* 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.
Part A:A mixture of 4-(4-bromophenyl)pipeτidine (1 ) (960 mg, 4.0 mmol) and di-tert-bulyl dicarbonate (960 mg, 4.4 mmol) at 0 "C in DCM ( 10 mL) was warmed to room temperature and stirred for 3 hours. LC-MS analysis indicated the reaction was complete.Dichloromethane (10 mL) was added and the solution washed with IN HCl (10 mL). Drying over magnesium sulfate, concentration and purification by flash column chromatography, gradient elution (0 to 100 percent) hexane / ethyl acetate, afforded compound 2 as a white solid ( 1.36 g, 100 percent yield). HPLC-MS tR = 2.50 min (UV2* nm), mass calculated for formulaC1^BrNO2 339.1 , observed LCMS m/z 284.1 (M+H-lBu).
100%
at 0 - 20℃;
Example 8: Example 8A; Part A:A mixture of 4-(4-bromophenyl)piperidine (37) (960 rng, 4.0 mmol) and di-ferf-buty. dicarbonate (960 mg, 4.4 mmol) at 0 0C in DCM (10 mL) was warmed to room temperature and stirred for 3 hours. LC-MS analysis indicated the reaction was complete. Dichloromethane (10 mL) was added and the solution washed with 1 I/ HCI (10 mL). Drying over magnesium sulfate, concentration and purification by flash column chromatography, gradient elution (0 to 100 percent) hexane / ethyl acetate, afforded compound 38 as a white solid (1.36 g, 100 percent yield). HPLC-MS tR - 2,50 min (UV254nm); mass calculated for formula Ci6H22BrNO2 339.1 , observed LCMS m/z 284.1 (M+H-'Bu).
96%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;
Atambient temperature, a suspension of 4-(4-bromophenyl)piperidine (1000 mg, 4.164 mmol) in DCM (20 mL) was treated with DIEA (1451 tL, 8.328 mmol) followed by Boc-anhydride (1064 tL, 4.58 1 mmol), and then stirred overnight. The reaction mixture was subsequently diluted with water (50 mL) and then extracted with DCM (3 x 50 mL). The combined organic extracts were dried (Mg504), filtered and concentrated in vacuo to afford the title compound (1363 mg, 96percent yield). ‘HNMR (CDC13) 7.42 (m, 2H), 7.07 (m, 2H), 4.24 (m, 2H), 2.79 (dt, 2H), 2.61 (tt, 1H), 1.79 (m, 2H), 1.58 (qd, 2H), 1.48 (s, 9H).
95%
With dmap; triethylamine In acetonitrile at 20℃; for 3 h;
To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine(2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours.Then water (20 mL) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 percent yield).
95%
With dmap; triethylamine In acetonitrile at 20℃; for 3 h;
To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine (2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- <n="190"/>tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 ml_) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 percent yield).
95%
With triethylamine In acetonitrile at 20℃; for 3 h;
To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine (2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 ml.) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 percent yield).
4.6 g
at 20℃; for 2 h;
A solution of 4-(4-bromophenyl)piperidine (2.7 g, 11.25 mmol) and di-tert-butyl dicarbonate (2.5 g, 11.47 mmol) in 20 mL of DCM was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to give 4.6 g of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate.
4-(4-Bromophenyl)piperidine HC1 (1 g, 3.7 mmol)in DCM (6 mE) was treated with K2C03 (1.3 g, 9 mmol, 2.5eq.) and 13oc20 (1.35 g, 6 mmol, 1.6 eq). The mixture wasdiluted with water, extracted with MTBE, washed with brine,dried on Na2504, and concentrated. Chromatographysilica gel (2—8percent EtOAc/hexanes) gave 1 -l3oc-4-(4-bro-mophenyl)piperidine (944 mg, 76percent)._This bromide was con-verted via Method 3 to 1 -l3oc-4-(4-boronophenyl)piperidinepinacol ester (1.16 g, quant.).
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 33, p. 9676 - 9679[2] Angew. Chem., 2016, vol. 128, # 33, p. 9828 - 9831,4
6
[ 1510865-53-8 ]
[ 5467-74-3 ]
[ 769944-78-7 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 1, p. 328 - 338
7
[ 84358-13-4 ]
[ 769944-78-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 33, p. 9676 - 9679[2] Angew. Chem., 2016, vol. 128, # 33, p. 9828 - 9831,4
8
[ 769944-78-7 ]
[ 769944-79-8 ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogenchloride In ethyl acetate at 20℃; for 5 h;
To A solution of furnished 4- (4-bromophenyl)-piperidine-l-carboxylic acid TERT-BUTYL ESTER (1114 mg, 3. 27 MMOL) IN ETHYL ACETATE (1 ML) WAS ADDED 4 N hydrogen chloride in ethyl acetate (2 mL) at room temperature. After stirring for 5 h, solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and dried in vacuo to afford (4- (4-BROMOPHENYL)-PIPERIDINE hydrochloride (884 mg, 98percent) as a white solid.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; Inert atmosphere; Sealed tube
In a pressure tube a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (1363 mg, 4.006 mmol) in dioxane was treated with bis(pinacolato)diboron (1526 mg, 6.009 mmol), KOAc (1179 mg, 12.02 mmol), and PdC12(dppf).DCM (327.1 mg, 0.4006 mmol). The mixture was sparged with nitrogen for 1 mm and then sealed and heated at 100 °C overnight. After cooling to ambient temperature, the reaction mixture was diluted with a mixture of EtOAc (75 mL)/water (50 mL)/ brine (25 mL), and the resulting emulsion was filtered through Celite® and rinsed with EtOAc. The biphasic filtrate was separated and the organic phase was washed with brine and then dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (0-50percent EtOAc/hexanes) to afford the title compound (1437 mg, 93percent yield). ‘H NMR (CDC13) 7.76 (d, 2H), 7.22 (m, 2H), 4.24 (d, 2H), 2.79 (dt, 2H), 2.65 (tt, 1H), 1.81 (m, 2H), 1.63 (dq, 2H), 1.48 (s, 9H), 1.33 (s, 12H).
86%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane at 80℃; Inert atmosphere
A mixture of tert-butyl 4- (4-bromophenyl) piperidine-1-carboxylate (510 mg, 1.499 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (761 mg, 3 mmol) and KOAc (441 mg, 4.5 mmol) in DME (20 ml) was degassed with N2 and PdCl2 (dppf) -CH2Cl2 (122 mg, 0.15 mmol) was added. The resulting mixture was degassed with N2 again and was heated to 80 overnight. After cooling to rt, the mixture was added with 10mL of NH4Cl (aq) , and extracted with EtOAc (20mL × 2) . The combined organic phase was washed with brine (20mL) , dried over Na2SO4 (anhydrous) , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EA/Hexane 0: 100-1: 5) to give the title compound (500 mg , 86) . 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 9H) , 1.34 (s, 12H) , 1.57 -1.72 (m, 2H) , 1.82 (br d, J13.05 Hz, 2H) , 2.66 (br s, 1 H) , 2.80 (br t, J12.05 Hz, 2H) , 4.25 (br d, J12.80 Hz, 2H) , 7.11 -7.42 (m, 2H) , 7.77 (d, J8.03 Hz, 2H) . LC-MS: [M+H-100] + 288.2.
3.81 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere
A solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (3.38 g, 11.25 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.57 g, 18 mmol), Pd(dppf)Cl2 (2.47 g, 3.38 mmol) and KOAc (3.32 g, 33.75 mmol) in 60 mL of DMSO, under N2, was stirred at 80° C. overnight. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (40:1˜1:1) to give 3.81 g of title compound.
With triethylamine In 1,4-dioxane at 110℃; for 1.5 h; Inert atmosphere
Step A: Preparation of tert-butyl 4-(4-(4A5,5-tetramethyl-1 ,2-dioxaborolan-2-yl)phenyl)piperidine- 1 -carboxylate : To a solution of tert-butyl 4-(4-bromophenyl) piperidine-l-carboxylate (13.5 g, 39.7 mmol) in dioxane (40 mL) was added 4,4,5,5- tetramethyl-l,3,2-dioxaborolane (8.64 mL, 59.5 mmol) and triethylamine (16.6 mL, 119 mmol). The solution was purged with argon for 5 minutes. Dichlorobis(acetonitrile) palladium (0.309 g, 1.19 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.95 g, 4.76 mmol) were then added, and the reaction mixture was again purged with argon for 5 minutes. The reaction mixture was then sealed and heated at 110 °C for 90 minutes. The reaction mixture was cooled to ambient temperature and filtered through a glass fiber filter paper. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with 5-10percent EtOAc in hexanes to afford tert-butyl 4-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-l-carboxylate (9.13 g, 23.6 mmol, 59.4percent yield) as a solid. MS (apci) m/z = 288.3 (M+H-Boc).
To a solution of 4-(4-Bromo-phenyl)-piperidine (1 g, 4.2 mmol) in DMF (8 mL) was added NaH (168 mg, 4.2 mmol, 60% in mineral oil). The slurry was stirred for 15 minutes, then di-'butyl dicarbonate (915 mg, 4.2 mmol) was added. The mixture was stirred for 18 hours, then quenched with methanol, and partitioned between 30% EtOAc/hexanes and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to yield the title compound as a white solid, which was taken on to the next step without further purification; 1H NMR (400 MHz, CDCI3-Cf) jdelta ppm 1.49 (s, 9 H) 1.58 (qd, J=12.67, 4.42 Hz. 2 H) 1.80 (d,J=13.14 Hz, 2 H) 2.61 (tt, J=12.22, 3.57 Hz. 1 H) 2.79 (t, J=12.63 Hz, 2 H) 4.24 (d, J=6.57 Hz, 2 H) 7.08 (m, 2 H) 7.43 (m, 2 H); MS (M+H)+ 340.8 and 342.8.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere; Sealed tube;
In a pressure tube a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (1363 mg, 4.006 mmol) in dioxane was treated with bis(pinacolato)diboron (1526 mg, 6.009 mmol), KOAc (1179 mg, 12.02 mmol), and PdC12(dppf).DCM (327.1 mg, 0.4006 mmol). The mixture was sparged with nitrogen for 1 mm and then sealed and heated at 100 C overnight. After cooling to ambient temperature, the reaction mixture was diluted with a mixture of EtOAc (75 mL)/water (50 mL)/ brine (25 mL), and the resulting emulsion was filtered through Celite and rinsed with EtOAc. The biphasic filtrate was separated and the organic phase was washed with brine and then dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (0-50% EtOAc/hexanes) to afford the title compound (1437 mg, 93% yield). ?H NMR (CDC13) 7.76 (d, 2H), 7.22 (m, 2H), 4.24 (d, 2H), 2.79 (dt, 2H), 2.65 (tt, 1H), 1.81 (m, 2H), 1.63 (dq, 2H), 1.48 (s, 9H), 1.33 (s, 12H).
86%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,2-dimethoxyethane; at 80℃;Inert atmosphere;
A mixture of tert-butyl 4- (4-bromophenyl) piperidine-1-carboxylate (510 mg, 1.499 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (761 mg, 3 mmol) and KOAc (441 mg, 4.5 mmol) in DME (20 ml) was degassed with N2 and PdCl2 (dppf) -CH2Cl2 (122 mg, 0.15 mmol) was added. The resulting mixture was degassed with N2 again and was heated to 80 overnight. After cooling to rt, the mixture was added with 10mL of NH4Cl (aq) , and extracted with EtOAc (20mL × 2) . The combined organic phase was washed with brine (20mL) , dried over Na2SO4 (anhydrous) , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EA/Hexane 0: 100-1: 5) to give the title compound (500 mg , 86) . 1H NMR (400 MHz, CDCl3) delta ppm 1.27 (s, 9H) , 1.34 (s, 12H) , 1.57 -1.72 (m, 2H) , 1.82 (br d, J13.05 Hz, 2H) , 2.66 (br s, 1 H) , 2.80 (br t, J12.05 Hz, 2H) , 4.25 (br d, J12.80 Hz, 2H) , 7.11 -7.42 (m, 2H) , 7.77 (d, J8.03 Hz, 2H) . LC-MS: [M+H-100] + 288.2.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 80℃; for 18h;Sealed vessel;
4-(4-Bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.4 g, 4.1 mmol) and bispinacolatodiboron (1.15 g, 4.53 mmol) were dissolved in DME (3 mL) in a pressure vessel, and to the solution was added PdCI2dppf (100 mg, 0.12 mmol) and KOAc (808 mg, 8.2 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and stirred at 800C for 18 hours. The reaction mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via flash chromatography on silica gel eluting with a gradient of EtOAc/hexanes (5-20%) to obtain the target compound as a solid: MS (M+H)+ 388.3.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 20 - 80℃; for 18h;
l,l'-Bis(diphenylphosphino)ferrocene dichloropalladium(IT) (0.082 g) was added to tert- butyl 4-(4-bromophenyl)piperidine-l -carboxylate (0.760 g), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (0.681 g) and potassium acetate (0.745 g) in DMSO (4 ml) at ambient temperature under an atmosphere of nitrogen. The resulting suspension was stirred at 800C for 18 hours. The mixture was allowed to cool and then partitioned between ethyl acetate (20 ml) and water (20 ml), the organic layer was collected, and the aqueous layer extracted with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine (20 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography (elution gradient 0 to 20% ethyl acetate in isohexane). There was thus obtained tert-butyl 4-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]piperidine-l- carboxylate (0.364 g); Mass Spectrum: (M-BoC)H-H+ 288.45; RT 2.57 min; NMR Spectrum: (DMSOd6) 7.61 (2H, d), 7.26 (2H, d), 4.01 - 4.13 (2H, m), 2.69 - 2.94 (2H, m), 2.65 - 2.75 (IH, m), 1.75 (2H, s), 1.42 (9H, s), 1.41 - 1.53 (2H, m), 1.28 (12H, s).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 74℃;Inert atmosphere;
Potassium acetate (1.44g, 14.69 mmol, 5 equiv.) and [1,1? bis (diphenylphosphino)ferrocene]dichloro-palladium(II) CH2C12 complex (0.308 g, 0.148 mmol, 0.05 equiv.) wereadded at room temperature to a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (1.Og, 2.94 mmol, 1 equiv.) and bis(pinacolato)diboron (0.896 g, 3.53 mmol, 1.2 equiv.) in DMF (66 mL). The reaction suspension was degassed and then stirred under N2 (g). The reaction was stirred in a 740C oil bath. After stirring overnight, the reaction was cooled to room temperature. The reaction suspension was filtered to remove insoluble solids. The collected solution was concentrated to a brown residue. The residue was dissolved in EtOAc / H20. After stirring, the EtOAc phase was separated, dried over Na2SO4, filtered, and concentrated toa brown residue / oil. Purification with Biotage SP-1 [0> 12% 2CV, 12> 100% 1OCV, 100%2CV] isolated the desired product as a foam, 0.68 g. LC-MS (ES, m/z): C22H34BN04: 387; Found 388 [M+H]+.
3.81 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃;Inert atmosphere;
A solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (3.38 g, 11.25 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.57 g, 18 mmol), Pd(dppf)Cl2 (2.47 g, 3.38 mmol) and KOAc (3.32 g, 33.75 mmol) in 60 mL of DMSO, under N2, was stirred at 80 C. overnight. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (40:1?1:1) to give 3.81 g of title compound.
With johnphos; sodium t-butanolate;palladium diacetate; In toluene; at 90℃; for 3h;
A suspension of 4- (4-BROMOPHENYL)-PIPERIDINE-L-CARBOXYLIC ACID tert-butyl ester (1. 97 g, 5. 79 MMOL), palladium acetate (54 mg, 0. 24 mmol), 2- (DI-T- BUTYLPHOSPHINO) biphenyl (154 mg, 0. 52 mmol), AND SODIUM T-BUTOXIDE (846 MG, 8. 80 mmol), PYRROLIDINE (587 mg, 8. 25 mmol) in TOLUENE (80 ML) WAS HEATED AT 90 C FOR 3 h under nitrogen atmosphere. The resulting suspension was passed through a Celite column and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by HPLC afforded 4-(4-PYRROLIDIN-1-L-PHENYL)-PIPERIDINE-1-CARBOXYLIC ACID tert-butyl ester as a solid that was used in the next step without further purification.
60%
With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; at 80℃; for 12h;
To a stirred solution of <strong>[769944-78-7]tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate</strong> (170 mg, 0.5 mmol) in toluene (5 mL), were added tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (62 mg, 0.1 mmol) and sodium tert-butoxide (96 mg, 2 mmol) and the flask was purged with argon. Pyrrolidine (71 mg, 1 mmol) was added to the mixture and heated to 80 oC for 12 hours. After the completion of the reaction (monitored by TLC) the solvent was removed under vacuum. Water was added (10 mL) and the mixture was extracted with ethyl acetate (3x30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (Biotage; eluting solvents hexane: EtOAc 10/1 ratio) to give tert-butyl 4-(4-(pyrrolidin-1-yl)phenyl)piperidine-1-carboxylate as colorless liquid (100 mg, 60 % yield).
With hydrogenchloride; In ethyl acetate; at 20℃; for 5h;
To A solution of furnished 4- (4-bromophenyl)-piperidine-l-carboxylic acid TERT-BUTYL ESTER (1114 mg, 3. 27 MMOL) IN ETHYL ACETATE (1 ML) WAS ADDED 4 N hydrogen chloride in ethyl acetate (2 mL) at room temperature. After stirring for 5 h, solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and dried in vacuo to afford (4- (4-BROMOPHENYL)-PIPERIDINE hydrochloride (884 mg, 98%) as a white solid.
Part A:A mixture of 4-(4-bromophenyl)pipetauidine (1 ) (960 mg, 4.0 mmol) and di-tert-bulyl dicarbonate (960 mg, 4.4 mmol) at 0 "C in DCM ( 10 mL) was warmed to room temperature and stirred for 3 hours. LC-MS analysis indicated the reaction was complete.Dichloromethane (10 mL) was added and the solution washed with IN HCl (10 mL). Drying over magnesium sulfate, concentration and purification by flash column chromatography, gradient elution (0 to 100 %) hexane / ethyl acetate, afforded compound 2 as a white solid ( 1.36 g, 100 % yield). HPLC-MS tR = 2.50 min (UV2* nm), mass calculated for formulaC1^BrNO2 339.1 , observed LCMS m/z 284.1 (M+H-lBu).
100%
In dichloromethane; at 0 - 20℃;
Example 8: Example 8A; Part A:A mixture of 4-(4-bromophenyl)piperidine (37) (960 rng, 4.0 mmol) and di-ferf-buty. dicarbonate (960 mg, 4.4 mmol) at 0 0C in DCM (10 mL) was warmed to room temperature and stirred for 3 hours. LC-MS analysis indicated the reaction was complete. Dichloromethane (10 mL) was added and the solution washed with 1 I?/ HCI (10 mL). Drying over magnesium sulfate, concentration and purification by flash column chromatography, gradient elution (0 to 100 %) hexane / ethyl acetate, afforded compound 38 as a white solid (1.36 g, 100 % yield). HPLC-MS tR - 2,50 min (UV254 nm); mass calculated for formula Ci6H22BrNO2 339.1 , observed LCMS m/z 284.1 (M+H-'Bu).
96%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
Atambient temperature, a suspension of 4-(4-bromophenyl)piperidine (1000 mg, 4.164 mmol) in DCM (20 mL) was treated with DIEA (1451 tL, 8.328 mmol) followed by Boc-anhydride (1064 tL, 4.58 1 mmol), and then stirred overnight. The reaction mixture was subsequently diluted with water (50 mL) and then extracted with DCM (3 x 50 mL). The combined organic extracts were dried (Mg504), filtered and concentrated in vacuo to afford the title compound (1363 mg, 96% yield). ?HNMR (CDC13) 7.42 (m, 2H), 7.07 (m, 2H), 4.24 (m, 2H), 2.79 (dt, 2H), 2.61 (tt, 1H), 1.79 (m, 2H), 1.58 (qd, 2H), 1.48 (s, 9H).
95%
With dmap; triethylamine; In acetonitrile; at 20℃; for 3h;
To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine(2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours.Then water (20 mL) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 % yield).
95%
With dmap; triethylamine; In acetonitrile; at 20℃; for 3h;
To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine (2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- <n="190"/>tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 ml_) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 % yield).
95%
With triethylamine;dmap; In acetonitrile; at 20℃; for 3h;
To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine (2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 ml.) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 % yield).
89%
With triethylamine; In dichloromethane; at 0 - 20℃; for 20h;
A well-stirred solution of 4-(4-bromophenyl) piperidine (460 mg, 1.92 mmol) in DCM (5 mE) was treated with triethylamine (583 mg, 5.76 mmol), followed by addition of t-13oc20 (503 mg, 2.3 mmol) at 0 C. The mixture was stirred at room temperature for 20 h and then quenched with H20 (10 mE), extracted with dichloromethane (10 mEx3), washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexanes/EtOAc=12/1) to afford tert-butyl 4-(4-bromophenyl)piperidine-1 -carboxylate (582 mg, yield 89%) as colorless oil. The sub-title compound was confirmed by comparison with publishedcharacterization data (see e.g., Allwood et al., J. Org. Chem.2014, 79:328-338).
4.6 g
In dichloromethane; at 20℃; for 2h;
A solution of 4-(4-bromophenyl)piperidine (2.7 g, 11.25 mmol) and di-tert-butyl dicarbonate (2.5 g, 11.47 mmol) in 20 mL of DCM was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to give 4.6 g of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate.
With cesium fluoride;palladium di-tert-butylphosphine; In 1,4-dioxane; at 90℃;
A mixture containing 4-(4-bromo-phenyl)-piperidine-1 -carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tribupsilontylstannanyl-pyrimidi?e (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was degassed three times with Ar. Dioxane was added and the formed reaction mixture was stirred at HO 0C overnight under Ar. Then the reaction mixture was filter through celite and the .solvent was removed under vacuum and crude product was used directly in the next step.
With cesium fluoride;palladium di-tert-butylphosphine; In 1,4-dioxane; at 90℃;
A mixture containing 4tau(4-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was degassed three times with Ar. Dioxane was added and the formed reaction mixture was stirred at 90 0C overnight under Ar. Then the reaction mixture was filter through celite and the solvent was removed under vacuum and crude product was used directly in the next step.
With cesium fluoride;bis-tributylphosphine palladium(0); In 1,4-dioxane; at 90℃;
A mixture containing <strong>[769944-78-7]4-(4-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester</strong> (100 mg, 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was <n="220"/>degassed three times with Ar. Dioxane was added and the formed reaction mixture was stirred at 90 C overnight under Ar. Then the reaction mixture was filter through celite and the solvent was removed under vacuum and crude product was used directly in the next step.
With triethylamine; In dichloromethane; at 20℃; for 1.16667h;
The tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperidine-l- carboxylate used as a reagent for this reaction was prepared as follows:Di-tert-butyl dicarbonate (0.914 ml) was added in one portion to 4-(4- bromophenyl)piperidine hydrochloride (1.00 g) and triethylamine (1.260 ml) in DCM (34 ml) at ambient temperature. The resulting solution was stirred for 70 minutes. The reaction mixture was evaporated and washed with isohexane. The filtrate was evaporated and there was thus obtained tert-butyl 4-(4-bromophenyl)piperidine-l-carboxylate (1.191 g); Mass Spectrum: (M-tBu)+H+ 281.28; RT 2.33 min; NMR Spectrum: (DMSOd6) 7.53 (2H, d), 7.27 (2H, d), 4.12 (2H, d), 2.75 - 2.96 (2H, m), 2.68 - 2.79 (IH, m), 1.79 (2H, d), 1.47 (9H, s), 1.44 - 1.58 (2H, m).
With caesium carbonate;dichloro bis(acetonitrile) palladium(II); XPhos; In acetonitrile; at 90℃; for 2.5h;Inert atmosphere;
Part B:A solution of compound 2 (600 mg, 1.76 mmol) in acetonitrilc (5 mL) was transferred to a Schlenk tube containing dichlorobis(acetonitrile)palladium (II) (4.6 mg, 17.6 mumol), X-Phos (25 mg. 52.9 mumol) and cesium carbonate (1.5 g, 4.59 mmol) and the reaction mixture was stirred at room temperature under an inert atmosphere for 25 minutes. 100 muL of a solution containing phenylacetylene (360 mg. 3.52 mmol) in acetonitrilc (2 mL) was added and the reaction mixture heated at 90 upsilonC for 15 minutes. The phenylacetylene solution (100 muL) was added every 15 minutes and the reaction mixture was heated at 9011C for a total of 2.5 hours. LC-MS analysis indicated the reaction was complete. Water (6 mL) was added and the crude product extracted into ethyl acetate (10 mL). Drying over magnesium sulfate, concentration and purification by flash column chromatography, gradient elution (0 to 100 %) hexane / ethyl acetate, afforded BOC-protected compound 3 as a yellow solid (546 mg, 86 % yield). HPLC- MS tR - 2.70 min (UV254 ,m,); mass calculated for formula C24H2VNO2361.2, observed LCMS m/z 306.2 (M÷H-'Bu). The BOC-protecting group was hydrolyzed by the addition of trifluoroaeetic acid (5 mL> and the resulting mixture stirred at room temperature for I minute. LC-MS analysis indicated hydrolysis was complete. The volatiles were removed in vacuo and the resulting residue re- dissolved in a 1 : 1 MeCN / water mixture ( 10 mL) and lyophilized for 18 hours to afford crude compound 3. HPLC-MS tR = 1.22 min (UV254 J; mass calculated for formula CI9HI9N 261.2, observed LCMS m/z 262.2 (M+H).
86%
Part B:A solution of compound 38 (600 mg, 1.76 mmol) in acetonItrile (5 mL) was transferred to a Schienk tube containing dichiorobis(acetonitrile)pal.adium (II) (4.6 mg, 17.6. mot), X-Phos (25 mg, 52.9 I¼moi) and cesium carbonate (1.5 g, 4.59 mmol) and the reaction mixture was stirred at room temperature under an inert atmosphere for 25 minutes. 100 I¼L of a solution containing phenylacetyiene (360 mg, 3.52 mmol) in acetonitrile (2 mL) was added and the reaction mixture heated at 90 0C for 15 minutes. The phenylacetyiene solution (100 I¼L) was added every 15 minutes and the reaction mixture was heated at 90 0C for a total of 2.5 hours. LC-MS analysis indicated the reaction was complete. Water (6 mL) was added and the crude product extracted into ethyl acetate (10 mL). Drying over magnesium sulfate, concentration and purification by flash column chromatography, gradient elution (0 to 100 %) hexane / ethyl acetate, afforded BGC-protected compound 39 as a yellow solid (546 mg, 86 % <n="52"/>yield). HPLC-MS IR = 2.70 min (UV254 nm); mass calculated for formula C24H27NO2 361.2, observed LCMS m/z 306.2 (M+hPBu).The BOC-protecting group was hydrotyzed by the addition of trifluoroacetic acid (5 mL) and the resulting mixture stirred at room temperature for 1 minute. LC-MS analysis indicated hydrolysis was complete. The volatiles were removed in vacuo and the resulting residue re-dissolved in a 1 :1 MeCN / water mixture (10 mL) and iyophilized for 18 hours to afford crude compound 39. HPLC-IvIS iR = 1.22 min (UV254 nm); mass calculated for formula Ci9H19N 261.2, observed LCMS m/z 262.2 (M+H).
With triethylamine;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; dichloro bis(acetonitrile) palladium(II); In 1,4-dioxane; at 110℃; for 1.5h;Inert atmosphere;
Step A: Preparation of tert-butyl 4-(4-(4A5,5-tetramethyl-1 ,2-dioxaborolan-2-yl)phenyl)piperidine- 1 -carboxylate : To a solution of tert-butyl 4-(4-bromophenyl) piperidine-l-carboxylate (13.5 g, 39.7 mmol) in dioxane (40 mL) was added 4,4,5,5- tetramethyl-l,3,2-dioxaborolane (8.64 mL, 59.5 mmol) and triethylamine (16.6 mL, 119 mmol). The solution was purged with argon for 5 minutes. Dichlorobis(acetonitrile) palladium (0.309 g, 1.19 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.95 g, 4.76 mmol) were then added, and the reaction mixture was again purged with argon for 5 minutes. The reaction mixture was then sealed and heated at 110 C for 90 minutes. The reaction mixture was cooled to ambient temperature and filtered through a glass fiber filter paper. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with 5-10% EtOAc in hexanes to afford tert-butyl 4-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-l-carboxylate (9.13 g, 23.6 mmol, 59.4% yield) as a solid. MS (apci) m/z = 288.3 (M+H-Boc).
4-(4-bromophenyl)piperidine hydrochloride[ No CAS ]
[ 769944-78-7 ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium carbonate; In dichloromethane;
4-(4-Bromophenyl)piperidine HC1 (1 g, 3.7 mmol)in DCM (6 mE) was treated with K2C03 (1.3 g, 9 mmol, 2.5eq.) and 13oc20 (1.35 g, 6 mmol, 1.6 eq). The mixture wasdiluted with water, extracted with MTBE, washed with brine,dried on Na2504, and concentrated. Chromatographysilica gel (2-8% EtOAc/hexanes) gave 1 -l3oc-4-(4-bro-mophenyl)piperidine (944 mg, 76%)._This bromide was con-verted via Method 3 to 1 -l3oc-4-(4-boronophenyl)piperidinepinacol ester (1.16 g, quant.).
ethyl 4-(4-(1-(4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-1,2,3-triazol-4-yl)butyl)piperidin-4-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoate[ No CAS ]
6-amino-9-(2-carboxy-4-((6-(4-(4-(4-(4-(3-carboxy-6-(4-(trifluoromethyl)phenyl)-naphthalen-1-yl)phenyl)piperidin-1-yl)-butyl)-1H-1,2,3-triazol-1-yl)hexyl)carbamoyl)-phenyl)-3-iminio-5-sulfo-3H-xanthene-4-sulfonate[ No CAS ]
4-(4-(1-(4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-1,2,3-triazol-4-yl)butyl)piperidin-4-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid[ No CAS ]
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine[ No CAS ]
tert-butyl 4-(4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 105℃; for 1h;Inert atmosphere; Microwave irradiation;
General procedure: Suzuki coupling: To a solution of tert-butyl cis-4-(4-(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)phenyl)-3,5-dimethylpiperazine-1-carboxylate 28 (49 mg, 0.1 mmol) in 1,4-dioxane (1.2 ml) was added the appropriate boronic acid or pinacol ester (0.15 mmol), Pd(PPh3)4 (8.1 mg, 0.007 mmol) and aqueous 2M Na2CO3 solution (0.3 mL, 0.6 mmol). The vessel was purged with nitrogen for 1 min then sealed and subjected to microwave irradiation at 105 C for 1 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. After the removal of organic solvent in vacuo, the residue was purified through SiO2 chromatography using Biotage SP-1 automated chromatography system.
n-l3utyllithium (2.5 M solution, 0.6 mE, 1.49 mmol) wasadded at -78 C. under stirring to the solution of tert-butyl4-(4-bromophenyl)piperidine- 1 -carboxylate (460 mg, 1.35mmol) in THF (4 mE) under argon. The mixture was stirred at -78 C. for 30 minutes and then the solution of iodine(412 mg, 1.62 mmol) in THF (2.5 mE) was added. Afterstirring at -78 C. for 2 hours the mixture was warmed toroom temperature, diluted with water (10 mE), and extracted with ethyl acetate (10 mEx3). The organic layers were combined, washed with water (20 mExl), saturatedNa25203 solution (10 mEx3), brine (10 mEx2), and driedwith Na2SO4. The solvent was removed in vacuo and theresidue was purified by column chromatography on silica gel (Hexanes/EtOAc=12/1) to afford tert-butyl 4-(4-iodo-phenyl)piperidine-1 -carboxylate S7-3 (410 mg, yield 78%)as colorless oil. The sub-title compound was confirmed bycomparison with published characterization data (see e.g., Allwood et al., J. Org. Chem. 2014, 79:328-338).
tert-butyl 4-(4-(pyrimidin-5-yl)phenyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation;
General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120°C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used).
8-(4-(2-(4-(4-(pyrimidin-5-yl)phenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one[ No CAS ]
8-(4-(2-(4-(4-(2-oxopyrrolidin-1-yl)phenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrido[3,4-d]pyrimidin-4(3H)-one[ No CAS ]
1-(4-(piperidin-4-yl)phenyl)pyrrolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;Microwave irradiation; Sealed tube; Inert atmosphere;
Pd2dba3 (16.2 mg, 0.018 mmol), Xantphos (7.7 mg, 0.013 mmol), cesium carbonate (402 mg,1.23 mmol) and <strong>[769944-78-7]tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate</strong> (300 mg, 0.88mmol) were added to a microwave vial which was sealed, evacuated and placed under N2.Pyrrolidin-2-one (0.1 mL, 1.32 mmol) and 1,4-dioxane (2 mL) were added into the vial andthe reaction mixture was heated thermally at 100 C for 16 h. The reaction mixture wasconcentrated onto silica to load onto a KP-Sil snap cartridge for purification (50% EtOAc incyclohexane) to give the product as a pale orange solid (148.5 mg, 49%);
methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)benzoate[ No CAS ]
tert-butyl 4-(3’-(methoxycarbonyl)-5'-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-[1,1’-biphenyl]-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 2h;Inert atmosphere;
The mixture of compound 58 (26 mg, 0.055 mmol), Pd(PPh3)4 (3.8 mg, 3.29 Lirnol) and potassium carbonate (23 mg, 0.165 mmol) i n N, N- dimethyl fo r ami d e (1.5 mL) was purged with nitrogen gas for 15 min, and then 7VBoc-(4-bromophenyl)piperidine (28 mg, 0.082 mmol) was added to the mixture. The mixture was stirred at 85 C for 2 h, and then allowed to be cooled at room temperature. This mixture was partitioned diethyl ether (5 mL) and water (10 mL). The aqueous layer was extracted with diethyl ether (5 mL x 2), and then the combined organic layer was washed with brine (3 mL), dried (MgSCL), filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4: l) to afford compound 59b (13 mg, 39%) as a white solid; >H NMR (400 MHz, CD3OD) d 9.26 (s, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.20 (d, J =8.44 Hz, 2H), 7.95 (d, J =8.56 Hz, 2H), 7.71 (d, J =8.20 Hz, 2H), 7.41 (d, J =8.20 Hz, 2H), 4.26 (d, J =12.96 Hz, 2H), 2.93 (broad s, 2H), 2.86-2.79 (m, 1H), 1.90 (d, J = 12.40 Hz, 2H), 1.72-1.61 (m, 2H), 1.51 (s, 9H); MS (ESI, m/z) 551.2 [M+lf; ESI-HRMS calcd. m/z for C29H26N4O4F3 551.1906, found 551.1902 [M+l]+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
