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Chemical Structure| 159635-49-1
Chemical Structure| 159635-49-1
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Product Details of [ 159635-49-1 ]

CAS No. :159635-49-1 MDL No. :MFCD01632522
Formula : C11H19NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :PDTZMULNKGUIEJ-UHFFFAOYSA-N
M.W : 197.27 Pubchem ID :2756808
Synonyms :

Safety of [ 159635-49-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 159635-49-1 ]

* 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.

  • Downstream synthetic route of [ 159635-49-1 ]

[ 159635-49-1 ] Synthesis Path-Downstream   1~48

  • 1
  • [ 2065-66-9 ]
  • [ 1220889-47-3 ]
  • [ 159635-49-1 ]
YieldReaction ConditionsOperation in experiment
82% With n-butyllithium In tetrahydrofuran at 0℃; for 2h;
  • 2
  • [ 589-87-7 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-(4-bromobenzyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate With 9-bora-bicyclo[3.3.1]nonane for 1h; Inert atmosphere; Heating; Reflux; Stage #2: 1,4-bromoiodobenzene With potassium carbonate In water monomer; N,N-dimethyl-formamide at 60℃; for 3h; Inert atmosphere; A81.A Example A81. (1 R,2S)-(E)-2-(3-(4-(( 1 -methylpiperidin-4-yl)methvnstyryl)- 1 H-indazol- 6-yl)spiro[cvclopropane-l,3'-indolinl-2'-one 2,2,2-trifluoroacetate sartA. tert-butyl 4-(4-bromobenzyl)piperidine-l-carboxylateTo a solution of tert-butyl 4-methylenepiperidine-l-carboxylate (1 g, 5.1 mmol) was added 9-BBN solution (10.2 mL of 0.5 M solution, 5.1 mmol) and the mixture was heated to reflux for 1 h under argon. The solution was then cooled to rt and 1 ,4- iodobromobenzene (1.3 g, 4.7 mmol) was added, followed by K2CO3 (843 mg, 6.1 mmol), DMF (10 mL), water (1 mL) and Pd(dppf)Cl2 (1 14 mg, 0.15 mmol). The solution was heated to 600C under argon for 3 h and cooled to rt. Ethyl acetate (250 mL) was added and the solution was washed with water (2 x 50 mL), brine (50 mL), dried over MgSO4 and concentrated to dryness. The crude product was purified by Biotage silica gel column (50:50 Hexane/Ethyl acetate) to give the title compound as a yellow solid (1.2 g, 72%).
72% Stage #1: t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate With 9-bora-bicyclo[3.3.1]nonane for 1h; Inert atmosphere; Reflux; Stage #2: 1,4-bromoiodobenzene With potassium carbonate In water monomer; N,N-dimethyl-formamide at 20 - 60℃; for 3h; Inert atmosphere; A81.A Example A81. (lR.2SV(EV2-(3-(4-(( l-methylpiperidin-4-vnmethvnstyrvn-lH-indazol-6- vDspiro [cyclopro ane- 1 ,3'-indolin1-2'-one 2,2,2-trifIuoroacetate saltA. tert-butyl 4-(4-bromobenzyl)piperidine-l-carboxylate[00243] To a solution of tert-butyl 4-methylenepiperidine-l-carboxylate (1 g, 5.1 mmol) was added 9-BBN solution (10.2 mL of 0.5 M solution, 5.1 mmol) and the mixture was heated to reflux for 1 h under argon. The solution was then cooled to rt and 1,4- iodobromobenzene (1.3 g, 4.7 mmol) was added, followed by 2C03 (843 mg, 6.1 mmol), DMF (10 mL), water (1 mL) and Pd(dppf)Cl2 (1 14 mg, 0.15 mmol). The solution was heated to 60°C under argon for 3 h and cooled to rt. Ethyl acetate (250 mL) was added and the solution was washed with water (2 x 50 mL), brine (50 mL), dried over MgS04 and concentrated to dryness. The crude product was purified by Biotage silica gel column (50:50 Hexane/Ethyl acetate) to give the title compound as a yellow solid (1.2 g, 72%).
60% Stage #1: t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate With 9-bora-[3.3.1]-bicyclononane dimer In tetrahydrofuran for 1h; Heating; Stage #2: 1,4-bromoiodobenzene With potassium carbonate In tetrahydrofuran; water monomer; N,N-dimethyl-formamide at 60℃; for 3h;
60% Stage #1: t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate With 9-bora-[3.3.1]-bicyclononane dimer In tetrahydrofuran for 1h; Heating; Stage #2: 1,4-bromoiodobenzene With triphenyl-arsane; Cs2CO3 In tetrahydrofuran; water monomer; N,N-dimethyl-formamide at 60℃; for 3h; Further stages.;
31.81% Stage #1: t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate With 9-bora-bicyclo[3.3.1]nonane at 70℃; for 1h; Inert atmosphere; Stage #2: 1,4-bromoiodobenzene With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In water monomer; N,N-dimethyl-formamide at 20 - 60℃; for 3h; Inert atmosphere;
Stage #1: t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: 1,4-bromoiodobenzene With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In tetrahydrofuran; water monomer; N,N-dimethyl-formamide at 60℃; for 3h; Sealed tube; Route 13 A 50 mL vial with stir bar was charged with tert-butyl 4-methylidenepiperidine-1-carboxylate (2.00 g, 10.14 mmol, 1.00 equiv.) and 9-BBN (0.5 M in THF, 20 mL, 20 mmol, 1.97 equiv.). The vial was evacuated and backflushed with nitrogen the resulting solution was refluxed for 1 h. And then the reaction mixture was cooled to room temperature. 4-bromoiodobenzene (2.58 g, 9.12 mmol, 0.90 equiv.), Pd(dppf)Cl2 (740 mg, 1.01 mmol, 0.10 equiv.), K2CO3 (1.82 g, 13.18 mmol, 1.30 equiv.), DMF (25.0 mL, 0.34 M) and H2O (5 mL) were added. The vial was capped and placed in an 60°C bath. The reaction mixture was stirred at 60°C for 3 h. The reaction mixture was cooled to room temperature, the mixture was poured into EtOAc (200 mL) and washed with brine (3 x 100 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography to yield the desired product.

  • 3
  • [ 3857-83-8 ]
  • [ 159635-49-1 ]
  • [ 252563-48-7 ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran for 1h; Heating; Stage #2: 2-naphthyl triflate With potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 3h;
82% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran for 1h; Heating; Stage #2: 2-naphthyl triflate With triphenyl-arsane; caesium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 3h; Further stages.;
  • 4
  • [ 444-29-1 ]
  • [ 159635-49-1 ]
  • [ 336182-27-5 ]
YieldReaction ConditionsOperation in experiment
70% C. To a degassed sample of 4-methylenepiperidine-1-carboxylic acid tert- butyl ester (0.527 g, 2.67 mmol) was added 9-borabicyclic[3,3,1]nonane (5.6 mL of a 0.5 M solution in THF, 2.8 mmol). The resulting solution was refluxed for 1 hour. After cooling to ambient temperature, the solution was added to a mixture of 1-iodo-2- trifluoromethylbenzene (0.707 mg, 2.600 mmol), Pd-catalyst (3 molpercent), DMF (25 mL), water (1 mL), and K2CO3 (0.6 g). The resulting mixture was heated at 600C for 3 hours. The mixture was cooled to ambient temperature and then poured into water. The pH of the solution was adjusted to 11 with 10percent NaOH solution and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and evaporated to give a crude oil, which was further purified by column chromatography to afford 4-(2- trifluoromethylbenzyl)piperidine-1-carboxylic acid te/t-butyl ester as a waxy solid (0.638 g) in 70 percent yield.
  • 5
  • [ 5455-14-1 ]
  • [ 159635-49-1 ]
  • [ 336182-19-5 ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran for 1h; Heating; Stage #2: phenyl 4-bromobenzenesulfonate With potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 3h;
80% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran for 1h; Heating; Stage #2: phenyl 4-bromobenzenesulfonate With triphenyl-arsane; caesium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 3h; Further stages.;
  • 6
  • [ 103962-05-6 ]
  • [ 159635-49-1 ]
  • 1-piperidinecarboxylic acid, 4-(4-trifluoromethoxyphenylmethyl),-1,1-dimethylethyl ester [ No CAS ]
  • 7
  • [ 154318-75-9 ]
  • [ 159635-49-1 ]
  • 1-piperidinecarboxylic acid, 4-[4-(dimethylethyl)phenylmethyl],-1,1-dimethylethyl ester [ No CAS ]
  • 8
  • [ 159635-49-1 ]
  • [ 336182-29-7 ]
  • 1-piperidinecarboxylic acid, 4-[4-(1-methylethyl)carbamoylphenylmethyl],-1,1-dimethylethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran for 1h; Heating; Stage #2: 4-bromo-N-isopropyl-benzamide With potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 3h;
98% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran for 1h; Heating; Stage #2: 4-bromo-N-isopropyl-benzamide With potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 3h; Further stages.;
  • 9
  • [ 159635-49-1 ]
  • [ 144230-50-2 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride In 1,4-dioxane at 20℃; for 0.5h; 26 4-methylenepiperidine hydrochloride Intermediate 21 (0.86 g, 4.3 mmol) was treated with HCl in dioxane (4N, 60 mL) at room temperature for 30 min. The solvent was removed and the residue was dried under high vacuum to give the title compound as a yellow solid (0.58 g, quant).
91% With hydrogenchloride In methanol 1 Example 1 Preparation of 4-methylenepiperidine hydrochloride 600 g (3.03 mol) of N-Boc-4-methylenepiperidine,And 3 L of methanol were added to a 5 L reaction flask, 768 g (7.56 mmol) of concentrated hydrochloric acid in an amount of 36%The reaction is completed,After concentration under reduced pressure,Join 2L ethyl acetate beating filter,Dried at room temperature under reduced pressure,This gave 338.4 g of 4-methylenepiperidine hydrochloride (yield 91.0%, purity 99.9%),
84% With hydrogenchloride In ethyl acetate for 1.5h; 6.A.1 23 (40.0 g, 0.203 mol) is vigorously stirred in EtOAc (200 ml) and concentrated aqueous HCl (80 ml) for 1.5 h. The solution is concentrated, diluted with Et2O (300 ml) and H2O (150 ml), the aqueous layer is separated and the organic layer is extracted once with H2O (20 ml). Combined aqueous layers are concentrated and the residue is dried 24 h under high vaccum to provide 26.7 g (84%) of a white solid. To this hydrochloride and N-tert-butoxycarbonyl-4-piperidone (43.8 g, 0.22 mol) in anhydrous ClCH2CH2Cl (80 mL) with 4 Å molecular sieves, are successively added DBU (33.2 ml, 0.22 mol) and titanium(IV) isopropoxide (65.5 ml, 0.22 mol) at 0° C, the reaction mixture is allowed to warm to RT and is stirred overnight at RT. The mixture is then cooled to 0 °C and diethylaluminum cyanide, 1 N in toluene (260 ml, 0.26 mol) is added with vigorous stirring. The reaction is allowed to warm to RT and stirred an additional 3 h, after which are added CH2Cl2 (300 ml), EtOAc (300 ml), and Celite (50 g). The reaction mixture is cooled to 0 °C, water (40 ml) is added slowly with vigorous stirring and, after an additional 5 min. stirring at RT, the excess of water is quenched with Na2SO4. The final mixture is then filtered over Celite, evaporated and subjected to flash chromatography over silica gel (eluting with Hexanes/EtOAc, 8:2), to provide 50.3 g (83%) of 24 as a colorless oil which solidifies upon standing.
With hydrogenchloride In ethyl acetate
With hydrogenchloride In ethyl acetate
With hydrogenchloride In ethyl acetate at 20℃; for 4.5h; 43 [Referential Example 43] 4-Methylenepiperidine hydrochloride [Show Image] 4M HCl-Ethyl acetate (5 mL) was added to 4-methylene-1-piperidinecarboxylic acid tert-butyl ester (0.230 g) at room temperature, and the mixture was stirred for 4.5 hours. The reaction solvent was evaporated under reduced pressure, to thereby give a crude product of the title compound.
7.6 g With hydrogenchloride In 1,4-dioxane at 0 - 20℃; Intermediate 6: 4-methylenepiperidine hydrochloride To a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (APOLLO, 10 g, 50. 7 mmol) in dioxane (130 mL) at 0 °C, a solution of HCI 4M in dioxane (ALFA-AESAR, 130mL, 507 mmol, 10 eq) was added and the mixture was stirred at rt overnight. Monitoring by UPLC and TLC showed the reaction was completed. The solvent was removed under vacuum to afford the desired compound 4-methylidenepiperidine hydrochloride which was used in the next step without further purification (7.6 g, 100%).1H NMR (400MHz, DMSO-cfe) δ ppm: 9.19 (br s, 2H), 4.86 (s, 2H), 3.06 (t, J = 6.0 Hz, 4H), 2.41 (t, J = 6.0 Hz, 4H).

  • 10
  • [ 159635-49-1 ]
  • [ 159635-22-0 ]
YieldReaction ConditionsOperation in experiment
49% With tert.-butylhydroperoxide; selenium(IV) oxide; In dichloromethane; water; at 0 - 20℃; for 17.5h; Selenium dioxide (2.81 g, 0.0253 mol) was suspended in CH2Cl2 (150 ml) and cooled to 0 C. t-Butylhydroperoxide (13.9 ml, 0.101 mol, 70% in water) was added and the mixture stirred at 0 C. for 30 mins. Compound 2 (10.0 g, 0.0507 mol) in CH2Cl2 (20 ml) was added and the mixture was stirred at 0 C. for 60 mins, then at 23 C. for 16 h. Ice chips and 10% by weight sodium bisulfite in water (150 ml) were added. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (eluant: 25% EtOAc-hexane to 50% EtOAc-hexane) gave 5.26 g (0.0247 mol, 49%) of the product 3 as a yellow oil. MS (FAB for M+1): m/e 214.
44% To a suspension of SeO2 (2.8 g, 25.3 mmol) in CH2Cl2 (150 ml) was added t-butyl peroxide (14 ml, 10.1 mmol) at 0 C. After stirring at 0 C. for 15 min, 62 (10.0 g, 50.6 mmol) in 20 CH2Cl2 (20 ml) was added dropwise. The mixture was stirred at 0 C. under N2 for 1 h, then at rt 20 h. The products were poured into 250 ml of 10% aqueous NaHSO4 solution, extracted with CH2Cl2, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum and purified by flash chromatography to give 63 (4.8 g, 44%).
  • 11
  • [ 1193-72-2 ]
  • [ 159635-49-1 ]
  • [ 849766-50-3 ]
  • 12
  • [ 694-80-4 ]
  • [ 159635-49-1 ]
  • [ 552868-05-0 ]
YieldReaction ConditionsOperation in experiment
84.9% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran for 3h; Reflux; Inert atmosphere; Stage #2: 2-bromo-1-chlorobenzene With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; 15.1 Step 1: tert-butyl 4-(2-chlorobenzyl)piperidine-1-carboxylate Step 1: tert-butyl 4-(2-chlorobenzyl)piperidine-1-carboxylate[00269j A mixture of tert-butyl 4-methylenepiperidine- 1 -carboxylate (3.00 g, 15.21 mmol) and 9-borabicyclo [3,3,ljnonane (30.0 mL, 15.00 mmol, 0.5 mol/L in THF) was refluxed under N2 for 3 hours. Then the mixture was cooled to room temperature, and to the mixture was added 1-bromo-2-chlorobenzene (2.77 g, 14.45 mmol), Pd(dppf)C12 (330 mg, 0.45 mmol), 30 mL of DMF, 5 mL of H20 and potassium carbonate (2.50 g, 18.25 mmol). The resulted mixture was heated to 60°C overnight. After the reaction was finished, the mixture was cooled to rt, and to the mixture was added H20 (100 mL). The mixture was adjusted to pH 11 with 10 % aquous NaOH solution and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with water (100 mL x 2) and brine (100 mL) in turn, dried over anhydrous Na2SO4 (20 g), filtered and concentrated in vacuo. The crude was purified by silica column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (4.00 g, 84.9 %).
84.9% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran for 3h; Reflux; Stage #2: 2-bromo-1-chlorobenzene With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; N,N-dimethyl-formamide at 60℃;
Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran Stage #2: 2-bromo-1-chlorobenzene With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide Heating;
  • 13
  • [ 1435-50-3 ]
  • [ 159635-49-1 ]
  • [ 849766-51-4 ]
  • 14
  • [ 60811-18-9 ]
  • [ 159635-49-1 ]
  • [ 849766-53-6 ]
  • 15
  • [ 56961-77-4 ]
  • [ 159635-49-1 ]
  • [ 849766-49-0 ]
  • 16
  • [ 33863-76-2 ]
  • [ 159635-49-1 ]
  • [ 849766-54-7 ]
  • 17
  • [ 159635-49-1 ]
  • [ 251107-31-0 ]
  • 19
  • [ 159635-49-1 ]
  • [ 180465-84-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 52 percent / 5percent SeO2/SiO2, t-BuOOH / Ambient temperature 2: 98 percent / thionyl chloride, 2,6-lutidine / toluene / 2 h / 35 °C 3: 52 percent / K2CO3 / ethanol / 80 °C 4: 59 percent / Bu3SnH, AIBN / benzene / 12 h / 100 °C
  • 20
  • [ 159635-49-1 ]
  • [ 389889-80-9 ]
YieldReaction ConditionsOperation in experiment
With water; 4-methylmorpholine N-oxide In tetrahydrofuran at 0℃; for 2h; 37.2 Synthesis of t-butyl 4-hydroxy-4-(hydroxymethyl)tetrahydropyridine-1 (2H)-carboxylate To a solution of 98 mg of t-butyl 4-methylenetetrahydropyridine-1(2H)- carboxylate in 2 ml of tetrahydrofuran-water (1:1), 88 mg of N-methyl morpholine-oxide and 0.1 ml of 2% osmium tetraoxide were added at 0° C., followed by 2 hours' stirring at the same temperature. Adding sodium sulfite to the reaction liquid, the reaction liquid was further stirred for 30 minutes, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 115 mg of the title compound was obtained.
With hydroquinine 1,4-phthalazinediyl diether In water; <i>tert</i>-butyl alcohol for 48h; 11 Example 114-[5-(4-Benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol dihydrochlorideTo a stirred solution of AD mix alpha (4.0 g) in tert-butyl alcohol (20 mL) and water was added 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (8.5 mmol, 1.68 g) dropwise. After stirring the reaction for 48 h, the reaction was quenched with sodium sulfite (5 g) and stirred. The reaction was then poured into ethyl acetate (100 mL). The organic layer was washed with brine, dried, and concentrated to give the crude product (1.8 g, 46 %). The compound may be purified by flash chromatography to give 4-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester.
  • 21
  • [ 24424-99-5 ]
  • [ 40064-34-4 ]
  • [ 159635-49-1 ]
  • 4-methylenepiperidine monohydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; In tetrahydrofuran; hydrogenchloride; methanol; water; 28a. 4-methylenepiperidine hydrochloride 6 g of di-t-butyldicarbonate, 2 g of <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> and 6.3 mL of pyridine were dissolved in 25 mL of tetrahydrofuran. After stirring for 4 days at room temperature the reaction mixture was concentrated, water was added, the pH adjusted to 3 and extracted with ethyl acetate. The ethyl acetate extracts were dried (magnesium sulfate) and concentrated. This residue (0.6 g) was transformed into Boc-4-methylenepiperidine using the procedure described in J. Am. Chem. Soc. 101, 7032 (1979). Boc-4-methylenepiperidine was dissolved in 3N hydrochloric acid in methanol and stirred for 19 hours at room temperature. Evaporation yielded 0.24 g of the title compound 28a. 1H-NMR 200 MHz (CDCl3) delta: 2.57 (4H, -br.s), 3.22 (4H, br.s), 4.88 (2H, s).
  • 22
  • [ 95080-93-6 ]
  • [ 159635-49-1 ]
  • [ 479636-65-2 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydrogencarbonate; In ethyl acetate; at 0 - 20℃; for 48.0h; Compound 7-a (1.0 g, 5.1 mmol) and sodium hydrogencarbonate (2.1 g, 0.025 mol) were dissolved in ethyl acetate (10 mL) After cooling, the mixture was cooled to 0 C and ethyl (2Z) -2-chloro-2- (hydroxyimino) acetate (prepared according to a known method (Tetrahedron Letters, 2011, 52 (43), 5656-5658 1.2 g, 7.6 mmol) was added, And the mixture was stirred at room temperature for 48 hours. After completion of the reaction, distilled water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 5: 95 ? 3: 7) to give the title compound 7-b (1.4 g, 93%) as a yellow solid.
  • 23
  • [ 127474-54-8 ]
  • [ 159635-49-1 ]
  • [ 1001647-37-5 ]
YieldReaction ConditionsOperation in experiment
47% [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(O-isopropoxyphenylmethylene)ruthenium; In dichloromethane; at 40℃; for 12h; Anhydrous dichloromethane (4 mL, 0.2 M) is added via syringe to 10-B (193 mg, 0.766 mmol, 1.0 eq.), and Hoveyda-Grubbs 2nd Generation metathesis catalyst (l,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene) dichloro (o- isopropoxyphenylmethylene) ruthenium II dichloride) (98 mg, 0.115 mmol, 15 mol %) under a nitrogen atmosphere. N-Boc-4-methylenepiperidine (604 mg, 3.06 mmol, 4.0 eq.) is added via syringe and the reaction is fitted with a reflux condenser and heated to 40 0C for 12 hours. After the reaction is complete as shown by LC/MS, the reaction mixture is directly purified by automated silica-gel purification (0-100% ethyl acetate in hexanes) to provide Reference Compound 10 as a dark green oil. MS m/z 422.3 (M-Boc + 1).
  • 24
  • [ 1120-87-2 ]
  • [ 159635-49-1 ]
  • [ 333986-17-7 ]
YieldReaction ConditionsOperation in experiment
76% To a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (6.00 g, 30.4 mmol, CAS159635-49-1) was added 9-BBN THF solution (0.5 M, 60.5 mL) at 25 C. The reaction mixture was stirred at 80 C. for 1 hour under N2. After cooling to 25 C., 4-bromopyridine (4.33 g, 27.4 mmol, CAS1120-87-2), K2CO3 (5.04 g, 36.5 mmol), Pd(dppf)Cl2-CH2Cl2 (683 mg, 836 umol), DMF (50 mL) and H2O (5 mL) were added to the reaction mixture was added. The reaction mixture was stirred at 60 C. for 3 hours. After cooling to 25 C., another charge of Pd(dppf)Cl2-CH2Cl2 (683 mg, 836 umol) was added to the reaction mixture. The mixture was stirred at 60 C. for 24 hours. On completion, the mixture was cooled to 25 C. and poured into water (60 mL). The pH was adjusted to 11 with 10% aq. NaOH. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over NaSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (5.80 g, 76% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.53-8.47 (m, 2H), 7.08 (d, J=6.0 Hz, 2H), 2.64 (t, J=12.0 Hz, 2H), 2.54 (d, J=7.6 Hz, 2H), 1.77-1.64 (m, 2H), 1.63-1.56 (m, 2H), 1.54-1.47 (m, 1H), 1.45 (s, 9H), 1.21-1.09 (m, 2H).
Description 1; 1 ,1-Dimethylethyl 4-(4-pyridinylmethyl)-1-piperidinecarboxylate (D1); 9-borabicyclo[3.3.1]nonane (101.5ml of a 0.5M solution in tetrahydrofuran) was added to a degassed sample of Lambda/-(tert-butoxycarbonyl)-4-methylene piperidine (may be prepared as described in A. Palani et al., J. Med. Chem., 2002, 45: 3145) (10g) and the resultant solution heated at reflux for 1h. After cooling to room temperature the reaction mixture was then added to a mixture of 4-bromopyridine (7.23g), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (1 :1) (1.14g), K2CO3 (8.42g), N,N-dimethylformamide (100ml) and water (10ml), and the resultant mixture heated at 600C for 3h. After cooling to room temperature, another charge of [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (1:1) (1.14g) was added to the reaction and heated at 6O0C overnight. The mixture was cooled to room temperature and poured into water, the pH was adjusted to 11 by the addition of 10% aqueous sodium hydroxide and extracted into ethyl acetate. Combined organic extracts were dried (Na2SO4) and evaporated to give the crude pyridine as a brown viscous oil. Chromatography [silica gel, eluting with ethyl acetate in hexanes, 0- 100%] gave the title compound (D1 ) as a pale yellow oil (7.5g).
  • 25
  • [ 89891-65-6 ]
  • [ 159635-49-1 ]
  • [ 1345445-56-8 ]
YieldReaction ConditionsOperation in experiment
50% Method of svnthesising quinoxaline D.51NBocED.8D*.5 D.51Methylene piperidine ED.8 (243 mg, 1 .23 mmol) is combined with 9-BBN (2.46 mL, 0.5 M in THF) and heated to 65C for 1 h. Then the mixture is cooled to 20C, quinoxaline D*.5 (300 mg, 1 .23 mmol), Pd(dppf) (50 mg, 10 mol %) and K2C03 (195 mg, 1 .41 mmol) are placed in DMF/H20 (1 .2 mL, 5: 1 ) and slowly the freshly prepared boronate is added dropwise. The reaction mixture is heated to 60C for 2 h, cooled, combined with NaHC03 and extracted with DCM (3 x 10 mL). The solvent is removed, the residue is purified by chromatography (45:55 to 90: 1 0 in 6 min CH3CN/H20) and quinoxaline D.51 (250 mg, 50 %) is obtained.
50% Method of Synthesising Quinoxaline D.51Methylene piperidine ED.8 (243 mg, 1.23 mmol) is combined with 9-BBN (2.46 mL, 0.5 M in THF) and heated to 65 C. for 1 h. Then the mixture is cooled to 20 C., quinoxaline D*.5 (300 mg, 1.23 mmol), Pd(dppf) (50 mg, 10 mol %) and K2CO3 (195 mg, 1.41 mmol) are placed in DMF/H2O (1.2 mL, 5:1) and slowly the freshly prepared boronate is added dropwise. The reaction mixture is heated to 60 C. for 2 h, cooled, combined with NaHCO3 and extracted with DCM (3×10 mL). The solvent is removed, the residue is purified by chromatography (45:55 to 90:10 in 6 min CH3CN/H2O) and quinoxaline D.51 (250 mg, 50%) is obtained.
  • 26
  • [ 159635-49-1 ]
  • [ 162102-79-6 ]
  • [ 1323264-30-7 ]
  • 27
  • [ 22282-99-1 ]
  • [ 159635-49-1 ]
  • [ 1400692-00-3 ]
YieldReaction ConditionsOperation in experiment
46% A 0.5 M sol. of 9-BBN (120 mL) in THF was added to a degassed intermediate 10 (11.3 g, 57.36 mmol) and the r.m. was heated at reflux for 1 h. After cooling to r.t., the r.m. was added to a mixture of <strong>[22282-99-1]4-bromo-2-methyl-pyridine</strong> (10.8 g, 63.09 mmol),Pd(dppf)Cl2 (1.259 g, 1.721 mmol) and K2C03 (23.7 g, 172.1 mmol) in DMF/water 10/1 (250 mL) and the r.m. was heated at 60 C for 4 h. Then the r.m. was cooled to r.t. and poured into water. The pH was adjusted to 11 by the addition of a 10% aq. NaOH sol. and extracted with EtOAc. The separated organic layer was dried (MgSC^), filtered and the solvent was evaporated. The residue was purified by flash columnchromatography (eluent: petroleum ether/EtOAc 20/1). The product fractions were collected and concentrated in vacuo. Yield: 7.6 g of intermediate 11 (46 %).
  • 28
  • [ 159635-49-1 ]
  • [ 240401-28-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: zinc/copper couple / 1,2-dimethoxyethane; tert-butyl methyl ether / 15 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: zinc/copper couple / diethyl ether; 1,2-dimethoxyethane / 6 h / 20 °C / Inert atmosphere 2: zinc; ammonium chloride / methanol / 10 h / 20 °C 3: sodium tetrahydroborate / methanol / 1 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: zinc-copper coupling reagent / tert-butyl methyl ether / 20 h / 20 °C 2: methanol; sodium tetrahydroborate / 2 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: Zn-Cu reagent / diethyl ether; 1,2-dimethoxyethane / 10 °C / Inert atmosphere 2: ammonium chloride; zinc / methanol / 20 °C 3: sodium tetrahydroborate / methanol / 1 h / 20 °C / Cooling with ice
Multi-step reaction with 3 steps 1: copper; zinc / diethyl ether; 1,2-dimethoxyethane / 10 - 20 °C / Inert atmosphere 2: zinc; ammonium chloride / methanol / 20 °C 3: sodium tetrahydroborate / methanol / 1 h / 20 °C / Cooling with ice
Multi-step reaction with 3 steps 1: zinc-copper / 1,2-dimethoxyethane / 20 °C / Inert atmosphere 2: ammonium chloride; zinc / methanol / 20 °C 3: methanol; sodium tetrahydroborate / 1 h / 20 °C / Cooling with ice

  • 29
  • [ 159635-49-1 ]
  • [ 76-02-8 ]
  • [ 203661-69-2 ]
YieldReaction ConditionsOperation in experiment
60% With zinc-copper coupling reagent; In tert-butyl methyl ether; at 20℃; for 20h; In a three-necked reaction flask equipped with a stirrer, 29.6 g of N-Boc-4-methylene piperidine and 65.4 g of a copper-copper coupling reagent were added and 600 ml of methyl tert-butyl ether was fed under reduced pressure,(136 g / 200 ml) was added dropwise at a temperature of 20 C, and the mixture was stirred at 20 C for 20 hours. After completion of the reaction, the reaction solution was cooled to 0 C , 600 ml of ammonium chloride saturated solution slowly dropping into the reaction flask to quench the reaction. During the dropwise addition, the control temperature was below 20 C. After quenching, the insoluble matter was removed by filtration and the filtrate was extracted with 200 ml of ethyl acetate. The organic phase was washed with 200 ml of saturated brine, dried over 100 g of sodium sulfate for 40 minutes and concentrated under reduced pressure to give crude N-Boc-7-azaspiroacetone, which was purified by column chromatography to give a solution having a purity of ~ 96% Product 146 grams, the yield of 60%.
15% With zinc/copper couple; In 1,2-dimethoxyethane; tert-butyl methyl ether; at 15 - 20℃;Inert atmosphere; General procedure: Step 2 tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate [00200] To a flame-dried RB flask with tert-butyl 4-methylenepiperidine-1- carboxylate (2.96 g, 15 mmol, 1.0 equiv) and Zn/Cu couple (6.54 g, 172.5 mmol, 11.5 equiv) under vacuum, t-BuOMe (60 mL) was charged and refilled the flask with N2 balloon. To the mixture thus obtained stirred at 15 C, a solution of 2,2,2- trichloroacetyl chloride in DME (20 mL) was added dropwise. The mixture was stirred at room temperature overnight after addition. To the reaction mixture stirred in an external ice- bath, a saturated solution of NH4CI (60 mL) was added slowly and carefully (especially the first few drops). After addition, the mixture was stirred at room temperature for 4 h, filtered to remove the solid. The phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2S04, concentrated to give the residue which was purified by CombiFlash (40 g silicagel column, EtOAc/Hexane: 0-40%) to afford 619 mg (15%) of tert-butyl 2- oxo-7-azaspiro[3.5]nonane-7-carboxylate. [00201] 1H NMR (CDCI3, 300 MHz): 53.41 (t, 4 H), 2.82 (s, 4 H), 1.70 (t, 4 H), 1.47 (s, 9 H).
  • 30
  • [ 159635-49-1 ]
  • [ 123387-50-8 ]
YieldReaction ConditionsOperation in experiment
97% With palladium on activated charcoal; hydrogen In methanol for 24h; Inert atmosphere;
With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran for 1h; Reflux; B54.2 (b) Step 2 [0533] A solution of tert-butyl 4-methylenepiperidine-1-carboxylate (0.256 g, 1.30 mmol) in THF (2 mL) was added dropwise with a 0.5 M solution of 9-BBN in THF (2.60 mL, 1.30 mmol). The reaction mixture was refluxed for 1 hour by heating, and then cooled to room temperature.
  • 31
  • [ 159635-49-1 ]
  • [ 50675-14-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 3-chloro-benzenecarboperoxoic acid / chloroform / 0.5 h / 0 - 20 °C 2.1: sodium hydride / 1.5 h / 0 °C 2.2: 1 h / 50 °C 3.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C
  • 32
  • [ 50998-17-9 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-(quinoxalin-6-ylmethyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a degassed sample of tert-butyl 4-methylenepiperidine-1 -carboxylate (0.6 g, 3.04 mmol) in dry THF (10 ml.) was added 9-BBN (6.1 ml_, 3.04mmol). The resulting mixture was refluxed for 1 h. After cooling to rt, <strong>[50998-17-9]6-bromo quinoxaline</strong> (0.55 g, 2.78mmol), Pd(dppf)CI2.CH2CI2 (0.15g, 0.18 mmol), DMF (10 ml_), water (1 ml.) and K2C03 (0.6 g, 4.5mmol) were added at rt. The resulting mixture was heated at 60 C for 3 h. The reaction mixture was then cooled to rt, diluted with water (20 ml_). The pH was adjusted to 1 1 with 10% aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04 and concentrated to get the crude product as colorless liquid. Tert-butyl 4-(quinoxalin-6-ylmethyl)piperidine-1 -carboxylate was used in the next step without further purification. Yield: 24% (0.23 g). H NMR (400 MHz, DMSO-d6): delta 8.89-8.86 (m, 2H), 8.04-8.01 (m, 3H), 2.73-2.67 (m, 2H), 2.25 (m, 9H), 1 .13 (s, 9H).
  • 33
  • [ 159635-49-1 ]
  • [ 145369-29-5 ]
  • tert-butyl 4-((6-cyanonaphthalen-2-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83.3% Step 1: tert-butyl 4-(2-chlorobenzyl)piperidine-1-carboxylate[00269j A mixture of tert-butyl 4-methylenepiperidine- 1 -carboxylate (3.00 g, 15.21 mmol) and 9-borabicyclo [3,3,ljnonane (30.0 mL, 15.00 mmol, 0.5 mol/L in THF) was refluxed under N2 for 3 hours. Then the mixture was cooled to room temperature, and to the mixture was added 1-bromo-2-chlorobenzene (2.77 g, 14.45 mmol), Pd(dppf)C12 (330 mg, 0.45 mmol), 30 mL of DMF, 5 mL of H20 and potassium carbonate (2.50 g, 18.25 mmol). The resulted mixture was heated to 60C overnight. After the reaction was finished, the mixture was cooled to rt, and to the mixture was added H20 (100 mL). The mixture was adjusted to pH 11 with 10 % aquous NaOH solution and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with water (100 mL x 2) and brine (100 mL) in turn, dried over anhydrous Na2SO4 (20 g), filtered and concentrated in vacuo. The crude was purified by silica column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (4.00 g, 84.9 %).Step 2: tert-butyl 4-((6-cyanonaphthalen-2-yl)methyl)piperidine-1-carboxylate[004461 The title compound was prepared by the procedure described in step 1 of Example 15 using tert-butyl 4-methylenepiperidine-1-carboxylate (1.91 g, 9.57 mmol), 9-borabicyclo [3,3,ljnonane (19.2 mL, 9.57 mmol,0.5 mol/L in THF), <strong>[145369-29-5]6-cyanonaphthalen-2-yl trifluoromethanesulfonate</strong> (2.62 g, 8.70 mmol), Pd(dppf)C12 (0.21 g,0.29 mmol) and potassium carbonate (1.44 g, 10.44 mmol) to give the title compound as colourless oil (2.54 g,83.3 %). The compound was characterized by the following spectroscopic data:MS(ESI, pos.ion)m/z: 295.20(M+1-t-Bu); exact mass of C22H26N202: 350.20.
  • 34
  • [ 917251-92-4 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-((5-(trifluoromethyl)quinolin-8-yl)methyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
28.7% Step 1: tert-butyl 4-(2-chlorobenzyl)piperidine-1-carboxylate[00269j A mixture of tert-butyl 4-methylenepiperidine- 1 -carboxylate (3.00 g, 15.21 mmol) and 9-borabicyclo [3,3,ljnonane (30.0 mL, 15.00 mmol, 0.5 mol/L in THF) was refluxed under N2 for 3 hours. Then the mixture was cooled to room temperature, and to the mixture was added 1-bromo-2-chlorobenzene (2.77 g, 14.45 mmol), Pd(dppf)C12 (330 mg, 0.45 mmol), 30 mL of DMF, 5 mL of H20 and potassium carbonate (2.50 g, 18.25 mmol). The resulted mixture was heated to 60C overnight. After the reaction was finished, the mixture was cooled to rt, and to the mixture was added H20 (100 mL). The mixture was adjusted to pH 11 with 10 % aquous NaOH solution and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with water (100 mL x 2) and brine (100 mL) in turn, dried over anhydrous Na2SO4 (20 g), filtered and concentrated in vacuo. The crude was purified by silica column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a white solid (4.00 g, 84.9 %).Step 1: tert-butyl 4-((5-(trifluoromethyl)quinolin-8-yl)methyl)piperidine-1-carboxylate[004661 The title compound was prepared by the procedure described in step 1 of Example 15 using tert-butyl 4-methylenepiperidine-1-carboxylate (1.72 g, 8.69 mmol), 9-borabicyclo [3,3,ljnonane (17.4 mL, 8.70 mmol,0.5 mol/L in THF), <strong>[917251-92-4]8-bromo-5-(trifluoromethyl)quinoline</strong> (2.00 g, 7.24 mmol), Pd(dppf)C12 (265 mg, 0.36 mmol) and aqueous sodium hydroxide solution (3 mol/L, 7.3 mL, 21.90 mmol) to give the title compound as a white solid (820 mg, 28.7%). The compound was characterized by the following spectroscopic data:MS(ESI, pos.ion)m/z: 395.1 (M+1); exact mass of C2,H25F3N202: 394.19.
  • 35
  • [ 159635-49-1 ]
  • [ 29683-84-9 ]
  • 1-N-boc-4-methylenepiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-chloro-succinimide In ethyl acetate at 0 - 20℃; for 0.833333h;
  • 36
  • [ 50904-38-6 ]
  • [ 159635-49-1 ]
  • [ 1229384-08-0 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran for 2h; Inert atmosphere; Reflux; Stage #2: 1-bromo-3-(4-fluorophenoxy)benzene With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 60℃; for 48h; Inert atmosphere; 4-[3-(4-Chloro-phenoxy)-benzyl]-piperidine-1-carboxylicacid tert-butyl ester 1-Boc-3-methylenepiperidine (222 mg, 1.12 mmol) was degassed (neat) by bubbling a stream of drynitrogen through the oil for 15 minutes and then treated with a THF solution of9-BBN (0.5 M in THF, 2.3 mL, 1.15 mmol).The reaction mixture was refluxed for 2 h, then cooled to rt. The reaction mixture was then added, viacannula, to a preformed solution of 3-(4-chloro-phenoxy)-bromobenzene (314 mg,111 mmol), Pd(dppf)Cl2•CH2Cl2 (28 mg, 0.038mmol), and potassium carbonate (213 mg, 1.54 mmol) in DMF/H2O (5mL/0.5 mL). The resultant mixture washeated at 60 °C for 48 h, cooled to rt, poured into water, treated with 1 NNaOH until pH 11, and extracted with EtOAc (3x). The organic layers werecombined, dried (Na2SO4), and concentrated. The cruderesidue was purified (FCC) to give the title compound (0.303 g, 68%); 1HNMR (600 MHz, CD3OD): δ 7.32 (d, J = 8.9 Hz, 2H), 7.29-7.25(m, 1H), 6.97-6.91 (m, 3H), 6.83-6.79 (m, 2H), 4.03 (d, J = 13.2 Hz,2H), 2.69 (br s, 2H), 2.53 (d, J = 7.2 Hz, 2H), 1.77-1.64 (m, 1H),1.65-1.51 (m, 2H), 1.44 (s, 9H), 1.14-1.05 (m, 2H).
  • 37
  • [ 159635-49-1 ]
  • [ 1263132-31-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium iodide / tetrahydrofuran / 65 °C / Inert atmosphere 2: hydrogenchloride / diethyl ether
  • 38
  • [ 402-31-3 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-(2,2-difluoro-2-(3-(trifluoromethyl)phenyl)ethyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With Cyclohexanethiol; 10-phenyl-10H-phenothiazine; sodium formate In water; dimethyl sulfoxide at 23℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; Schlenk technique;
  • 39
  • [ 1189-71-5 ]
  • [ 159635-49-1 ]
  • [ 1180112-41-7 ]
YieldReaction ConditionsOperation in experiment
To a solution of tert-butyl 4-methylenepiperidinyl-1-carboxylate (4 g, 20 mmol) in dichloromethane (50 mL) was added sulfurisocyanatidic chloride (3.4 g, 24 mmol) at 0 C. The resultant mixture was stirred at ambient temperature overnight and then diluted with diethyl ether (100 mL) and cooled to 0 C. The mixture was treated with a solution of sodium thiosulfate (9.5 g, 60 mmol) and potassium hydroxide (2.24 g, 40 mmol) in water (50 mL) at 0 C. The resultant mixture was stirred at 0 C for 3 hours and extracted with ethyl acetate (2 x 50 mL). The organic phase was dried anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil (4.1 g crude). The oil was dissolved in tetrahydrofuran (30 mL) and borane-dimethyl sulfide complex (2 M, 15 mL, 30 mmol) was added. The resultant mixture as stirred at 70 C overnight. The mixture was cooled to ambient temperature and concentrated under reduced pressure to give the title compound (4.5 g, crude) as a yellow oil which was used in the next step without further purification. LCMS m/z = 227.1 [M+H]+.
  • 40
  • [ 74213-24-4 ]
  • [ 159635-49-1 ]
  • [ 1250999-79-1 ]
YieldReaction ConditionsOperation in experiment
92% With sodium hydrogencarbonate; In ethyl acetate; at 20℃; for 120h; To a suspension of tert-butyl 4-methylenepiperidine-1-carboxylate (FLUOROCHEM, 2 g, 10.14 mmol) and sodium bicarbonate (8.52 g, 101 .38 mmol) in EtOAc (50 ml.) was added <strong>[74213-24-4]dibromoformaldoxime</strong> (FLUOROCHEM, 5 g, 24.74 mmol). The reaction mixture was stirred for 5 days at rt. Celite was added and the resulting slurry was filtered under vacuum and washed with EtOAc. The solvent was evaporated and the residue was purified by silica chromatography column using a gradient of CyHex/EtOAc as eluents (CyHex/EtOAc 95/5 to 90/10) to yield the title compound (7.29 g, 92%) as a white solid.1H NMR (300 MHz, CDCI3) delta ppm: 3.72-3.64 (m, 2H), 3.40-3.31 (m, 2H), 2.95 (s, 2H), 1.92-1.84 (m, 2H), 1.72-1 .65 (m, 2H), 1.45 (s, 9H). [ES+ MS] m/z 319, 321 (MH+).
89% With sodium hydrogencarbonate; In ethyl acetate; at 20℃; for 120h;Inert atmosphere; General procedure: To a suspension of alkene (100 mol-%) and sodium bicarbonate (1000 mol-%) in ethyl acetate (0.5 M relative to starting alkene) was added <strong>[74213-24-4]dibromoformaldoxime</strong> (150 mol-%) under an atmosphere of argon. The reaction mixture was stirred at rt until the completion of the reaction (as monitored by LC-MS or TLC analysis), therefore the resulting slurry was filtered through Celite and washed with ethyl acetate. The solvent was evaporated and the residue purified by flash chromatography.
  • 41
  • [ 911434-05-4 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-[(6-methyl-5-nitro-3-pyridyl)methylene]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With potassium acetate; palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 100℃;Sealed tube; To a solution of <strong>[911434-05-4]5-bromo-2-methyl-3-nitro-pyridine</strong> (500 mg, 2.304 mmol) in dimethylformamide (10 mL) in a 20 mL microwave tube were added tiphenylphosphine (121 mg, 0.4613 mmol), palladium acetate (II) (52 mg, 0.2316 mmol), potassium acetate (455 mg, 4.636 mmol), and tert-butyl 4- methylenepiperidine-1-carboxylate (460 mg, 2.332 mmol). The mixture was degassed with nitrogen for 5 minutes. The tube was sealed and heated at 100 C overnight. The mixture was cooled to room temperature and water (10 mL) was added to the reaction mixture followed by extraction with ethyl acetate (3 X 20 mL). The combined organic fractions were washed with water (1 X 20 mL), brine (1 X 20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography (4 g column; 0-50 % ethyl acetate/hexane) to afford tert-butyl 4-[(6-methyl-5-nitro-3- pyridyl)methylene]piperidine-1-carboxylate (320 mg, 42%). ESI-MS m/z calc. 333.16885, found 334.15 (M+l)+; Retention time: 0.8 minutes.
  • 42
  • [ 152849-72-4 ]
  • [ 159635-49-1 ]
  • tert-butyl-4-(5-(methoxycarbonyl)-2,4-dimethylbenzylidene)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
8% With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine; In acetonitrile; at 80.0℃; for 17.0h; To a solution of <strong>[152849-72-4]methyl-5-bromo-2,4-dimethylbenzoate</strong> (9.8 g, 40.09 mmol) in CH3CN (50 mL) was added added tert-butyl 4-methylenepiperidine-1-carboxylate (11.85 g, 60.14 mmol), Et3N (14.3 g, 142.1 mmol), tri(o-tolyl)phosphine (106.28 mg, 0.34 mmol), Pd(OAc)2 (19.59 mg,0.082 mmol). The mixture was stirred for 17 h at 80 C, then diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na2 SO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography(silica, EtOAc/PE = 1/20) to afford tert-butyl-4-(5 -(methoxycarbonyl)-2,4-dimethylbenzylidene)piperidine-1-carboxylate (1.22 g, 3.4 mmol, 8%) as a white solid. ESI-MS (EI+, m/z): 360 [M+H]t ?H NIVIR (500 MHz, CDC13) 7.64 (s, 1H), 7.05 (s, 1H), 6.25 (s, 1H), 3.86 (s, 3H), 3.50-3.52 (m, 2H), 3.36-3.38 (m, 2H), 2.53-2.55 (m, 3H), 2.32-2.34 (m, 2H), 2.23-2.26 (m, 4H), 1.48 (s, 1OH).
  • 43
  • [ 159635-49-1 ]
  • [ 1239319-82-4 ]
  • 44
  • [ 886762-86-3 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-[(3,4-diamino-2-fluorophenyl)methyl]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-bora-bicyclo[3.3.1]nonane at 70℃; for 2h; Stage #2: 4-bromo-3-fluoro-benzene-1,2-diamine With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In water; N,N-dimethyl-formamide at 60℃; for 3h; tert-Butyl 4-[(3,4-diamino-2-fluorophenyl)methyl]piperidine-1-carboxylate A mixture of tert-butyl-4-methylenepiperidine-1-carboxylate (157 mg, 0.79 mmol) and 9-BBN (1.6 mL, 0.80 mmol) was heated at 70°C for 2 h. After cooling, 4- bromo-3-fluorobenzene-1,2-diamine (150 mg, 0.73 mmol), K2CO3 (133 mg, 0.95 mmol), DMF (1.46 mL), water (0.15 mL) and Pd(dppf)Cl2.DCM (18 mg, 0.02 mmol) were added. The mixture was heated at 60°C for 3 h, then cooled and partitioned between EtOAc and water. The organic layers were washed with brine and dried over MgSO4, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc/hexanes (0-100% gradient), to yield the title compound (70 mg, 30%) as a yellow oil. LCMS (Method 5): [M+H-BOC]+ m/z 224, RT 1.33 minutes.
  • 45
  • [ 59447-06-2 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-(2-chloro-4,5-difluorobenzyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
11% To a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (22 mL, 11 mmol, 0.5 M) at 25 C under argon was added tert-butyl 4-methylenepiperidine-1-carboxylate (2.17 g, 11 mmol). The mixture was stirred at 65 C for 2 h. The mixture was cooled down to 25 C and added to a solution of 1-bromo-2- chloro-4,5-difluorobenzene (2.5 g, 11 mmol), potassium carbonate (1.97 g, 14.3 mmol) and 1,1’- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (449 mg, 0.55 mmol) in N,N-dimethylformamide/water (17.6 mL/1.76 mL) at 25 C. The resulting mixture was heated at 60 C for 20 h. The reaction was quenched with 1 N aqueous sodium hydroxide solution and the aqueous layer was stirred at 25 C for 1 h. The solution was diluted with ethyl acetate (200 mL) and washed with brine (150 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 33/1) to give tert-butyl 4-(2-chloro-4,5-difluorobenzyl)piperidine-1-carboxylate (430 mg, 1.25 mmol, 11%) as a colorless oil. LCMS (ESI) m/z: 290.0 [M-56+H]+.
  • 46
  • [ 1060813-07-1 ]
  • [ 159635-49-1 ]
  • tert-butyl 4-(3-chloro-4,5-difluorobenzyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% Stage #1: tert-butyl 4-methylidenepiperidine-1-carboxylate With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran at 25 - 65℃; for 2h; Inert atmosphere; Stage #2: 5-bromo-1-chloro-2,3-difluorobenzene With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 25 - 60℃; for 20h; 8.1 Step 1: Preparation of tert-butyl 4-(3-chloro-4,5-difluorobenzyl)piperidine-1-carboxylate To a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (22 mL,11 mmol, 0.5 M) at 25 C was added tert-butyl 4-methylenepiperidine-1-carboxylate (2.17 g, 11 mmol) under argon. The mixture was stirred at 65 C for 2 h. The mixture was cooled to 25 C and added to a solution of 5-bromo-1- chloro-2,3-difluorobenzene (2.5 g, 11 mmol), potassium carbonate (1.97 g, 14.3 mmol) and 1,1’- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (449 mg, 0.55 mmol) in N,N-dimethylformamide/water (18 mL/1.8 mL) at 25 C. The resulting mixture was heated at 60 C for 20 h. The reaction was quenched with 1 N aqueous sodium hydroxide solution and the aqueous layer was stirred at 25 C for 1 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with brine (200 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 25/1) to give tert-butyl 4-(3-chloro-4,5-difluorobenzyl)piperidine-1- carboxylate as a brown oil (1.25 g, 3.62 mmol, 33%). LCMS (ESI) m/z: 290.1 [M-56+H]+.
  • 47
  • [ 75927-49-0 ]
  • [ 159635-49-1 ]
  • [ 1425970-61-1 ]
YieldReaction ConditionsOperation in experiment
With 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(iso-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methylene ruthenium(II) dichloride In toluene at 90℃; for 3h; A Step A: tert-Butyl 4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylidene]piperidine-1- carboxylate (I3a) To a solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.03 g, 45.6 mmol) in toluene (60 mL) were added tert-butyl 4-methylenepiperidine-1-carboxylate (3.0 g, 15.2 mmol) and dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5- [(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (0.56 g, 0.76 mmol) and the reaction mixture was warmed to 90 °C and allowed to stir for 3 h. The reaction mixture was cooled to ambient temperature and water (20 mL) added and the resulting mixture extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (20 mL), dried (sodium sulfate), and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of petroleum ether:ethyl acetate - 95:5 to 90:10 to afford compound I3a. MS: m/z = 224.1 [M-100+H].
  • 48
  • [ 159635-49-1 ]
  • [ 1373028-17-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 3 h / Reflux 1.2: 60 °C 2.1: hydrogenchloride / ethyl acetate / 20 °C
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