Hydrochloric Acid → Methyl 1-benzyl-2-oxoazepane-3-carboxylate

HRID 479822Notes

Reaction equation

HRID 479822 reaction equation
[CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li:8]CCCC.[Li+].CC([N-]C(C)C)C.[CH2:21]([N:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:36](=O)([O:39]C)[O:37][CH3:38].Cl>CCOCC.C1COCC1>[Li+:8].[CH3:2][CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:38][O:37][C:36]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][N:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:29]1=[O:35])=[O:39]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 7912DiisopropylamineHCID 12021Dimethyl CarbonateHCID 14910681-Benzylazepan-2-oneHCID 2724682Lithium diisopropylamideHCID 178418339Butyllithium

Product 2

HCID 2724682Lithium diisopropylamideHCID 21902024Methyl 1-benzyl-2-oxoazepane-3-carboxylateYield 77%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

LDA was prepared as follows: Diisopropyl amine (15.2 mL, 110 mmol) freshly distilled under N2 and over CaH2 was added to 110 mL of anhydrous THF in a dry flask, and the solution was cooled to 0° C. in an ice bath. nBuLi (73.3 mL, 111 mmol) was added dropwise, and the reaction was stirred at 0° C. for 1 hour. The freshly prepared LDA was added dropwise to a −70° C. solution of 1-Benzyl-azepan-2-one (142) (10.98 g, 544.0 mmol) dissolved in anhydrous Et2O (70 mL). The reaction was stirred at −70° C. for 1 hour, then dimethyl carbonate (4.55 mL, 544 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight. The reaction was judged complete by HPLC, and was slowly poured into 5N HCl stirring in an ice bath. The organic layer was extracted. The aqueous layer was washed with CH2Cl2 two times, and the combined organics were dried with sodium sulfate, filtered and concentrated in vacuo. Crude material was purified on an automated flash column with 80:20 Hexanes:EtOAc to obtain 10.85 g, (77%) of 1-benzyl-2-oxo-azepane-3-carboxylic acid methyl ester (143) as a pale yellow oil. 1H NMR (CDCl3) 7.42-7.10 (5H, broad s), 4.61 (1H, d, J=14.7 Hz), 4.50 (1H, d, J=14.7 Hz), 3.74 (3H, s), 3.7-3.64 (1H, m), 3.40-3.13 (2H, m), 2.12-1.98 (1H, m), 1.92-1.73 (2H, m), 1.66-1.42 (2H, m), 1.32-1.16 (1H, m) ppm. 13C NMR (CDCl3, 75 MHz) 171.94, 171.04, 137.28, 128.55, 128.24, 127.43, 52.15 (2), 51.27, 48.31, 27.87, 27.41, 25.91 ppm. LRMS: 261.73.

Workup

  1. stirringThe reaction was stirred at −70° C. for 1 hour
  2. temperatureto warm to room temperature overnight
  3. extractionThe organic layer was extracted
  4. washThe aqueous layer was washed with CH2Cl2 two times
  5. dry with materialthe combined organics were dried with sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customCrude material was purified on an automated flash column with 80:20 Hexanes

Sources & evidence

ORD record
ord-1b7c1223bb314ae591dc3a48058c03aa
Source dataset
uspto-grants-2003_11
Patent number
US06645980B1

Reaction notes

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