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

HRID 1160339Notes

Reaction equation

HRID 1160339 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 (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 Na2SO4 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 as a pale yellow oil. 1H NMR (CDCl3, 300 MHz) 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 Na2SO4
  6. concentrationconcentrated in vacuo
  7. customCrude material was purified on an automated flash column with 80:20 Hexanes

Sources & evidence

ORD record
ord-5e6d279ac7c3466383cff27ba456bca8
Source dataset
uspto-grants-2010_10
Patent number
US07816375B2

Reaction notes

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