Lithium Hexamethyldisilazide → 1,4-Piperidinedicarboxylic acid, 4-[[5-bromo-1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]methyl]-, 1-(1,1-dimethylethyl) 4-ethyl ester

HRID 711014Notes

Reaction equation

HRID 711014 reaction equation
[N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:29][C:30]1[N:34]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:33]=[CH:32][C:31]=1[CH2:39]Br>C1COCC1>[Br:29][C:30]1[N:34]([C:35]([CH3:37])([CH3:36])[CH3:38])[N:33]=[CH:32][C:31]=1[CH2:39][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 674914615-Bromo-4-(bromomethyl)-1-(1,1-dimethylethyl)-1H-pyrazole

Product 1

HCID 674915481,4-Piperidinedicarboxylic acid, 4-[[5-bromo-1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]methyl]-, 1-(1,1-dimethylethyl) 4-ethyl esterYield 48%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (0.37 mL, 1.47 mmol) in THF (15 mL) was cooled to −78° C. and then treated with lithium bis(trimethylsilyl) amide (1.48 mL, 1.48 mmol, 1 M toluene), dropwise. The reaction was stirred 15 minutes at −78° C., warmed to 0° C. for 30 minutes and then cooled back to −78° C. A solution of 5-bromo-4-(bromomethyl)-1-tert-butyl-1H-pyrazole (335 mg, 1.13 mmol) in THF (10 mL) was added, the mixture was stirred 1 hour at −78° C., and then allowed to stir 18 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (20 mL), stirred 30 minutes at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by flash chromatography (5-40% ethyl acetate/heptane, 25 g silica gel) to yield 256 mg of 1-tert-butyl 4-ethyl 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate as a clear oil. +ESI (M+H) 474.2, (M+2+H) 476.2; 1H NMR (400 MHz, CDCl3, δ): 7.20 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.93 (br. s., 2H), 2.84 (m, 2H), 2.66 (s, 2H), 2.10 (d, J=12.5 Hz, 2H), 1.72 (s, 9H), 1.45 (m, 11H), 1.25 (t, J=7.1 Hz, 3H).

Workup

  1. temperaturewarmed to 0° C. for 30 minutes
  2. temperaturecooled back to −78° C
  3. stirringthe mixture was stirred 1 hour at −78° C.
  4. stirringto stir 18 hours at room temperature
  5. customThe reaction was quenched with saturated aqueous ammonium chloride (20 mL)
  6. stirringstirred 30 minutes at room temperature
  7. additiondiluted with water (50 mL)
  8. extractionextracted with ethyl acetate (2×50 mL)
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe resultant residue was purified by flash chromatography (5-40% ethyl acetate/heptane, 25 g silica gel)

Sources & evidence

ORD record
ord-68d1d7a5c0d34a53a7b0f116bec4e0d6
Source dataset
uspto-grants-2015_11
Patent number
US09181252B2

Reaction notes

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