: 84%.
76%
With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 17h;
Intermediate 291 , 1 -Dimethylethyl 4-iodo- 1 -piperidinecarboxylateTo a solution of 1,1 -dimethylethyl 4-hydroxy-l -piperidinecarboxylate (5.35 g, 26.6 mmol), imidazole (2.18 g, 32.0 mmol), and triphenylphosphine (8.45 g, 32.2 mmol) in THF (13 mL) at 0 0C under N2 was added a solution of I2 (8.11 g, 32.0 mmol) in THF (13 mL) dropwise. The mixture was allowed to warm to room temperature and stirred under N2 for 17 h, then quenched with 10% aq NaHSO3 (10 mL), concentrated to remove most of the THF, poured into H2O, and extracted with hexanes (2x). The extracts were washed with H2O, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of hexanes to 20% EtOAc in hexanes to give the title compound as a white solid (6.32 g, 76%). LC-MS (ES) m/z = 256 [M-C4H9+H]+.
70%
With 1H-imidazole; iodine; triphenylphosphine; In acetonitrile; at 20℃; for 24h;
2.15 g of triphenylphosphine(8.2 mmole) and 2.08 g of iodine (8.2 mmole) are dissolved in 30 ml of acetonitrile. The reaction mixture is stirred for 10 minutes at ambient temperature then 918 mg of imidazole (13.5 mmol) is added and stirring is maintained for another 10 minutes at ambient temperature. Then 1 g (5 mmol) of tert-butyl 4-hydroxy-1-piperidinecarboxylate of the preceding stage is added and stirring is maintained for 24 hours at ambient temperature. The reaction is treated by adding an aqueous solution of sodium thiosulphate and the acetonitrile is evaporated off under reduced pressure (2 kPa), followed by taking up in ethyl acetate, extracting and washing with an aqueous solution of sodium thiosulphate. The organic phases are dried over MgSO4, filtered and the ethyl acetate is evaporated off under reduced pressure (2 kPa). After chromatography on Silicagel eluding with dichloromethane then dichloromethane/methanol 90:10, 1.1 g (yield=70%) of a colourless oil is recovered. TLC: Rf=0.8 (silicagel, eluent: CH2Cl2/MeOH 90:10 1H-NMR (CDCl3): delta 1.47 (s, 9H, tBu); 2.03 (m, 4H, -C2-CH1-C2-); 3.30 and 3.60 (2m, 4H, -C-N-C2-); 4.46 (m, 1H-C1-);
66%
With 1H-imidazole; iodine; triphenylphosphine; In acetonitrile; at 0 - 20℃; for 120h;
STEP B: Imidazole (1.196 g, 17.57 mmol), triphenylphospine (3.72 g, 14.19 mmol) and iodine (3.60 g, 14.19 mmol) are added at 0C to the solution of N-Boc-4-hydroxypiperidine (2.72 g, 13.51 mmol) in CH3CN (113 mL). The reaction is stirred at 0C for 30 min and then for 5 days at RT. The organic solvent is removed at reduced pressure and the residue is dissolved in DCM. The organic phase is washed with a solution of tiosulfate and then with brine. The organic phase is dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (eluent petroleum ether/EtOAc from 100/0 to 95/5) to yield the title compound (2.76 g, 8.87 mmol, Yield: 66%) as light yellow oil..1H-NMR (DMSO-d6) delta (ppm): 4.60 (tt, J=8.5, 4.1 Hz, 1 H); 3.39-3.53 (m, 2 H); 3.08-3.24 (m, 2 H); 1.96-2.12 (m, 2 H); 1.79-1.96 (m, 2 H); 1.40 (s, 9 H)
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; for 3h;
Part B: Compound 741 (2.25 g, 11.25 mmol), triphenylphosphine (3.84 g, 17.6 mmol), imidazole (1.15 g, 16.8 mmol) and iodine (3.4 g, 12.3 mmol) were dissolved in methylene chloride (15 ml_) and stirred for 3 hours. The reaction was quenched with water and ether. The ether layer was dried over sodium sulfate and concentrated. The residue was triturated with hexanes to provide compound 742 (3.1 g).
With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 18 - 20℃; for 6h;Cooling with ice;
A solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (246 g, 1.224 mol), imidazole (100 g, 1.469 mol, 1.2 eq.) and triphenylphosphine (385 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was cooled using an ice bath. Then a solution of iodine (373 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was added slowly over a period of 1 hour while keeping the internal temperature below 18 C. The resulting mixture was allowed to stir at room temperature for 5 hours and the mixture was diluted with ethyl acetate (2 L), brine (1 L) and water (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 L x 2). The organic layers were combined, washed with 15% aqueous sodium sulfite (1 L), brine (1 L), dried and concentrated. The resulting residue was stirred with hexanes (2 L) and the solid was removed by filtration. The solid was stirred with hexanes (2 L x 2) and filtered. The filtrate was concentrated to give 363 g of crude oil which was purified by column chromatography (eluting with hexanes/ethyl acetate = 50: 1 to 20: 1) to afford 319 g of tert-butyl 4-iodopiperidine-l-carboxylate.
With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; Cooling with ice;
STEPA: 4-Iodo-piperidine-1-carboxylic acid tert-butyl esterA 2-necks round-bottom flask equipped with a stirring bar, addition 25 funnel and a nitrogen inlet, was charged with 4-hydroxy-piperidine-1 -carboxylic acid tert-butyl ester (25 g, 124 mmol), triphenylphosphine (39.1 g, 149 mmol) and imidazole (10.2 g, 149 mmol) in dry THF (150 ml) and cooled in ice bath under light nitrogen steam. A solution of iodine (37.8 g, 149 mmol) in dry THF (75 ml) was added dropwise from the addition funnel over 30 minutes. The mixture was then allowed to warm up to room temperature overnight with stirring. The mixture was then cooled again in ice bath and diluted with water (100 ml) and 10% NaHSO3(30 ml) was added. The organics were extracted with heptane (300 ml). The organic layer was dried over MgSO4, then filtered. 5 Most of the THF was removed to induce crystallization of triphenylphosphine oxide, which was removed by filtration. The filtrate was further concentrated to an oil. Filtration over a short column of silica gel eluting with 10% ethyl acetate in heptane yielded a clear oil that crystallized upon standing.1H NMR (300 MHz, CDCl3) ppm 1.46 (s, 9 H), 2.03 (q, J=5.8 Hz, 4 H), 3.24 - 3.33 (m, 2 H), 10 3.56 - 3.64 (m, 2 H), 4.45 (quint, J=6.0 Hz, 1 H). MS m/z 312 (M+H)+
1000 g
With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 2 - 20℃;Large scale;
Example 2: A mixture of raw material 1(1000 g, 4.96piomicron1), triphenylphosphine (1560 g, 5.96piomicron1) and imidazole (4050 g, 5.96piomicron1) were dissolved in anhydrous tetrahydrofuran (4000 ml) At a temperature of 2-3 C, and then iodine (1510 g, 5.96 mol) was dissolved in anhydrous tetrahydrofuran and the reaction solution was added dropwise. The dropping temperature was not more than 12 C. After the addition was complete, the room temperature was restored and stirred overnight. The product Rf was about 0.5 in terms of petroleum ether: ethyl acetate (volume ratio) = 5: 1. After the reaction was tested, 10% by mass of NaHS03 (800 mL) was added to 8C. Spin the solution, then add n-hexane (4000mL), suction filter, first pour the upper overnight, and then filter out the bottom of the solid, filter with a large number of n-hexane washing. The upper layer of the night with lmol / L hydrochloric acid to wash to neutral, and then water, saturated NaCl were washed, sodium sulfate drying, filtration, spin to get crude. The crude product was dissolved in 3017 mL of ethanol and then cooled to -5 C. 2700 mL of water was added three times with stirring over 20 minutes while maintaining a temperature of about -5 C, with a large amount of solid precipitated. After adding water, stirring was continued for 1 hour, and the mixture was filtered to obtain a white solid.
tert-butyl 4-[4-methoxy-2-(methoxycarbonyl)phenyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81 % Chromat.
Stage #1: tert-butyl 4-iodopiperidine-1-carboxylate With chloro-trimethyl-silane; ethylene dibromide; zinc In N,N-dimethyl acetamide for 0.5h;
Stage #2: methyl 2-bromo-5-methoxybenzoate In N,N-dimethyl acetamide at 80℃;
With caesium carbonate; In acetonitrile; at 150 - 180℃; for 0.333333h;Microwave heating;
A mixture of 4-(4-bromophenyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (0.002 mol), 1,1- dimethylethyl ester of 4-iodo-l-piperidine carboxylic acid (0.003 mol) and Cs2CO3 (0.004 mol) in CH3CN (7 ml) was heated for 10 minutes under microwave conditions at 150 C and then for 10 minutes at 180 C. The resulting solids were filtered off and the solvent was evaporated. The residue was purified over a filter using CH2Cl2 and then CH2C12/CH3OH (98/2) and the desired product was collected. Yield: 0.25 g of interme- diate compound 1 (30 %).
With chloro-trimethyl-silane; ethylene dibromide; zinc; In ISOPROPYLAMIDE; at 20 - 66℃; for 0.916667h;
Zinc dust (1.66 g, 25.4 mmol) was suspended in dimethylacetamide (DMA, 4.3 ml) and a solution of trimethylsilyl chloride/1, 2-dibromoethane (7:5 w/w, 0.45 ml) was added via syringe over several minutes. The temperature rose to ~ 60C and stirring was continued for 15 minutes while the reaction mixture cooled back to rt. A solution of the commercially available iodide 61- 1 (6.5 g, 20.9 mmol) in DMA (10 ml) was then added from a syringe over 5 minutes. The temperature rose again to ~66C. Stirring was continued for 35 min. while the mixture cooled back to rt again, and then filtered through Celite under nitrogen rinsing the flask and filter with DMA (2.0 ml). This gave a 0.95 M solution in DMA of the zinc iodide insertion product. The triflate 61-2 (2.16 g, 6.46 mmol) (preparation of this material is described in the literature and was obtained from WuXi Pharma Tech) was dissolved in DMA (5.5 ml) and PdCl2(dppf) catalyst (159 mg, 0.19 mmol) and CuI (74 mg, 0.39 mmol) was added. The mixture was degassed with alternate N2/high vacuum purges (3x) and a 0.95M solution of the zinc iodide intermediate from above (13.6 ml, 12.9 mmol) was added, then the mixture was heated to 80C for 3.5 hr, then then cooled in an ice bath. NH4Cl-H2O and ether were added with vigorous stirring. The mixture was filtered through Celite and washed with water, EtOAc and ether. The layers were separated and extracted the aqueous layer with ether (2x). The combined extracts were washed with brine (Ix), dried over MgSO4, filtered and evaporated. The resulting oil was purified by flash chromatography on silica gel (hexane-ethyl-acetate, 9: 1) to give 61-3 as a viscous yellow oil
With chloro-trimethyl-silane; ethylene dibromide; zinc; In N,N-dimethyl acetamide; at 20 - 65℃;
Zinc activation. A schlenk flask was charged with Celite (1.28 g) and dried by heating in vacuo. Then zinc dust (6.51 g) and dry N,N-dimethylacetamide (15 ml) were added. The mixture was stirred at room temperature while a 7:5 v/v mixture of chlorotrimethylsilane (1.14 ml) and 1,2-dibromoethane (0.80 ml) as solution in N,N-dimethylacetamide (1 ml) was added at a rate to maintain the temperature below 65C (?15 min). The resulting slurry was aged for 15 min. Zink insertion. A solution of Boc-4-iodopiperidine (24.8 g) in N,N-dimethylacetamide (39 ml) was slowly added to the mixture described above at a rate to maintain a temperature below 65C (?20 min). The resulting reaction mixture was then aged for 30 min at room temperature. The suspension was filtered through a frit under argon to remove all solids. The resulting pale yellow solution was stored at room temperature under argon and was directly used for the coupling reactions.
With chloro-trimethyl-silane; ethylene dibromide; zinc; In N,N-dimethyl-formamide; at 20 - 65℃; for 0.75h;
The procedure followed was analogous to that described in Journal of Organic Chemistry ^2004, 69, 5120-5123. To a slurry of zinc dust (4.22 g, 64.5 mmol) and Celpure P65 (0.83 g) in yV,/V-dimethylformamide (10.4 ml_) was added a 7:5 v/v mixture of chlorotrimethylsilane:1 ,2-dibromoethane (1.25 ml_) over a 10 min period at room temperature. The internal temperature was EPO <DP n="229"/>maintained below 65 0C during the addition. The slurry was stirred for 15 min and a solution of 1 ,1-dimethylethyl 4-iodo-1-piperidinecarboxylate (16.50 g, 52.0 mmol, prepared as in the literature reference cited above) in N,N- dimethylformamide (26 ml_) was added slowly at a rate to maintain temperature below 65 0C. The reaction mixture was heated at 65 0C for 5 min and allowed to cool to room temperature with stirring for 30 min. The mixture was filtered to afford a solution of the desired product in Lambda/,LambdaA dimethylformamide of undetermined concentration.
With chloro-trimethyl-silane; zinc; 1,2-dibromomethane; In 1,2-dimethoxyethane; at 58 - 60℃;Inert atmosphere;
Step 1 :The 4-zinc-iodopiperidine-1-carboxylic acid compound was synthesized first. Celpure P65 is mixed with the zink dust in DME under nitrogen, and TMS-CI dissolved in 1 ,2-dibromo- methane was added in small portions. The reaction mixture was stirred at RT for additional 30 min. 4-lodopiperidine-1-carboxylic acid dissolved in dry DME was added at a speed to keep the temperature between 58 and 600C. To secure a total conversion, the reaction mixture was heated for additional 30 min. This reaction mixture was used in the next step after a filtration through a column with Celpure P65. The column was washed with an extra volume of dry DME to secure all material from the column.
With chloro-trimethyl-silane; zinc; In N,N-dimethyl acetamide; ethylene dibromide; at 20℃; for 2.5h;Inert atmosphere;
Zinc dust (521 mg, 8.0 mmol, 1.25 eq) and Celpure 65 (100 mg) are suspended in DMA (1.3 mL). The mixture is then degassed under vacuum, and filled with argon. A trimethylsilyl chloride/i ,2- dibromoethane mixture (7: 5, V:V, 150 jiL) is added dropwise, and the reaction mixture is stirred for 15 mm at room temperature. The N-Boc protected iodopiperidine (2 g, 6.4 mmol, 1 eq.) in DMA (3.2 mL) is added to the previous solution dropwise, over 15 mm under argon. The reaction is then stirred at room temperature for 1 h. Stirring is then stopped for the solid to settle at the bottom of the flask for 2 h. The solution was syringed out, filtered into a sealed tube, purged with argon, and kept at room temperature, as a 1 M solution, for next coupling step.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
Example 11; N-(2-ethoxybenzyl)-1-(1-(2-(methylamino)ethyl)piperidin-4-yl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (98); Step 1 tert-butyl 4-(5-(ethoxycarbonyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)piperidine-1- carboxylate (93); [0268] tert-Butyl 4-iodopiperidine-i-carboxylate (5 683, 18 26 mmol, E G Corley et al, JOC, 2004, 69, 5120-5123) in DMF (30 7 ml) was added to a mixture of ethyl 3- (trifluoromethyl)-1 H-pyrazole-5-carboxylate (3 2 g, 15 37 mmol, M -A Plancquaert et al, Tetrahedron, 52, 4383-4396) and potassium carbonate 95 31 g, 38 4 mmol) and the mixture was stirred at 80oC for 16h After cooling, water was added and the mixture was extracted with EtOAc, and the organic extraxts were dried, filtered and concentrated Chromatographic purification of the residue by Biotage (5-20% EtOAc m Hexanes, 25M column) gave compound 93 as colorless oil (2 4 g, 39 9% yield) LFRMS (ESI) calc 391 4, found 414 1 (M+Na)+
Common Intermediates: 1-tert-Butoxycarbonylpiperidin-4-yl)(iodo)zinc: [Show Image] Zinc activation. A Schlenk flask was charged with Celite (174 mg) and dried by heating in vacuo. Then zinc dust (883 mg) and dry N,N-dimethylacetamide (2 ml) were added. The mixture was stirred at room temperature while a 7:5 v/v mixture of chlorotrimethylsilane (153 mul) and 1,2-dibromoethane (108 mul) as solution in N,N-dimethylacetamide (1 ml) was added at a rate to maintain the temperature below 65 C (?5 min). The resulting slurry was aged for 15 min. Zink insertion. A solution of Boc-4-iodopiperidine (3.36 g) in N,N-dimethylacetamide (6 ml) was slowly added to the mixture described above at a rate to maintain a temperature below 65 C (?5 min). The resulting reaction mixture was then aged at room temperature for 30 min. The suspension was filtered through a frit under argon to remove all solids. The resulting pale yellow solution was stored at room temperature under argon and was directly used for the coupling reactions.
STEP 2: TERT-BUTYL 4-(3-FLUOROPYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE In an oven-dried 25 mL round-bottomed flask was charged dry DMA (1 mL), zinc dust (0.430 g, 6.58 mmol). The mixture was stirred at RT while the mixture of chlorotrimethylsilane (0.07 mL, 0.553 mmol) and 1,2-dibromoethane (0.05 mL, 0.580 mmol) was added slowly. The resulting slurry was aged for 15 min. A solution of n-boc-4-iodo-piperidine (1.65 g, 5.30 mmol) in DMA (2.6 mL) was added slowly to the above mixture. Zinc slurry reacted exothermically with the gradual addition of the iodide. After stirring for 30 min, the resulting milky solution was cooled to RT and used directly in the next step. In an oven-dried flask were charged 2-fluoro-3-iodopyrazine (0.829 g, 3.70 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(ii)complex with dichloramethane (0.091 g, 0.111 mmol), copper(i) iodide (0.042 g, 0.222 mmol), and DMA (3 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (1.951 g, 5.18 mmol) solution from previous step was filtered into the mixture. It was degassed one more time and then heated to 80 C. with stirring for 16 h. After cooling to RT, the reaction mixture was treated with methyl tert-butylether (13 ml) and 1 N NH4Cl (13 ml). The organic layer was partitioned between EtOAc and 1 N NH4Cl and the aqueous layer was back extracted with EtOAc (2 x). The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluding with a gradient of 0% to 20% EtOAc in hexane, to provide tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate as orange oil. MS (ESI, pos. ion) m/z: 226.0 (M-56).
first step:In a dry four-necked bottle,Under nitrogen protection,422 mg (6.45 mmol) of zinc powder was added,And DMAC (dimethylacetamide) 4 ml.1,2-dibromoethane 90 mul (1 mmol)Heated to the internal temperature to 56 degrees,The reaction flask is a gray suspension,After heating for 5 min,The reaction solution was cooled to about 33 degrees,TMSCl (trimethylchlorosilane 170 mul, 1.34 mmol) was added,Exotherm, the temperature naturally rose to 57 degrees,The reaction solution was cooled to 40 C,And keep for 15min,SR-1 (1.02 g, 3.26 mmol), DMAC 0.5 ml was added dropwise,Exothermic reaction, the reaction solution was cooled to room temperature,Stirring 1H,Reaction finished,Pumping with nitrogen protection directly for the next step reaction (used in the 1HR,Concentration of the solution to determine the iodine content).
With chloro-trimethyl-silane; In N,N-dimethyl acetamide; ethylene dibromide; at 70℃; for 0.5h;Inert atmosphere;
To a mixture of zinc powder (1.26 g, 19.2 mmol) in dimethylacetamide (10 mL) was added TMSCl (174 mg, 1.61 mmol) and 1,2-dibromoethane (301 mg, 1.61 mmol) at 60 C under nitrogen. Then <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (5.00 g, 16.0 mmol) in dimethylacetamide (5 mL) was added at 70 C and the reaction mixture was stirred at 70 C for 0.5 hr. The green liquid (1 M) was for the next step directly.
Zinc powder (5 g, 76 mmol) was suspended in N,N-dimethylacetamide (10 mL) under argon. A mixture of 1,2-dibromoethane (520 mu, 6.02 mmol) and chlorotrimethylsilane (730 mu, 5.74 mmol) was added dropwise over 10 min. Over the course of the addition the internal temperature rose to 50 C. The reaction mixture was allowed to cool to room temperature. A solution of tert-butyl 4-iodopiperidine-l-carboxylate (16.5 g, 53.0 mmol) in N,N- dimethylacetamide (26 mL) was added dropwise over 20 min. The reaction mixture was filtered through Celite in a Schlenk filter to yield roughly 50 mL of ~1M (l-tert-butoxycarbonyl-4- piperidyl)-iodo-zinc solution. 2-Chloro-6-(2,7-dimethyl-2H-indazol-5-yl)-8-fluoroquinoline (25 mg, 0.077 mmol) was combined with the l-ieri-butoxycarbonylpiperidin-4-ylzinc iodide solution (0.25 mL, 0.25 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l, -biphenyl)(2'-amino- l,l'-biphenyl-2-yl) palladium(II) (4 mg, 0.005 mmol) and 1,4-dioxane (1 mL). The mixture was stirred at 80 C for 2 h. The mixture was cooled to room temperature. The mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-10% MeOH in EtOAc to yield tert-butyl 4-[6-(2,7-dimethylindazol-5-yl)-8-fluoro-2-quinolyl]piperidine-1-carboxylate (30 mg, 82%).
With chloro-trimethyl-silane; ethylene dibromide; In N,N-dimethyl acetamide; at 20 - 55℃;Inert atmosphere;
Zinc powder (2.11 g, 32.3 mmol) was suspended in dimethylacetamide (5.2 mL) at room temperature under argon. A mixture of 1,2-dibromoethane (260 muL, 3 mmol) and TMSCl (365 muL, 8.22 mmol) was added dropwise to the zinc suspension at such a rate as to keep the internal temperature below 45 oC. Once addition was complete, the reaction mixture was stirred for another 15 min, by which time the internal temperature dropped to 30 oC. A solution of <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (8.25 g, 26 mmol) in DMA (13 mL) was added to this mixture at such a rate that the internal temperature did not rise above 55 oC. Upon completion of the addition, the mixture was allowed to cool to ambient temperature. The mixture was filtered under an inert argon atmosphere through glass wool to yield 20 mL of ~ 1M of (1-(tert- butoxycarbonyl)piperidin-4-yl)zinc(II) iodide in DMA.
Zinc dust (6.38 g, 97.7 mmol) was suspended into tetrahydrofuran (10 mL), and 1,2-dibromoethane (0.55 mL, 6.43 mmol) was added. The slurry was heated to reflux with a heat gun 3 times. Upon cooling to ambient temperature, trimethylsilyl chloride (0.78 mL, 6.15 mmol) was added. After 15 min, the iodo compound of Part A (22.5 g, 72.3 mmol) was added. After 30 min, 2,5-dibromopyridine (17.1 g, 72.3 mmol) in N,N-dimethylacetamide(50 mL) was added, followed by tris(dibenzylideneacetone)dipalladium(0) (659 mg, 0.72 mmol) and tri-2-furylphosphine (671 mg, 2.90 mmol). The solution was then heated at 80 C. for 18 hr. Afterward, the solution was cooled to ambient temperature and filtered through Celite, rinsing with ethyl acetate and water. The filtrate was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. Concentration in vacuo produced tert-butyl 4-(5-bromopyridin-2-yl)piperidine-1-carboxylate as an orange oil (16.44 g, 67% yield). MS(CI) M-tBu calculated for C15H21N2O2Br: 286, found 286.
Part C: Zinc (0.34 g, 5.17 mmol) was suspended in THF (4 ml_) and 1 ,2-dibromoethane (0.029 ml_, 0.34 mmol) and trimethylsilylchloride (0.041 ml_, 0.032 mmol) were added and resulting mixture was stirred at 60 0C for 10 minutes. Compound 742 (1.1 g, 3.5 mmol) was added in DMA (5 ml_) and the resulting mixture was stirred at 600C for 5 minutes and then 20 minutes at room temperature. 2,5- Dibromopyridine (906 mg, 3.83 mmol), Pd(dppf)CI2 (130 mg), and CuI (30 mg) were added to the reaction and stirred for 2 hours at 80 0C. The reaction was quenched with water and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified using column chromatography (3:1 Hexanes/ethyl acetate) to provide compound 743 (300 mg). 1H NMR (400 MHz, CDCI3): delta 8.6 (m, 1 H), 7.8 (m, 1 H), 7.1 (m, 1 H), 4.25 (m, 2H), 3.0-2.9 (m, 2H), 1.9 (m, 2H), 1.7 (m, 3H), 1.5 (s, 9H).
Example 2; tert-Butyl 4-(6-((2-fluoro-4-(methylsulfonyl)phenoxy)methyl)pyridin-2- yl)piperidine- 1 -carboxylateStep 1: Methyl 6-(l-(fert-butoxycarbonyl)piperidin-4-yl)picolinate; 1, 2-Dibromoethane (0.15 niL) was added to a suspension of zinc powder (1.3 g) in anhydrous THF (10 rnL). The resulting suspension was heated at 65 0C for 5 minutes and then allowed to cool to room temperature. Trimethylsilyl chloride (0.2 mL) was added and the reaction was stirred at room temperature for 30 minutes. iV-tert-butoxycarbonyl-4-iodo- piperdine (4.5 g) in THF (10 mL) was added. The reaction mixture was stirred at 50 0C for 2 hours and cooled to room temperature. Meanwhile, a mixture of tri-2-furylphosine (0.2 g) and tris(dibenzylidendacetone)-dipalladium(0) (0.2 g) was dissolved in THF under a nitrogen atmosphere, stirred at room temperature for 30 minutes, and added to the organozinc solution. A solution of <strong>[6636-55-1]methyl 6-chloropicolinate</strong> (2.9 g) in THF was added. The reaction mixture was warmed to 80 0C and stirred for 4 hours and subsequently cooled to room temperature, filtered through a pad of celite. The filter cake was washed with ethyl acetate and the filtrate was washed with saturated NaHCCb, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silca gel (1 :1 hexanes/ethyl acetate) to afford the desired product. 1H NMR (CDCl3): delta 7.97 (IH, d), 7.78 (IH, t), 7.34 (IH, d), 4.26 (2H, br), 3.99 (3H, s), 3.04 (IH, m), 2.84 (2H, m), 1.95 (2H, m), 1.7 (2H, m), 1.47 (9H, s).
1,2-Dibromoethane (0.15 mL) was added to a suspension of zinc powder (1.3 g) in anhydrous THF (10 mL). The resulting suspension was heated at 65 C. for 5 minutes and then allowed to cool to room temperature. Trimethylsilyl chloride (0.2 mL) was added and the reaction was stirred at room temperature for 30 minutes. N-tert-butoxycarbonyl-4-iodo-piperidine (4.5 g) in THF (10 mL) was added. The reaction mixture was stirred at 50 C. for 2 hours and cooled to room temperature. Meanwhile, a mixture of tri-2-furylphosine (0.2 g) and tris(dibenzylidendacetone)-dipalladium(0) (0.2 g) was dissolved in THF under a nitrogen atmosphere, stirred at room temperature for 30 minutes, and added to the organozinc solution. A solution of <strong>[6636-55-1]methyl 6-chloropicolinate</strong> (2.9 g) in THF was added. The reaction mixture was warmed to 80 C. and stirred for 4 hours and subsequently cooled to room temperature, filtered through a pad of celite. The filter cake was washed with ethyl acetate and the filtrate was washed with saturated NaHCO3, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silca gel (1:1 hexanes/ethyl acetate) to afford the desired product. 1H NMR (CDCl3): delta 7.97 (1H, d), 7.78 (1H, t), 7.34 (1H, d), 4.26 (2H, br), 3.99 (3H, s), 3.04 (1H, m), 2.84 (2H, m), 1.95 (2H, m), 1.7 (2H, m), 1.47 (9H, s)
Example 7; tert-QvXy 4-(4-((2-fluoro-4-(lH-tetrazol-l-yl)phenoxy)methyl)pyrimidin-2- yl)piperidine- 1 -carboxylate; Step 1: Methyl 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)pyrimidine-4-carboxylate; To a slurry of Rieke zinc (0.252 g, 3.86 mmol) in THF (5 mL) was added tert-hvXy 4-iodopiperidine-l -carboxylate (1.06 g, 3.21 mmol). The suspension was stirred at 50 0C for 1.5 hours and then cooled to room temperature. Meanwhile, in a separate flask, a mixture of tri-2-furylphosine (0.060 g, 0.256 mmol) and tris (dibenzylidendacetone)- dipalladium(O) (0.066 g, 0.064 mmol) was stirred in THF under a nitrogen atmosphere for 30 minutes. The contents were subsequently added to the organozinc solution. Methyl 2- chloropyrimidine-4-carboxylate (0.72 g, 4.17 mmol) (see US PCT 2007/225271 Al ex. C4.1) in a solution of THF (5mL) and DMF (2 mL) was immediately added to the mixture. The solution was then stirred at 80 0C for 3.5 hours. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (1 : 1 hexanes/ethyl acetate) to afford the desired product. 1H NMR (CDCl3): delta 8.91 (IH, d), 7.80 (IH, d), 4.21 (2H, m), 4.01 (3H, s), 3.18 (IH, m), 2.87 (2H, m), 1.99 (2H, m), 1.84 (2H, m), 1.43 (9H, s).
To a slurry of Rieke zinc (0.252 g, 3.86 mmol) in THF (5 mL) was added tert-butyl 4-iodopiperidine-1-carboxylate (1.06 g, 3.21 mmol). The suspension was stirred at 50 C. for 1.5 hours and then cooled to room temperature. Meanwhile, in a separate flask, a mixture of tri-2-furylphosine (0.060 g, 0.256 mmol) and tris (dibenzylidendacetone)-dipalladium(0) (0.066 g, 0.064 mmol) was stirred in THF under a nitrogen atmosphere for 30 minutes. The contents were subsequently added to the organozinc solution. Methyl 2-chloropyrimidine-4-carboxylate (0.72 g, 4.17 mmol) (see US PCT 2007/225271 A1 ex. C4.1) in a solution of THF (5 mL) and DMF (2 mL) was immediately added to the mixture. The solution was then stirred at 80 C. for 3.5 hours. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (1:1 hexanes/ethyl acetate) to afford the desired product. 1H NMR (CDCl3): delta 8.91 (1H, d), 7.80 (1H, d), 4.21 (2H, m), 4.01 (3H, s), 3.18 (1H, m), 2.87 (2H, m), 1.99 (2H, m), 1.84 (2H, m), 1.43 (9H, s)
With chloro-trimethyl-silane; ethylene dibromide; zinc;copper(l) iodide; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ISOPROPYLAMIDE; at 20 - 60℃; for 15.75h;
Intermediate 301 , 1 -Dimethylethyl 4-(4-nitrophenvD- 1 -piperidinecarboxylateA solution of trimethylsilyl chloride (158 muL, 136 mg, 1.25 mmol) and 1,2- dibromoethane (108 muL, 235 mg, 1.25 mmol) in dry dimethyl acetamide (DMA) (5 mL) was added dropwise to a stirred suspension of Zn dust (652 mg, 9.97 mmol) in dry DMA at room temperature under N2, which caused a 10 0C exotherm. That mixture was stirred at room temperature under N2 for 15 minutes, then a solution of Intermediate 29 (2.345 g, 7.54 mmol) in dry DMA (5 mL) was added dropwise so as to maintain an internal <n="48"/>temperature below 35 0C, and stirring continued at room temperature for 30 min. Meanwhile, a suspension of <strong>[4487-59-6]2-bromo-5-nitropyridine</strong> (1.02 g, 5.04 mmol), Cl2Pd(dppf>CH2Cl2 (124 mg, 0.15 mmol), and CuI (62 mg, 0.32 mmol) in dry DMA (10 mL) was degassed with N2. The preformed alkylzinc reagent was transferred to a syringe and filtered through an acrodisc (that had been pre-rinsed with dry DMA) into the aryl bromide mixture, and the resulting dark mixture was stirred at 60 0C under N2 for 15 h, cooled to room temperature, and quenched with 1 M aq NH4Cl with stirring for 15 minutes. It was then made basic with sat. aq NaHCO3 and extracted with EtOAc (3x). The extracts were washed repeatedly with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a dark oil. Purification by flash chromatography on silica gel eluting with a gradient of 1 :1 hexanes: CH2Cl2 to 5:4:1 hexanes:CH2Cl2:CH3CN gave the title compound (ca. 90% pure) as an orange oil (540 mg, 35%). LC-MS (ES) m/z = 208 [M-C5H9O2+H]+.
In an oven-dried 25 mLround bottomed flask was charged dry DMA (1 mL), zinc dust (0.430 g, 6.58 mmol). The mixture was stirred at RT while the mixture of chlorotrimethylsilane (0.07 mL, 0.553 mmol) and 1 ,2-dibromoethane (0.05 mL, 0.580 mmol) was added slowly. The resulting slurry was aged for 15 min. A solution of n-boc-4-iodo- piperidine (1.65 g, 5.30 mmol) in DMA (2.6 mL) was added slowly to the above mixture. Zinc slurry reacted exothermically with the gradual addition of the iodide. After stirring for 30 min, the resulting milky solution was cooled to RT and used directly in the next step. [00403] In an oven-dried flask were charged 2-fluoro-3-iodopyrazine (0.829 g, 3.70 mmol), l,r-bis(diphenylphosphino)ferrocene]dichloride palladium(ii)complex with dichloramethane (0.091 g, 0.111 mmol), copper iodide (0.042 g, 0.222 mmol), and DMA (3 mL). The resulting mixture was degassed with alternating vacuum/nitrogen purges. The (l-(tert- butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (1.951 g, 5.18 mmol) solution from previous step was filtered into the mixture. It was degassed one more time and then heated to 80 0C with stirring for 16 h. After cooling to RT, the reaction mixture was treated with methyl bert- butylether (13 ml) and 1 N NH4Cl (13 ml). The organic layer was partitioned between EtOAc and 1 N NH4Cl and the aqueous layer was back extracted with EtOAc (2x). The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude material was chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine- 1-carboxylate as orange oil. MS (ESI, pos. ion) m/z: 226.0 (M-56).
The starting reagent terf-butyl 4-iodopiperidine-1-carboxylate (2.0 g, 6.3 mmol), as made according literature procedure (Billotte, S; Syn. Lett., 4, 1998; 379-380), was dissolved in anhydrous THF (3 mL) under nitrogen atmosphere. Rieke zinc (1.0 N, 8.4 mL, 6.4 mmol) was added to the reaction mixture and it was then warmed to 65 0C and stirred for 0.5 h. 6-Bromonicotinonitrile (1.0 g, 5.7 mmol), DIEA (1.0 mL, 6.3 mmol), dppf (0.14 g, 0.16 mmol) and copper iodide (0.064g, 0.32) were added to the reaction mixture and stirred for 18 h, After cooling to 25 0C, the mixture was filtered through Celite, diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (2 X 30 mL). The organic layer was dried over sodium sulfate and then purified by flash column chromatography through silica gel eluting with EPO <DP n="39"/>hexanes: ethyl acetate (1:1). The purified fractions were concentrated to afford title product as white solid (1.6 g, 96%). HPLC R1: 3.914 (86.4%); 1H NMR (400 MHz, CDCI3) delta ppm: 1.46 - 1.48 (m, 9 H), 1.69 - 1.75 (m, 2 H), 1.90 (d, J=12.88 Hz, 2 H), 2.84 (s, 1 H), 2.86 - 2.96 (m, 2 H), 4.27 (br. s., 2 H), 7.29 (d, J=8.08 Hz, 1 H), 7.90 (dd, J=8.21, 2.15 Hz, 1 H), 8.81 (d, J=1.77 Hz, 1 H).
(2) To a suspension of zinc powder (227 mg) in N,N-dimethylacetamide (3 mL) was added iodine (50 mg) and the mixture was stirred for 10 minutes. To the suspension was added dropwise a solution of tert-butyl 4-iodopiperidin-1-carboxylate (722 mg) in N,N-dimethylacetamide (3 mL) and the mixture was stirred at 80 C for 260 minutes. After cooling, to the reaction mixture was added tetrakis(triphenylphosphine) palladium(0) (100 mg), a solution of the compound obtained in the above step (1) (500 mg) in N,N-dimethylacetamide (3 mL) and 0.5M solution of zinc chloride in tetrahydrofuran (9.3 mL) at room temperature and the mixture was stirred at 90 C for 15 hours. After cooling, the reaction mixture was filtered through Cerite and to the filtrate was added water. The mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by a column chromatography on silica gel (Solvent; n-hexane/ethyl acetate = 5: 1) to give 6-chloro-1-(3-ethoxybenzyl)-4-(1-tert-butoxycarbonyl-4-piperidyl)-1H-pyrazolo[3,4-d] pyrimidine (594 mg, yield: 81 %) as a yellow oil. MS(APCI)m/z; 472/474 [M+H]+
4) Synthesis of 6-(2,5-dimethyl-pyrrol-1-yl)-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester 284 mg (4.34 mmol) of electrolytic zinc is placed in suspension, under an argon atmosphere, then 0.033 ml of 1,2-dibromoethane and 1 ml of tetrahydrofuran are added. The reaction medium is stirred for 3 minutes at 60 C. and is then left to return to ambient temperature. 0.047 ml of trimethylsilyl chloride is added followed by stirring for 30 minutes at ambient temperature. 1 g (3.2 mmol) of N-t.butoxycarbonyl-4-iodo-1-piperidine solubilized beforehand in 2 ml of tetrahydrofuran is added. This reaction mixture is stirred for 45 minutes at ambient temperature and a solution containing 30 mg (0.032 mmol) of tris(dibenzylideneacetone) dipalladium marketed by Aldrich and 30 mg (0.13 mmol) of tris (2-furyl)phosphine are added to it. Then 1 g (4 mmol) of 2-bromo-6 (2,5-dimethyl-pyrol-1-yl)-pyridine solubilized beforehand in 10 ml of tetrahydrofuran is added. The reaction mixture is left under magnetic stirring at 60 C. for 2 hours, then left to return to ambient temperature, filtered on Clarcel and extracted between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The aqueous phase is extracted twice with ethyl acetate, then the organic phases are collected and dried over magnesium sulphate. The ethyl acetate is evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silica gel eluding with a heptane/ethyl acetate mixture 4:1. 350 mg of expected product is recovered in the form of yellow oil. TLC: Rf=0.2 (silica gel, eluent:heptane/ethyl acetate 90:10). 1H-NMR (CDCl3): delta 1.50 (s, 9H, tBu); 1.78 and 1.97 (m, 4H, -C-CH2-N-CH2-C-); 2.18 (s, 6H, -CC=CH-CH=CC-); 2.85 and 2.95 (m, 3H, C-CH2-CH-N-CH-CH2-); 4.28 (m, 2H, -CH2-CH-N-CH-CH2-); 5.92 (s, 2H, -CH3C=C-C=CCH3-); 7.08 (d, 1H, H3 or H5); 7.16 (d, 1H, H3 or H5); 7.29 (t, 1H, H4).
2) Synthesis of N-t.butoxycarbonyl-4-iodo-1-piperidine 2.15 g of triphenylphosphine (8.2 mmole) and 2.08 g of iodine (8.2 mmole) are dissolved in 30 ml of acetonitrile. The reaction medium is left under stirring for 10 minutes at ambient temperature then 918 mg of imidazole (13.5 mmol) is added and stirring is maintained for another 10 minutes at ambient temperature. Then 1 g (5 mmol) of N-t.butoxycarbonyl-4-hydroxy-1-piperidine is added and stirring is maintained for 24 hours at ambient temperature. The reaction is treated by adding an aqueous solution of sodium thiosulphate and the acetonitrile is evaporated off under reduced pressure (2 kPa), followed by taking up in ethyl acetate, extracting and washing with an aqueous solution of sodium thiosulphate. The organic phases are dried over MgSO4, filtered and the ethyl acetate is evaporated off under reduced pressure (2 kPa), followed by chromatography on silica gel eluding with dichloromethane then dichloromethane/methanol 90:10. 1.1 g (Yield=70%) of colourless oil is recovered. TLC: Rf=0.8 (silica gel, eluent: CH2Cl2/MeOH 90:10 1H-NMR (CDCl3): delta 1.47 (s, 9H, tBu); 2.03 (m, 4H, -C-CHI-C2-); 3.30 and 3.60 (2m, 4H, -C-N-C-); 4.46 (m, 1H -CI-)
With C26H32Cl2FeN3O2; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;
General procedure: Alkyl halide (Method A: 0.5 mmol, Method B: 0.25 mmol) was dissolved in THF [3.0 mL (A)/1.5 mL (B)] and a stock solution (25 mM) of [Fe(Bopa-tBu)Cl2] (1d) [1.0 mL (A)/0.5 mL (B)] was added. Afterwards PhMgCl (1.00 M) [0.5 mL (A)/0.25 mL (B)] was added over a time period of 15 min. The solution was stirred for another 45 min. Method A: The reaction was then quenched with H2O (20 mL), acidified with aq 1 M HCl, and extracted with CH2Cl2 (3 × 20 mL). The crude extract was dried (Na2SO4) and further purified by chromatography on silica gel (eluent: 1% to 45% EtOAc in hexanes). Method B: The reaction was quenched by adding EtOH (0.5 mL). The reaction mixture was transferred on a preparative TLC plate and then further separated (eluent:EtOAc-hexanes).
Stage #1: N,N-diethyl-4-iodobenzamide With Bis<2-(N,N-dimethylamino)aethyl>aether; isopropylmagnesium chloride In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: tert-butyl 4-iodopiperidine-1-carboxylate With [((Me)NN2)NiCl] In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
A 100 mL 3 -neck round bottom flask fitted with a magnetic stirrer and flushed with nitrogen was charged with zinc dust (813 mg, preactivated according to the abovePreparation 1, 12.7 mmol, 2.0 eq.) and DMA (10 mL, anhydrous). 1, 2-dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was added slowly, followed by TMSCI (137 mg, 1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A solution of 4-iodo-piperidine-l-carboxylic acid tert- butyl ester (38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added dropwise. The suspension was stirred for 1 h at RT.[00254] A 100 mL 3 -neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dichloro-pyrazine (6) (0.95 g, 6.4 mmol, 1.0 eq), Pd(dppf)Cl2 (446 mg, 0.64 mmol, 0.1 eq), cuprous iodide (121 mg, 0.64 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark solution was degassed for 15 min. The clear zinc reagent solution above the residual solid zinc was transferred to the above 100 mL flask by cannulation. The dark solution was degassed and heated to 80C for 16 h. The reaction was diluted with brine and extracted with EtOAc (3 x 100 mL). The combined organics were washed with water (2 x 100 mL) and brine (100 mL), followed by drying over sodium sulfate. The solution was concentrated and the residue was purified by flash column chromatography on silica gel (PE: EAOAc = 2: 1) to give the title compound (39) (0.95 g, 3.2 mmol, 50% yield) as a light yellow solid.ESI-MS (M+l): 298 calc. for C14H20
47%
To a suspension of activated zinc dust (84.4 g, 1.29 mol, 1.94 eq.) in anhydrous DMA (270 mL) was added 1 ,2-dibromoethane (9.1 mL, 0.106 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (13.5 mL, 0.106 mol, 0.16 eq.) over a period of 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of tert-butyl 4-(3- chloropyrazin-2-yl)piperidine-l -carboxylate (329 g, 1.06 mol, 1.59 eq.) in anhydrous DMA (670 mL) was added to the above suspension over a period of 45 min keeping the internal temperature below 65 C. The resulting mixture was stirred for 1 h while cooling back to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2,3-dichloropyrazine (99 g, 0.664 mol, 1 eq.), PdCl2(dppf) CH2Cl2 (16.3 g, 19.9 mmol, 0.03 eq.) and Cul (7.8 g, 41.2 mmol, 0.062 eq.) in anhydrous DMA (670 mL) using a cannula. DMA (400 mL) was used to rinse the remaining zinc dust and added to the above mixture. The resulting mixture was heated to 80 C under nitrogen and stirred overnight (19 h). The mixture was cooled to room temperature and diluted with brine (1 L) and ethyl acetate (6 L). The aqueous phase was extracted with ethyl acetate (4 L) and organic extracts were combined, washed with brine (1 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate = 9:1 to 6: 1) to give 92 g tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-l-carboxylate. Yield: 47%.
To a suspension of activated zinc dust (84.4 g, 1.29 mol, 1.94 eq.) in anhydrous DMA (270 mL) was added 1,2-dibromoethane (9.1 mL, 0.106 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (13.5 mL, 0.106 mol, 0.16 eq.) over a period of 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of tert-butyl 4- iodopiperidine-l-carboxylate (329 g, 1.06 mol, 1.59 eq.) in anhydrous DMA (670 mL) was added to the above suspension over a period of 45 min keeping the internal temperature below 65 C. The resulting mixture was stirred for 1 hour while cooling back to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2,3-dichloropyrazine (99 g, 0.664 mol, 1 eq.),PdCl2(dppfyCH2Ci2 (16.3 g, 19.9 mmol, 0.03 eq.) and Cul (7.8 g, 41.2 mmol, 0.062 eq.) in anhydrous DMA (670 mL) using a cannula. DMA (400 mL) was used to rinse the remaining zinc dust and added to the above mixture. The resulting mixture was heated to 80 C under nitrogen and stirred overnight (19 hours). The mixture was cooled to room temperature and diluted with brine (1 L) and ethyl acetate (6 L). The aqueous phase was extracted with ethyl acetate (4 L) and organic extracts were combined, washed with brine (1 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate = 9: 1 to 6: 1) to give 92 g of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-l-carboxylate.
3-bromo-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: tert-butyl 4-iodopiperidine-1-carboxylate With chloro-trimethyl-silane; ethylene dibromide; zinc In dimethyl amine at 20℃; for 1h; Inert atmosphere;
Stage #2: 2,3-dibromopyridine With copper(l) iodide In dimethyl amine at 80℃; for 16h; Inert atmosphere;
32.1
A 100 mL 3 -neck round bottom flask fitted with a magnetic stirrer and flushed with nitrogen was charged with zinc dust (813 mg, preactivated according to the abovePreparation 1, 12.7 mmol, 2.0 eq.) and DMA (10 mL, anhydrous). 1, 2-dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was added slowly, followed by TMSCI (137 mg, 1.27 mmol, 0.2 eq). The reaction was stirred for 15 min at RT. A solution of 4-Iodo-piperidine-l -carboxylic acid tert- butyl ester (38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added dropwise. The suspension was stirred for 1 h at RT. [00318] A 100 mL 3 -neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dibromo-pyridine (1) (1.5 g, 6.4 mmol, 1.0 eq), PdCl2(dppf) (446 mg, 0.64 mmol, 0.1 eq), Cul (121 mg, 0.64 mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark solution was degassed for 15 min. The clear zinc reagent solution above the residual solid zinc was transferred to the above 100 mL flask by cannulation. The dark solution was degassed and heated to 80 °C for 16 h. The reaction was diluted with brine and extracted with EtOAc (3 x 100 mL). The combined organics were washed with water (2 x 100 mL) and brine (100 mL), followed by drying over sodium sulfate. The solution was concentrated and the residue was purified by flash column chromatography (PE: EtOAc = 2: 1) provides the title compound (101) (761 mg, 2.3 mmol, 35% yield) as a light yellow solid.ESI-MS (M+l): 341 calc. for Ci5H2iBr
With nickel(II) bromide dimethoxyethane; bathophenanthroline; potassium <i>tert</i>-butylate; iso-butanol In 1,4-dioxane at 60℃; for 15h; Inert atmosphere; Glovebox;
(4-(7-Fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalen-1-yl)-piperidine-1-carboxylic acid tert-butyl ester An oven-dried 3-neck 50 mL round-bottom flask equipped with a 100 mL addition funnel, a rubber septum, and an L-shape adapter was charged with zinc dust (1.31 g, 20.0 mmol) and lithium chloride (848 mg, 20.0 mmol) under nitrogen. The solids were stirred and the mixture was heated at 171 C. under high vacuum for 1.5 hours. The flask was cooled to room temperature, backfilled with nitrogen, and dry tetrahydrofuran (2.0 mL) was added to the grey mixture. The reaction flask was equipped with a thermometer. To the reaction mixture was added 1,2-dibromoethane (376 mg, 2.00 mmol) and the suspension was heated gently with heat gun to the point of gas evolution and foaming. Upon completion of the gas evolution, the mixture was allowed to cool to 50 C. and heated again. This process was repeated three times to make sure the zinc dust was activated completely. The activated zinc dust was treated with chlorotrimethylsilane (217 mg, 2.00 mmol) and the suspension was stirred for 15 minutes at room temperature. The resulting mixture was treated with a solution of <strong>[301673-14-3]4-iodopiperidine-1-carboxylic acid tert-butyl ester</strong> (3.112 g, 10.0 mmol) in tetrahydrofuran (5.0 mL) at room temperature. After the addition, the reaction mixture was heated with a heat gun to initiate the reaction and the temperature increased to 68 C. After cooling to 50 C., it was again heated to 60 C. (oil bath temperature) and stirred for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran (5 mL) and stirring was stopped to allow the excess zinc dust to settle over three hours. In a separate single-neck 50 mL round bottom flask, palladium(II) acetate (112 mg, 0.5 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos) (411 mg, 1 mmol) were combined with dry tetrahydrofuran (3 mL) at room temperature under nitrogen. After stirring for 10 minutes at room temperature, a solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 1.52 g, 4.00 mmol) was added to the light greenish-brown solution. After 2-3 minutes, the freshly prepared and clear organozinc compound in THF (described above) (?5.0 mmol) was added at room temperature. The resulting light greenish-brown solution was stirred at 65 C. for 15 hours under nitrogen. The reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution. The organic compound was extracted into ethyl acetate (3*50 mL) and the combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration and concentration gave the crude product which was purified by flash chromatography (150 g ISCO column, eluting with 0-50% ethyl acetate/hexanes) to give (4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalen-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 61%) as a light yellow solid. MS cald. for C24H31FNO4 [(M+H)+] 416, obsd. 416.2.
tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
Step 1 : tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-l-carboxylate Under a nitrogen atmosphere, zinc dust (4.06 g, 62.1 mmol) was suspended in N,N-dimethylacetamide (5 mL) and a mixture oftrimethylsilylchloride (0.946 mL, 7.30 mmol) and 1,2-dibromoethane (0.636 mL, 7.30 mmol) was added cautiously over 10 min. After stirring for a further 15 min, a solution ofN-(tert-butoxycarbonyl)-4-iodopiperidine (16.74 g, 51.11 mmol) in N,N-dimethylacetamide (20 mL) was added over 30 min and stirring was continued for an additional 30 min. In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide. The resulting yellow solution was injected into a separately prepared, nitrogen flushed suspension of [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.35 g, 1.83 mmol), copper(I) iodide (695 mg, 3.65 mmol) and <strong>[98027-84-0]2,6-dichloro-4-iodopyridine</strong> (10.0 g, 36.5 mmol) in N,N-dimethylacetamide (30 mL) and this mixture was stirred at 80 C for 16.5 fir. After cooling to rt, the mixture was diluted with EtOAc and water and partitioned. Filtration through Celite was necessary to break the emulsion, following which, the organics were washed with water and then dried over MgS04. After being freed of volatiles, the resultant residue was purified by flash column chromatography (100:0 - 70:30 heptanes/EtOAc) to afford tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-l-carboxylate as a white solid (7.49 g, 62%); 1H NMR (400 MHz, CDC13) delta 7.11 (s, 2H), 4.19 (m, 2H), 2.78 (m, 2H), 2.71 (m, 1H), 1.81 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H).
Compound 62.4. tert-Butyl 4-(lH-indazol-5-yl)piperidine-l-carboxylate. Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of Zn (990 mg, 15.1 mmol) in DMA (1 mL). A 7:5 v/v mixture of TMSCl/l ,2-dibromoethane (0.12 mL) was added drop-wise at a rate to maintain the temperature below 65 C, then the mixture was stirred for an additional 10 min. A solution of tert-butyl 4-iodopiperidine- l -carboxylate (3.17 g, 10.2 mmol) in DMA (2 mL) was added drop- wise and stirred at 40-45 C for 30 min. The resulting mixture was added to a mixture of 5-bromo-lH-indazole ( 1.00 g, 5.08 mmol), Cul (80 mg, 0.42 mmol) and Pd(dppf)Cl2 (260 mg, 0.36 mmol) in DMA (1 mL) in a 50-mL round-bottom flask under a nitrogen atmosphere. The resulting mixture was stirred overnight at 85 C, then cooled and diluted with ethyl acetate (50 mL) and washed with brine (3 x 20 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) as the eluent to yield the title compound as a yellow solid (200 mg, 12%).
12%
Compound 62.4. teri-Butyl 4-(lH-indazol-5-yl)piperidine-l-carboxylate. Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of Zn (990 mg, 15.1 mmol) in DMA (1 mL). A 7:5 v/v mixture of TMSCl/l,2-dibromoethane (0.12 mL) was added drop-wise at a rate to maintain the temperature below 65 C, then the mixture was stirred for an additional 10 min. A solution of tert-butyl 4-iodopiperidine-l-carboxylate (3.17 g, 10.2 mmol) in DMA (2 mL) was added drop-wise and stirred at 40-45 C for 30 min. The resulting mixture was added to a mixture of 5-bromo-lH-indazole (1.00 g, 5.08 mmol), Cul (80 mg, 0.42 mmol) and Pd(dppf)Ci2 (260 mg, 0.36 mmol) in DMA (1 mL) in a 50-mL round-bottom flask under a nitrogen atmosphere. The resulting mixture was stirred overnight at 85 C, then cooled and diluted with ethyl acetate (50 mL) and washed with brine (3 x 20 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) as the eluent to yield the title compound as a yellow solid (200 mg, 12%).
With silver carbonate; In n-heptane; at 150℃; for 1.16667h;Microwave irradiation;
2-Hydroxy-5-pyridinecarbaldehyde (123 mg, 1 mmol) and N-boc-4-iodopiperidine(622 mg, 2 mmol) were mixed in heptanes in a microwave vial and AgCO3 (331 mg,1.2 mmol) was added. The vial was capped and heated to 150C for 70 minutes. Thebatch was filtered and concentrated. Purification over silica (EtOAc/Heptanes 2:3)afforded the product aimed for (92 mg, 0.3 mmol, 30%).
4-(4-imidazol-1-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
STEP B: 4-(4-Imidazol-1-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl esterZn dust (5.30 g, 81.3 mmol) was suspended in DMA (35 ml) under nitrogen atmosphere and then treated with 1 ,2-dibromoethane (0.67 ml, 7.8 mmol). The mixture was briefly heated to 60-70C and allowed to cool to room 15 temperature (3 times). Chlorotrimethylsilane (0.66 ml, 5.2 mmol) was then added dropwise and the resulting mixture aged for 30 minutes. A solution of 4- iodo-piperidine-1 -carboxylic acid tert-butyl ester (20.2 g, 65 mmol) in DMA (35 ml) was then added slowly added at a rate to maintain a temperature <65C. The exothermic zinc insertion was allowed to cool to room temperature and20 stirring maintained for 1 hour, to yield a a0.92 M solution of (1-tert-butoxycarbonylpiperidin-4-yl)(iodo)zinc. A freshly prepared solution of <strong>[10040-96-7]1-(4-bromophenyl)-1H-imidazole</strong> (4.0 g, 17.9 mmol), copper(I) iodide (0.204 g, 1.07 mmol) and Pd(dppf)Cl2?CH2Cl2(0.441 g, 0.54 mmol) was then treated with 19 ml of the above solution (17.9 25 mmol) and mixture heated to 80C overnight. The reaction mixture wasallowed to cool to room temperature, diluted with ethyl acetate (100 ml) saturated aqueous NH4Cl, (100 ml), water (50 ml) and stirred for 20 minutes. The mixture was filtered through a pad of CELITE that was further washed with ethyl acetate (2 × 25 ml). The phases were separated, and aqueous layer 30 extracted once more with ethyl acetate (50 ml). The combined organic layer were washed with brine (2 × 100 ml), dried over MgSO4, filtered and concentrated to yield a residue. Purification of the residue over silica gel eluting with a gradient of MeOH in DCM from 0 to 5% yielded 4-(4-imidazol-1 - yl-phenyl)-piperidine-1 -carboxylic acid tert-butyl ester as beige solid.1H NMR (300 MHz, CDCl3) ppm 1.50 (s, 9 H), 1.56 - 1.71 (m, 2 H), 1.81 - 1.91 (m, 2 H), 2.67 - 2.89 (m, 3 H), 4.20 - 4.36 (m, 2 H), 7.31 (d, J=8.7 Hz, 1 H), 7.34 (br s, 4 H), 7.65 (d, J=8.7 Hz, 1 H). MS m/z 328 (M+H)+
(S)-N-tert-butoxycarbonyl-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
N-tert-butoxycarbonyl-4-bromopiperidine in Example 1 was replaced by an equimolar amount of N-t-butoxycarbonyl-4-iodopiperidine,The same operation as in Example 1 was followed except that the yield of the product was 84%. (S) - (4-chlorophenyl) (2-pyridyl) -methanol 21.9 g (0.1 mol) of the formula (II)Was dissolved in 160 mL of tetrahydrofuran,41 g (0.1 mol) of sodium hydride in a mass fraction of 60% was added portionwise with stirring,Stirring for 2 hours to no bubbles,The reaction was allowed to cool under ice-coolingA solution of 26.4 g (0.1 mol) of N-t-butoxycarbonyl-4-bromopiperidine was added dropwise,After completion of the dropwise addition, the reaction was gradually warmed to room temperature with stirring for 5 hours,The reaction solution was added to 200 mL of saturated ammonium chloride solution,Stirred for 30 minutes,The reaction solution was extracted twice with 300 mL of ethyl acetate,The organic phases were combined,Dried over anhydrous sodium sulfate for 2 hours,filter,The mother liquor was evaporated to dryness to give 34.3 g of product,The product was directly subjected to the next reaction without purification,Yield 85%.
tert-butyl 4-(3-(methoxycarbonyl)-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;
tert-Butyl 4-iodopiperidine-l-carboxylate (11.26g, 36.23 mmol) was slowly added to a stirred solution of methyl 4-nitro-lH-pyrazole-3-carboxylate (5g, 24.15 mmol) and K2C03 (9.99g, 72.46 mmol) in DMF (50mL) at 0 C. The reaction mass was stirred at room temperature for 18hr. Quenched the reaction with ice cold water (lOOmL) and ethyl acetate (25mL). The aqueous layer was separated and extracted with ethyl acetate (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The crude residue was purified by column chromatography by eluting with 10% ethyl acetate -hexane on silica gel to afford the desired title compound (Polar spot in TLC, 1.6g, 18.7%). ESI-MS: m/z = 255(M- Boc+H)+.
tert-butyl 4-(4-(methoxymethoxy)phenyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With iron(II) chloride; In tetrahydrofuran; at -20 - 25℃; for 16h;Inert atmosphere; Schlenk technique;
General procedure: A dry and argon-flushed 20 mL Schlenk tube, equipped with a stirring bar and a septum, was charged withanhydrous FeCl2 (25 mg, 0.20 mmol, 20 mol%). The alkyl halide (1 mmol, 1.0 equiv) and THF (1 mL) were addedand the mixture was cooled to -20 C. The di(hetero)arylmanganese reagent (0.7 mmol, 0.7 equiv) was addeddropwise and the mixture was allowed to warm to room temperature overnight. A sat. aq. solution of NH4Cl(5 mL) and EtOAc (5 mL) were added, the phases were separated and the aqueous phase was extracted withEtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solventswere evaporated. The residue was subjected to column chromatography purification (SiO2; i-hexane/EtOAc)yielding the corresponding title compound.
With 3,5-dihydroxyphenol; sodium nitrite; In dimethyl sulfoxide; at 45℃;Inert atmosphere;
Raw material 2 (1000 g, 2.67 mol), sodium nitrite (368 g, 5.33 mol) and phloroglucinol (538 g, 4.27 mol) were dissolved in DMS0 (4 L) in a reaction flask and then under nitrogen Stir at 45 C overnight. Products in petroleum ether:Ethyl acetate (volume ratio) = 5: 1, the rf value was about 0.3. After completion of the reaction, 20 L of water was added and stirred for 30 minutes. Then, the mixture was extracted with a mixed solvent of petroleum ether: ethyl acetate (v / v) = 5: 1, and whether or not the extraction was complete (with ninhydrin). The organic phase was washed with saturated NaCl, dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography to give 290 g of an oil product.
With 3,5-dihydroxyphenol; sodium nitrite; In dimethyl sulfoxide; at 45℃; for 16h;
To a stirred solution of tert-butyl 4-iodopiperidine-1 -carboxylate (A) ( 20 g, 64.308 mmol) in DMSO (100 mL) was added phloroglucinol (12.9 g, 102.89 mmol), followed by sodium nitrite (8.8 g, 128.6 mmol) at room temperature and stirred at 45C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (250 mL) and extracted with diethyl ether (3 x 100 mL), combined organic layers were washed with water (2 x 50 mL), brine solution (50 mL), dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to afford tert-butyl 4-nitropiperidine-1-carboxylate (B). TLC system: 50% EtOAc/Pet ether l: 0.45
tert-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
A 100-mL 3-necked round-bottom flask was charged with zinc powder (546 mg, 8.40 mmol, 2.00 equiv) and N, N-dimethylacetamide (40 mL) under nitrogen. 1,2-Dibromethane (158 mg, 0.840 mmol, 0.20 equiv) and chlorotrimethylsilane (91.6 mg, 0.840 mmol, 0.20 equiv) were added in sequence. The resulting solution was stirred for 15 mm at room temperature and then <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (1.96 g, 6.30 mmol, 1.50 equiv) was added. The resulting solution was stirred for 1 h at room temperature before the addition of 2-iodo-4- (trifluoromethyl)benzaldehyde (1260 mg, 4.20 mmol, 1.00 equiv), 1,1?- bis(diphenylphosphino)ferrocenepalladium (294 mg, 0.400 mmol, 0.10 equiv) and cuprous iodide (80.0 mg, 0.400 mmol, 0.10 equiv). The reaction mixture was stirred overnight at 80 C and quenched with water (20 mL). The mixture was extracted with dichloromethane (3 x 40 mL) and the organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 640 mg (43% yield) of tert-butyl 4-(2-formyl-5 -(trifluoromethyl)phenyl)piperi dine-i -carboxylate as yellow oil. LCMS (ESI, m/z): 358 [M+H].
43%
A flask was charged with zinc powder (546 mg, 8.40 mmol, 2.00 equiv) and N, N-dimethylacetamide (40 mL) under nitrogen. 1,2-Dibromoethane (158 mg, 0.840 mmol, 0.20 equiv) and chlorotrimethylsilane (91.6 mg, 0.840 mmol, 0.20 equiv) were then added in sequence. The resulting solution was stirred for 15 min at room temperature and then t-butyl 4-iodopiperidine-1-carboxylate (1960 mg, 6.30 mmol, 1.50 equiv) was added. The resulting solution was stirred for 1 h at room temperature. 2-Iodo-4-(trifluoromethyl)benzaldehyde (1260 mg, 4.20 mmol, 1.00 equiv), 1,1'-bis(diphenylphosphino)ferrocenepalladium (294 mg, 0.400 mmol, 0.10 equiv) and copper(I) iodide (80.0 mg, 0.400 mmol, 0.10 equiv) were then added. The resulting solution was stirred overnight at 80 C. and quenched with water (20 mL). The mixture was extracted with DCM (3*40 mL) and the organic layers were combined, washed with brine (3*10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to provide 640 mg (43% yield) t-butyl 4-(2-formyl-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 358 [M+H]+.
4-chloro-3-mercapto-N-(3,4,5-trifluorophenyl)benzamide[ No CAS ]
[ 301673-14-3 ]
C23H24ClF3N2O3S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
A stirred solution of the compound from Step 1c (128 mg, 0.41 mmol) and tertbutyl 4-iodopiperidine-1-carboxylate (252 mg, 0.81 mmol) in DMF (4.0 mL) was treated with K2CO3 (112 mg, 0.81 mmol) at rt overnight. It was diluted with EtOAc, washed with water and brine, dried over Na2SO4, concentrated. The crude was chromatographed (silica, EtOAc/hexanes) to give the desired compound (195 mg, 96%) as colorless oil, ESIMS m/z=499.11, 501.11 [M+H]+.
2,2-dimethyl-4-(pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-(2,2-dimethyl-4-(pyridin-2-yl)tetrahydro-2H-pyran-4 yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
To a solution of the product obtained in step a (0.4 g, 1.85 mmol) in dry THF (18.5mL), cooled at -40 00, lithium naphthalenide solution (11.1 mL, 0.5 M in THE, 5.55mmol; prepared as described in Tetrahedron Lett. 1997, 38, 2253) was added dropwise under an argon atmosphere and it was stirred at -40 C for 40 mm. A solution of <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (2.3 g, 7.4 mmol) in dry THE (5 mL) was added at -40 C and the mixture was further stirred at -40 C for 1 h and thenat rt overnight. NH4CI sat aqueous solution was added and it was extracted 3 times with DCM. The organic phases were combined, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:9) and then further purified by flash chromatography, C18, gradient aqueous NH4HCO3 (pH 8) to acetonitrile to give thetitle compound (190 mg, 27% yield). HPLC retention time (method A): 4.57 mm; MS: 375.2 (M+H).
With iron(II) chloride; In tetrahydrofuran; at -20 - 25℃; for 16h;Inert atmosphere; Schlenk technique;
General procedure: A dry and argon-flushed 20 mL Schlenk tube, equipped with a stirring bar and a septum, was charged withanhydrous FeCl2 (25 mg, 0.20 mmol, 20 mol%). The alkyl halide (1 mmol, 1.0 equiv) and THF (1 mL) were addedand the mixture was cooled to -20 C. The di(hetero)arylmanganese reagent (0.7 mmol, 0.7 equiv) was addeddropwise and the mixture was allowed to warm to room temperature overnight. A sat. aq. solution of NH4Cl(5 mL) and EtOAc (5 mL) were added, the phases were separated and the aqueous phase was extracted withEtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solventswere evaporated. The residue was subjected to column chromatography purification (SiO2; i-hexane/EtOAc)yielding the corresponding title compound.
With 2,6-dimethylpyridine; deuteromethanol; bismuth(III) oxide; para-thiocresol; for 8h;Irradiation;
General procedure: Iodide compound 3 (30 mg), bismuth trioxide (0.4 mg, 1 mol%), p-methylthiophenol (55.2 mg, 5 equiv) were weighed into a 10 mL reaction flask.Then, acetonitrile (1.5 ml), heavy water (1.5 ml) and 2,6-lutidine (51.3 muL, 5 equiv) were added in sequence, and the reaction was carried out under a light of 1 W blue LED, and the reaction was terminated after the consumption of the iodo compound 3 was completed. .The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate.The crude product was concentrated to give a compound 3a (18.1 mg).It was a white solid with a yield of 96% and a deuteration rate of 98%.
With potassium carbonate; In N,N-dimethyl-formamide; for 24h;Reflux;
A mixture of 3-methyl-4-nitro-lH-pyrazole (1.36 g, 10.71 mmol), tert-butyl-4- iodopiperidine-l-carboxylate (10.00 g, 32.14 mmol) and K2CO3 (2.96 g, 21.42 mmol) in DMF (16.6 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over MgS04, filtered and was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH 40 muiotaeta, 80 g, mobile phase: heptane/DCM, gradient from 50:50 to 0: 100). The pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 349 and intermediate 349' (540.00 mg, 16% yield).
4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
4-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of 3-methyl-4-nitro-lH-pyrazole (1.36 g, 10.71 mmol), tert-butyl-4- iodopiperidine-l-carboxylate (10.00 g, 32.14 mmol) and K2CO3 (2.96 g, 21.42 mmol) in DMF (16.6 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over MgS04, filtered and was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH 40 muiotaeta, 80 g, mobile phase: heptane/DCM, gradient from 50:50 to 0: 100). The pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 349 and intermediate 349' (540.00 mg, 16% yield). intermediate 350 intermediate 350' At 0C, HC1 (4M in dioxane) (15.00 mL, 60.00 mmol) was added to a solution of a mixture of intermediates 349 and 349' (0.54 g, 1.74 mmol) in 1,4-dioxane (4 mL). The reaction was stirred at rt overnight. The solvent was evaporated until dryness. The residue was taken up into DCM and basified with a 10% aqueous solution of K2C03. The organic layer was dried over MgS04, filtered and the solvent was evaporated until dryness. The residue (817 mg) was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 muiotaeta, 40 g, mobile phase: 98% DCM, 2% MeOH (+ 10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 0.480 g of a mixture of intermediates 350 and 350' used as it for the next step.
1-methyl-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
1-methyl-4-(5-methyl-4-nitro-1H-pyrazol-1-yl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%; 36%
A mixture of 3-methyl-4-nitro-lH-pyrazole (1.36 g, 10.71 mmol), tert-butyl-4- iodopiperidine-l-carboxylate (10.00 g, 32.14 mmol) and K2CO3 (2.96 g, 21.42 mmol) in DMF (16.6 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, dried over MgS04, filtered and was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (irregular SiOH 40 muiotaeta, 80 g, mobile phase: heptane/DCM, gradient from 50:50 to 0: 100). The pure fractions were combined and the solvent was evaporated to give a mixture of intermediate 349 and intermediate 349' (540.00 mg, 16% yield). intermediate 350 intermediate 350' At 0C, HC1 (4M in dioxane) (15.00 mL, 60.00 mmol) was added to a solution of a mixture of intermediates 349 and 349' (0.54 g, 1.74 mmol) in 1,4-dioxane (4 mL). The reaction was stirred at rt overnight. The solvent was evaporated until dryness. The residue was taken up into DCM and basified with a 10% aqueous solution of K2C03. The organic layer was dried over MgS04, filtered and the solvent was evaporated until dryness. The residue (817 mg) was purified by column chromatography on silica gel (stationary phase: irregular SiOH, 15-40 muiotaeta, 40 g, mobile phase: 98% DCM, 2% MeOH (+ 10% NH4OH) to 95% DCM, 5% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 0.480 g of a mixture of intermediates 350 and 350' used as it for the next step. A mixture of intermediates 350 and 350' (0.48 g, 2.28 mmol), formaldehyde (0.21 mL, 2.80 mmol) in MeOH (2.70 mL) and AcOH (0.32 mL, 5.59 mmol) was stirred for 10 min. Then, sodium cyanoborohydride (0.17 g, 2.75 mmol) was added. The reaction was stirred at rt over the weekend. DCM and a 10% solution of K2CO3 were added. The organic layer was washed with water, dried over MgS04, filtered and evaporated. The residue (538 mg) was purified by achiral SFC (Stationary phase: CHIRALPAK IC 5 muetaiota 250 x 20 mm, mobile phase: 75% CO2, 25% MeOH). The pure fractions were collected and the solvent was evaporated until dryness to give: 248 mg of intermediate 351 (49% yield) and 184 mg of intermediate 351 ' (36% yield).
With bismuth(III) oxide; N-ethyl-N,N-diisopropylamine; para-thiocresol; In dichloromethane; for 4h;Irradiation;
General procedure: Iodide compound 4 (18 mg),Bismuth oxide (0.1mg, 1mol%),P-methylthiophenol (10 mg, 5 equiv) was weighed into a 5 mL reaction flask.Then add dichloromethane (0.17ml)And N,N-diisopropylethylamine (15 muL, 5 equiv),The reaction was carried out under the illumination of 1W blue LED light.The reaction was terminated after the consumption of the iodo compound 4 (0.5 h).The reaction solvent and the volatile matter were removed by rotary distillation, and purified by column chromatography to give Compound 4a (15.6 mg).
5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
A solution of 5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.67 mmol, 1.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (629 mg, 2.02 mmol, 3.00 equiv) and potassium carbonate (279 mg, 2.02 mmol, 3.00 equiv) in DMF (5 mL) was stirred for 12 h at 80 C., and then the resulting solution was diluted with 50 mL of H2O, extracted with 3*50 mL of EtOAc and the organic layers combined, washed with 1*50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (3:1) to give 153 mg (36%) of the title compound as yellow oil. LCMS (ESI, m/z): 629.27 [M+H]+.
5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With silver carbonate; In d7-N,N-dimethylformamide; at 80℃; for 4h;
A solution of 5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (500 mg, 1.17 mmol, 1.00 equiv), Ag2CO3 (640 mg, 2.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (1 g, 3.21 mmol, 3.00 equiv) in DMF (15 mL) was stirred for 4 h at 80 C. The resulting solution was diluted with 15 mL of water and extracted with 3*15 mL of EtOAc, the organic layers combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1/4) to afford 500 mg (73%) of the title compound as yellow oil. LCMS (ESI, m/z): 612.28 [M+H]+.
53%
With silver carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
A solution of 5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.47 mmol, 1.00 equiv), Ag2CO3 (247 mg, 2.00 equiv), and <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (416 mg, 1.34 mmol, 3.00 equiv) in DMF (15 mL) was stirred for 4 h at 80 C. The resulting solution was extracted with 3*10 mL of EtOAc and the organic layers combined. After concentration, the residue was applied onto a silica gel column with EtOAc/petroleum ether (1:9) to afford 150 mg (53%) of title compound as a yellow oil. LCMS: [M+H]+ 612.30.
5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With silver carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
A solution of 5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (250 mg, 0.58 mmol, 1.00 equiv), Ag2CO3 (322 mg, 2.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (545 mg, 1.75 mmol, 3.00 equiv) in DMF (15 mL) was stirred for 4 h at 80 C. The resulting solution was diluted with 15 mL of water and extracted with 3*15 mL of EtOAc, the organic layers combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM/methanol (19/1) to afford 240 mg (67%) of the title compound as a yellow solid. LCMS (ESI, m/z): 612.28 [M+H]+.
5-[6-hydroxy-1H, 2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With silver carbonate; In N,N-dimethyl-formamide; at 80℃; for 10h;
A solution of 5-[6-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (870 mg, 2.03 mmol, 1.00 equiv), Ag2CO3 (1.13 g, 2.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (1.27 g, 4.08 mmol, 2.00 equiv) in DMF (25 mL) was stirred for 10h at 80 C. The resulting solution was diluted with 20 mL of water and extracted with 3*100 ml of EtOAc. The organic layers combined, washed with 3*100 mL of brine, dried over Na2SO4. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (3/7) to afford 1.21 g (97%) of the title compound as yellow oil. LCMS (ESI, m/z): 612.28 [M+H].
5-[4-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With silver carbonate; In N,N-dimethyl-formamide; at 80℃; for 48h;
A solution of 5-[4-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (115 mg, 0.27 mmol, 1.00 equiv), Ag2CO3 (149 mg, 0.54 mmol, 20.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (168 mg, 0.54 mmol, 2.00 equiv) in DMF (10 mL) was stirred for 48 h at 80 C. The resulting solution was diluted with 20 mL of water and extracted with 3*20 ml of EtOAc. The organic layers combined, washed with 3*40 mL of brine, dried over Na2SO4. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1/1) to afford 146 mg (89%) of the title compound as yellow oil. LCMS (ESI, m/z): 612.28 [M+H].
5-(4-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 72h;
A solution of 5-(4-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.1 g, 2.57 mmol, 1.00 equiv), potassium carbonate (1.8 g, 13.02 mmol, 5.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (4.0 g, 12.86 mmol, 5.00 equiv) in DMF (30 mL) was stirred for 3 days at 80 C. in an oil bath. After concentration, the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1:3) to afford 1.3 g (83%) of the title compound as a yellow solid. LCMS (ESI, m/z): 611.28 [M+H]+.
5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one[ No CAS ]
[ 301673-14-3 ]
tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 48h;
A solution of 5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (4.5 g, 10.53 mmol, 1.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (20 g, 64.28 mmol, 8.00 equiv), potassium carbonate (15 g, 108.53 mmol, 10.00 equiv), and DMF (50 mL) was stirred for 2 days at 80 C. The resulting solution was extracted with 2*200 mL of EtOAc and the organic layers combined and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with EtOAc/petroleum ether to afford the title compound (2 g, 31%) as a yellow oil. LCMS: [M+H]+ 611.15.
31%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
A solution of 5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (4.5 g, 10.53 mmol, 1.00 equiv), <strong>[301673-14-3]tert-butyl 4-iodopiperidine-1-carboxylate</strong> (20 g, 64.28 mmol, 8.00 equiv), potassium carbonate (15 g, 108.53 mmol, 10.00 equiv), and DMF (50 mL) was stirred for 2 days at 80 C. The resulting solution was extracted with 2*200 mL of ethyl acetate and the organic layers combined and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether to afford the title compound (2 g, 31%) as a yellow oil. LCMS: [M+H]+ 611.15.
6-bromo-2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one[ No CAS ]
[ 301673-14-3 ]
4-(4-oxo-2-thieno[2,3-c]pyridin-5-yl-3,4-dihydro-quinazolin-6-yl)piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Under inert atmosphere, at 0 C, to a suspension of zinc dust (126 mg, 8.24 mmol) in dry DMA (0.7 ml.) were added trimethylsilylchloride (28 mI_, 0.22 mmol) and 1 ,2-dibromoethane (20 mI_, 0.23 mmol) successively. The resulting slurry was stirred at room temperature for 15 minutes before addition of a solution of tert-butyl-4- iodopiperidine-1-carboxylate (770 mg, 2.47 mmol) in dry DMA (2.1 ml_). The reaction mixture was stirred at room temperature for 30 minutes. Then, a solution of 6-bromo- 2-thieno[2,3-c]pyridin-5-yl-3H-quinazolin-4-one (350 mg, 0.98 mmol) in dry DMA (9.0 mL), copper iodide (19 mg, 0.10 mmol) and Pd-PEPPSI-IPentCI-o-pinacoline (41 mg, 0.05 mmol) were added to the reaction mixture, which was then heated at 80 C for 16 h. The reaction mixture was poured into cold water (50 mL) and the resulting grey precipitate was collected by filtration. Purification by column chromatography on silica gel, using hexane / ethyl acetate as eluent, afforded 4-(4-oxo-2-thieno[2,3-c]pyridin-5- yl-3,4-dihydro-quinazolin-6-yl)-piperidine-1 -carboxylic acid tert-butyl ester 55 (350 mg, 77%) as a white solid. (1046) (1047) M/Z (M+H)+ = 463.0.
With dipotassium hydrogenphosphate; C4H8N2O2*Co(3+)*C4H7N2O2(1-)*2Cl(1-); triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; Irradiation; chemoselective reaction;
tert-butyl 4-(2-(2-oxo-2-(quinolin-8-ylamino)ethyl)hexyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With nickel(II) iodide; manganese; In N,N-dimethyl-formamide; at 50℃; for 18h;Inert atmosphere; Glovebox;
General procedure: In a N2-filled glovebox, to an oven-dried 5 mL vial equipped with a magnetic stir bar wereadded alkene substrate (0.1 mmol), aryl iodide (0.15 mmol), alkyl iodide or bromide (ifsolid, added at this time) (0.2 mmol), NiI2 (0.01 mmol) and Mn powder (0.25 mmol). Themixture was then dissolved in 0.3 mL dry DMF. The vial was tightly capped and removedfrom the glovebox. The alkyl iodide or bromide (if liquid, added at this time) was addedby a micro-syringe. The mixture was allowed to vigorously stir at 40 oC for 18 h (unlessotherwise stated). After 18 h, the alkene was almost fully consumed (monitored by GCMS).The mixture was directly subjected to flash silica gel column chromatography to afford thepure product
NaH (1 g; 41.7 mmol) was added to a solution of methyl 1 //~l ,2,4-triazole-3- carboxylate (Sigma-Aldrich, US) (2.8 g; 22 mmol) in DMF (130 mi.). The reaction mixture was stirred at 25C for 20 min followed by 1 h at 70 C. fe/ -butyi 4-iodopiperidme-l- carboxylate (Alfa Aesar, US) (6 g, 19.3 mmol) was added and the reaction mixture was heated at 70 C for 48 h. The solution was cooled to 0C and the insoluble material was removed by filtration. The filtrate was diluted with DCM and washed with water, brine, dried over Na2S04, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (mobile phase: petroleum ether/ethyl acetate 1 /5) to render 1.5 g of intermediate 14. (0183) Yield 25%. (0184) 1H-NMR (400 MHz, CDCb) d (ppm): 7.98 (d, J= 0.6 Hz, 1H), 5.32 (s, 1H), 4.24 (t, J= 16.7 Hz, 2H), 4.01 (s, 3H), 2.91 (s, 2H), 2.
25%
NaOH (1.0 g; 41.7 mmol) was added to a solution of methyl l//~i,2,4~triazole-3-carboxylate [Sigma-Aldrich, US] (2.8 g: 22 mmol) in M (130 mL). The reaction mixturewas stirred at 25 C for 20 minutes followed by at 70 C, /erf-butyl 4-iodopiperidine-l -carboxylate [Alfa Aesar, US] ( g, 9.3 mmol) was added and the reaction mixture was heatedat 70 C for 48 h . The solution was cooled to 0 C and the insoluble material was removed byfiltration. The filtrate was diluted w th DCM and washed with water and brine. The organicextract was dried over Na2S0 4, filtered and evaporated to dryness. The residue was purified bychromatography over silica gel (mobile phase: petroleum ether/ethyl acetate 1:5) to render .5g of intermediate 4 . Yield 25%. -NMR (400 MHz, CDCb) d (ppm): 7.98 (d, J =0.6 Hz, 1H), 5.32 (s, 1H), 4.24 (t, J = 16.7Hz, 2H), 4.01 (s, 3H), 2.91 (s, 2H), 2 .
tert-butyl 4-(((3s,5s,7s)-adamantan-1-yl)carbamoyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: 1-adamantyl isocyanide; tert-butyl 4-iodopiperidine-1-carboxylate With bis(1,5-cyclooctadiene)nickel (0); water; 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium chloride; sodium t-butanolate In <i>tert</i>-butyl alcohol at 100℃; for 12h; Inert atmosphere;
Stage #2: With hydrogenchloride In <i>tert</i>-butyl alcohol at 20℃; for 0.0833333h; Inert atmosphere;
With 2,2':6,2''-terpyridine; copper(II) bis(trifluoromethanesulfonate); (2,4,6-trimethylphenyl)diazonium tetrafluoronorate In dimethyl sulfoxide at 20℃; for 0.75h; Inert atmosphere; Sealed tube; Schlenk technique;
With tetrakis(actonitrile)copper(I) hexafluorophosphate; tributyl-amine; trimethylsilyl(cumyl) peroxide; N,N,N′,N′-tetramethyl-N″-tert-butylguanidine In acetonitrile; <i>tert</i>-butyl alcohol at 20℃; for 1h; Sealed tube; Inert atmosphere;
General procedure for the amination of alkyl iodides.
General procedure: An oven-dry tube equipped with a stirring bar was charged with the alkyl iodide (0.20 mmol, 1.0 equiv.), the N-nucleophile (0.30 mmol, 1.5 equiv.) and [Cu(MeCN)4]PF6 (7.5 mg, 0.020 mmol, 10 mol%). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl) and evacuated and refilled with N2 (three times). Dry and degassed CH3CN (1.0 ml), t-BuOH (1.0 ml), (n-Bu)3N (238 μl, 1.0 mmol, 5.0 equiv.), BTMG (80 μl, 0.40 mmol, 2.0 equiv.) were sequentially added. The resulting solution was treated with cumOOTMS (224 mg, 238 μl, 1.00 mmol, 5.0 equiv.) dropwise under vigorous stirring. After 1 h the tube was opened and the mixture diluted with brine (2 ml) and EtOAc (2 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 ml × 2). The combined organic layers were dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography on silica gel.
With tributyl-amine; trimethylsilyl(cumyl) peroxide; N,N,N′,N′-tetramethyl-N″-tert-butylguanidine; copper(l) chloride In acetonitrile; <i>tert</i>-butyl alcohol at 0℃; for 1h; Sealed tube; Inert atmosphere;
General procedure for the amination of alkyl iodides.
General procedure: An oven-dry tube equipped with a stirring bar was charged with the alkyl iodide (0.20 mmol, 1.0 equiv.), the N-nucleophile (0.30 mmol, 1.5 equiv.) and [Cu(MeCN)4]PF6 (7.5 mg, 0.020 mmol, 10 mol%). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl) and evacuated and refilled with N2 (three times). Dry and degassed CH3CN (1.0 ml), t-BuOH (1.0 ml), (n-Bu)3N (238 μl, 1.0 mmol, 5.0 equiv.), BTMG (80 μl, 0.40 mmol, 2.0 equiv.) were sequentially added. The resulting solution was treated with cumOOTMS (224 mg, 238 μl, 1.00 mmol, 5.0 equiv.) dropwise under vigorous stirring. After 1 h the tube was opened and the mixture diluted with brine (2 ml) and EtOAc (2 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 ml × 2). The combined organic layers were dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography on silica gel.
With copper(l) iodide; tributyl-amine; trimethylsilyl(cumyl) peroxide; N,N,N′,N′-tetramethyl-N″-tert-butylguanidine In acetonitrile; <i>tert</i>-butyl alcohol at 20℃; for 1h; Sealed tube; Inert atmosphere; chemoselective reaction;
General procedure for the amination of alkyl iodides.
General procedure: An oven-dry tube equipped with a stirring bar was charged with the alkyl iodide (0.20 mmol, 1.0 equiv.), the N-nucleophile (0.30 mmol, 1.5 equiv.) and [Cu(MeCN)4]PF6 (7.5 mg, 0.020 mmol, 10 mol%). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl) and evacuated and refilled with N2 (three times). Dry and degassed CH3CN (1.0 ml), t-BuOH (1.0 ml), (n-Bu)3N (238 μl, 1.0 mmol, 5.0 equiv.), BTMG (80 μl, 0.40 mmol, 2.0 equiv.) were sequentially added. The resulting solution was treated with cumOOTMS (224 mg, 238 μl, 1.00 mmol, 5.0 equiv.) dropwise under vigorous stirring. After 1 h the tube was opened and the mixture diluted with brine (2 ml) and EtOAc (2 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 ml × 2). The combined organic layers were dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography on silica gel.
tert-butyl 4-(4-(morpholinosulfonyl)phenyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With tributyl-amine; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; NiBr2.(4,4′-ditert-butyl-2,2′-bipyridyl) In 1,4-dioxane at 32℃; for 40h; Inert atmosphere; Sealed tube; Irradiation;
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