Lithium diisopropylamide → 4-[1-(3-Bromo-5-methoxymethyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 501304Notes

Reaction equation

HRID 501304 reaction equation
C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[C:12]([CH2:15][O:16][CH3:17])[S:13][CH:14]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:36])N(OC)C)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([C:14]2[S:13][C:12]([CH2:15][O:16][CH3:17])=[CH:11][C:10]=2[Br:9])=[O:36])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 11065582tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylateHCID 150183124-Bromo-2-(methoxymethyl)thiophene

Product 1

HCID 588176604-[1-(3-Bromo-5-methoxymethyl-thiophen-2-yl)-methanoyl]-piperidine-1-carboxylic acid tert-butyl esterYield 90.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Add lithium diisopropyl amide (13.20 mL, 26.37 mmol, 1.05 equivalents) to a stirred, cold (−78° C.) solution of 4-bromo-2-methoxymethyl-thiophene (5.20 g, 25.11 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 24.30 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (6.84 g, 25.11 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 16.40 mL), dropwise. Stir the resulting solution at −78° C. for 3 hours. Quench the reaction mixture with saturated sodium chloride (aqueous, 50 mL). Allow the resulting mixture to warm to room temperature and extract with a mixture of ethyl acetate: diethyl ether (1:1, 3×35 mL). Combine the extracts, dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with a mixture of n-heptane:ethyl acetate (4:1) to yield the desired product as a yellow oil (9.47 g). LC/MS (ESI), m/e 362 (M-56) and 418 (MH+), retention time 2.08 minutes. Condition II.

Workup

  1. stirringStir the resulting solution at −78° C. for 3 hours
  2. customQuench the reaction mixture with saturated sodium chloride (aqueous, 50 mL)
  3. temperatureto warm to room temperature
  4. extractionextract with a mixture of ethyl acetate: diethyl ether (1:1, 3×35 mL)
  5. dry with materialCombine the extracts, dry over magnesium sulfate
  6. filtrationfilter
  7. customevaporate
  8. customPurify the residue via flash column chromatography
  9. washeluting with a mixture of n-heptane:ethyl acetate (4:1)

Sources & evidence

ORD record
ord-56f5adfb38f84eaba34c1bea232475ed
Source dataset
uspto-grants-2010_08
Patent number
US07772252B2

Reaction notes

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