Lithium Hexamethyldisilazide → 1-tert-butyl 4-ethyl 4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate

HRID 880900Notes

Reaction equation

HRID 880900 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[CH2:30][C:31]1[C:32]([I:39])=[N:33][N:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=1>O1CCCC1>[I:39][C:32]1[C:31]([CH2:30][C:4]2([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]2)=[CH:35][N:34]([CH:36]([CH3:38])[CH3:37])[N:33]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 674917084-(bromomethyl)-3-iodo-1-isopropyl-1H-pyrazole

Product 1

HCID 674915631-tert-butyl 4-ethyl 4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylateYield 78.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (0.54 mL, 2.11 mmol) in tetrahydrofuran (15 mL) in a dry 100 mL round bottom flask under nitrogen was cooled to −78° C. and then treated with lithium bis(trimethylsilyl) amide (1 M toluene, 2.13 mL, 2.13 mmol). After stirring for 45 minutes at −78° C., 4-(bromomethyl)-3-iodo-1-isopropyl-1H-pyrazole (535 mg, 1.63 mmol) was added as a suspension in 10 mL tetrahydrofuran. The mixture was stirred 1 hour at −78° C. and then allowed to stir 18 hours at room temperature. The reaction mixture was quenched with 20 mL saturated aqueous ammonium chloride, stirred 30 minutes at room temperature, diluted with 50 mL water and then extracted with ethyl acetate (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-80% ethyl acetate/heptanes, 25 g silica gel) to yield 1-tert-butyl 4-ethyl 4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (645 mg) as a clear oil. +ESI (M-tBu) 450.1; 1H NMR (400 MHz, CDCl3, δ): 7.02 (s, 3H), 4.44 (spt, J=6.6 Hz, 1H), 4.17 (m, 2H), 3.92 (m, 2H), 2.86 (m, 2H), 2.62 (s, 2H), 2.08 (m, 2H), 1.46 (m, 17H), 1.25 (t, J=7.1 Hz, 3H).

Workup

  1. stirringThe mixture was stirred 1 hour at −78° C.
  2. stirringto stir 18 hours at room temperature
  3. customThe reaction mixture was quenched with 20 mL saturated aqueous ammonium chloride
  4. stirringstirred 30 minutes at room temperature
  5. additiondiluted with 50 mL water
  6. extractionextracted with ethyl acetate (2×50 mL)
  7. dry with materialThe combined organics were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by flash chromatography (10-80% ethyl acetate/heptanes, 25 g silica gel)

Sources & evidence

ORD record
ord-cb77ae7a6e0e41309d7d30bdef44cb85
Source dataset
uspto-grants-2015_03
Patent number
US08993586B2

Reaction notes

Loading…