Nitrogen → HCID 86639445, compound

HRID 451683Notes

Reaction equation

HRID 451683 reaction equation
N#N.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].[Li]CCCC.CON(C)[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20]>C1COCC1>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([C:19](=[O:20])[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=2[F:10])[CH2:22]1)=[O:28])([CH3:33])([CH3:32])[CH3:31].[F:3][C:4]1[C:5]([F:10])=[CH:6][CH:7]=[CH:8][C:9]=1[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20]

Participants

6

Reactant 4

HCID 947NitrogenHCID 97061,2-DifluorobenzeneHCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 86639445HCID 86639445, compoundYield 70.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Under protection of N2, 1,2-difluorobenzene (22 g, 0.19 mol) in anhydrous THF (300 mL) was cooled to −78° C. and 2.5 M n-BuLi solution in hexanes (76 mL, 0.19 mol) was added dropwise slowly. The reaction mixture was stirred at −78° C. for 1 hr, the solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (47.7 g, 0.175 mol) in anhydrous THF (200 mL) was slowly added dropwise. The reaction mixture warmed to rt and stirred for 2 hrs. The mixture was quenched with saturated NH4Cl (300 mL), extracted three times with ethyl acetate, and dried over Na2SO4. Solvent removal and flash column chromatography afforded crude (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (R)-tert-butyl 3-(2,3-difluorobenzoyl)piperidine-1-carboxylate (40 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 7.51 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 4.19 (d, 1H), 3.96 (m, 1H), 3.23 (m, 1H), 3.04 (t, 1H), 2.85 (m, 1H), 2.06 (m, 1H), 1.75 (m, 1H), 1.62 (m, 4H), 1.44 (s, 9H).

Workup

  1. temperatureThe reaction mixture warmed to rt
  2. stirringstirred for 2 hrs
  3. customThe mixture was quenched with saturated NH4Cl (300 mL)
  4. extractionextracted three times with ethyl acetate
  5. dry with materialdried over Na2SO4
  6. customSolvent removal and flash column chromatography

Sources & evidence

ORD record
ord-e1a133133c3f4463b5003ddeab9e1e9e
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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