Methyl iodide → 1-Benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate

HRID 2409901Notes

Reaction equation

HRID 2409901 reaction equation
[N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 2733832Lithium HexamethyldisilazideHCID 17999271Benzyl ethyl piperidine-1,3-dicarboxylate

Product 1

HCID 534862661-Benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylateYield 75.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent2×

Conditions

Temperature
-60 °C

Procedure

To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (2.107 g, 7.23 mmol) in dry THF (22 mL) and DMPU (1.4 mL, 1160 mmol) cooled at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (1.271 g, 7.59 mmol, 7.60 mL of 1M solution in THF). After addition, the reaction mixture was stirred at −60° C. for 1 h. Then iodomethane (0.520 mL, 8.32 mmol) in DMPU (0.344 mL, 2.86 mmol was added dropwise. After addition, the reaction was stirred at −60° C. for 1.5 h, then slowly warmed up to −20° C. over approximately 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction solution was extracted with EtOAc (2×). The combined organics were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex. The desired fractions were concentrated to give product, benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (1.66 gm, 5.44 mmol, 75.2% yield) as a light brown oil. Anal. Calcd. for C17H23NO4 m/z 305.3, found: 306.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.27 (m, 5 H), 5.20-5.09 (m, 2 H), 4.24-4.04 (m, 2 H), 3.99 (d, J=13.19 Hz, 1 H), 3.59 (br. s., 1 H), 3.27 (d, J=7.15 Hz, 1 H), 3.13 (d, J=12.64 Hz, 1 H), 2.16-1.95 (m, 1 H), 1.74-1.52 (m, 2 H), 1.51-1.39 (m, 1 H), 1.25-1.07 (m, 6 H).

Workup

  1. additionAfter addition
  2. additionAfter addition
  3. stirringthe reaction was stirred at −60° C. for 1.5 h
  4. temperatureslowly warmed up to −20° C. over approximately 1 hr
  5. customThe reaction was quenched by the addition of saturated aqueous NH4Cl
  6. extractionThe reaction solution was extracted with EtOAc (2×)
  7. washThe combined organics were washed with saturated aqueous NH4Cl and saturated aqueous NaCl
  8. dry with materialThe organic layer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified
  12. washeluting with a gradient of 0-30% EtOAc/Hex
  13. concentrationThe desired fractions were concentrated

Sources & evidence

ORD record
ord-c4b5637a31de48b5a6213faa1bdfc88e
Source dataset
uspto-grants-2014_08
Patent number
US08815909B2

Reaction notes

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