tert-Butyl 4-oxopiperidine-1-carboxylate → Tert-butyl 4-(4-bromo-1,3-thiazol-2-yl)-4-hydroxypiperidine-1-carboxylate

HRID 1051646Notes

Reaction equation

HRID 1051646 reaction equation
C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>ClCCl>[Br:12][C:10]1[N:11]=[C:7]([C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[S:8][CH:9]=1

Participants

5

Reactant 3

HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 27632972,4-Dibromo-1,3-thiazoleHCID 178418339Butyllithium

Product 1

HCID 66749307Tert-butyl 4-(4-bromo-1,3-thiazol-2-yl)-4-hydroxypiperidine-1-carboxylateYield 95%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

n-Butyllithium (1.6 M in hexanes, 1.48 mL, 2.37 mmol) was added dropwise to a −78° C. solution of 2,4-dibromothiazole (0.524 g, 2.16 mmol) in dichloromethane (11 mL). The mixture stirred at −78° C. for 20 minutes, and then tert-butyl 4-oxopiperidine-1-carboxylate (0.516 g, 2.59 mmol) was added in 8 portions. The reaction mixture stirred at −78° C. for 10 minutes. The cooling bath was removed, and the reaction was allowed to warm to rt over 1 h. The reaction mixture was cooled to −30° C. and was then quenched by the addition of saturated aqueous ammonium chloride solution. The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 5-60% ethyl acetate-hexane) to afford tert-butyl 4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.744 g, 95%). MS (ESI, pos. ion) m/z 363, 365 [M+H]+.

Workup

  1. stirringThe reaction mixture stirred at −78° C. for 10 minutes
  2. customThe cooling bath was removed
  3. temperatureto warm to rt over 1 h
  4. temperatureThe reaction mixture was cooled to −30° C.
  5. customwas then quenched by the addition of saturated aqueous ammonium chloride solution
  6. customThe aqueous phase was separated
  7. extractionextracted with dichloromethane
  8. dry with materialthe combined organic phases were dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 5-60% ethyl acetate-hexane)

Sources & evidence

ORD record
ord-a4732ae397034b34b4661568f26869cc
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

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