Lithium diisopropylamide → 4-[1-(3-Bromo-4-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1986913Notes

Reaction equation

HRID 1986913 reaction equation
C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:14]([CH3:15])=[CH:13][S:12][CH:11]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:34])N(OC)C)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([C:11]2[S:12][CH:13]=[C:14]([CH3:15])[C:10]=2[Br:9])=[O:34])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 27349353-Bromo-4-methylthiopheneHCID 11065582tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate

Product 1

HCID 588177114-[1-(3-Bromo-4-methyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl esterYield 89.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Under inert conditions, add a 2.0 M solution (in tetrahydrofuran/n-heptane) of lithium diisopropylamide (29.65 mmol, 14.83 mL, 1.05 equivalents) to a cold (−78° C.) solution of 3-bromo-4-methylthiophene (28.24 mmol, 5.00 g, 1.00 equivalents) in dry tetrahydrofuran (27.33 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (28.24 mmol, 7.69 g, 1.00 equivalents), dropwise. Continue stirring at −78 ° C. for 3 hours. Quench the reaction mixture with saturated ammonium chloride (aqueous, 55 mL) and allow to warm to room temperature. Extract the reaction mixture with a mixture of ethyl acetate : diethyl ether (1:1, 3×40 mL). Combine the extracts and dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography using a mixture of n-heptane:ethyl acetate (4:1) to yield a yellow, crystalline solid (9.84 g).

Workup

  1. stirringContinue stirring at −78 ° C. for 3 hours
  2. customQuench the reaction mixture with saturated ammonium chloride (aqueous, 55 mL)
  3. temperatureto warm to room temperature
  4. extractionExtract the reaction mixture
  5. additionwith a mixture of ethyl acetate : diethyl ether (1:1, 3×40 mL)
  6. dry with materialCombine the extracts and dry over magnesium sulfate
  7. filtrationfilter
  8. customevaporate
  9. customPurify the residue via flash column chromatography
  10. additiona mixture of n-heptane:ethyl acetate (4:1)

Sources & evidence

ORD record
ord-ca9f9a9757334661b1f180c66725dd6a
Source dataset
uspto-grants-2009_06
Patent number
US07550469B2

Reaction notes

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