Formaldehyde → 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid

HRID 1584385Notes

Reaction equation

HRID 1584385 reaction equation
[Li+:1].CCC[CH2-].[CH:6]([NH:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([N-]C(C)C)(C)C.[Li+].[CH2:37]=[O:38]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:1].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([CH2:37][OH:38])([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

9

Reactant 5

HCID 712FormaldehydeHCID 7912DiisopropylamineHCID 61028n-Butyl lithiumHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 2724682Lithium diisopropylamide

Product 2

HCID 2724682Lithium diisopropylamideHCID 212242511-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acidYield 20%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 12679HexamethylphosphoramideSolvent

Procedure

Lithium diisopropylamide was prepared by the addition of 2.45M N-butyllithium (69 mL, 168.8 mmol) in hexanes to a solution diisopropylamine (24 mL, 171.2 mmmol) in tetrahydrofuran (40 mL) at 0° C. with stirring for 20 minutes. Then a solution of N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (18 g, 78.5 mmol) in tetrahydrofuran (35 mL) was added to the solution of lithium diisopropylamide over 15 minutes to form a slurry, followed by hexamethylphosphoramide (2 mL). The resulting solution was stirred for 25 minutes, then stream of gaseous formaldehyde (prepared by heating paraformaldehyde (16.4 g, 189 mmol) at 175-200° C. over 5-10 minutes) was passed through the solution, which was allowed to immediately warm to room temperature. The slurry was concentrated at ambient temperature, acidified to pH 4 with 6M hydrochloric acid, saturated with solid sodium chloride, and extracted with ethyl acetate (8×100 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 1% methanol/methylene chloride, afforded N-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid as a white solid (4 g, 20%). mp 156.6-157.3° C.; 1HNMR (DMSO-d6) δ 1.25-1.37 (m, 2H), 1.38 (s, 9H), 1.85 (dm, J=13.7 Hz, 2H), 2.78-2.94 (br m, 2H), 3.41 (s, 1H), 3.70 (dm, J=12.8 Hz, 2H), 4.87 (br s, 1H), 12.34 (s, 1H); Anal. Calcd. for C12H21NO5 : C, 55.58; H, 8.16; N, 5.40. Found: C, 55.72; H, 8.10; N, 5.53.

Workup

  1. customto form a slurry
  2. stirringThe resulting solution was stirred for 25 minutes
  3. concentrationThe slurry was concentrated at ambient temperature
  4. extractionextracted with ethyl acetate (8×100 mL)
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. washChromatography over silica gel, and eluting with 1% methanol/methylene chloride

Sources & evidence

ORD record
ord-15648c7059c549d9af241fa08cb4273a
Source dataset
uspto-grants-1999_08
Patent number
US05932595

Reaction notes

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