Benzaldehyde → 3-Amino-1-benzyl-3-[4-(benzyloxy)benzyl]azepan-2-one

HRID 1271491Notes

Reaction equation

HRID 1271491 reaction equation
S([O-])([O-])(=O)=O.[Mg+2].[NH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22].C(N(CC)CC)C.C(=O)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:48]([O:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Cl)=[CH:58][CH:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl.O1CCCC1>[NH2:7][C:8]1([CH2:60][C:59]2[CH:62]=[CH:63][C:56]([O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:57][CH:58]=2)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=[O:22]

Participants

9

Reactant 6

HCID 240BenzaldehydeHCID 8471TriethylamineHCID 24083Sulfuric acid magnesium salt (1:1)HCID 700424-Benzyloxybenzyl chlorideHCID 2733832Lithium HexamethyldisilazideHCID 186125993-Amino-1-benzyl-azepan-2-one

Product 1

HCID 184519093-Amino-1-benzyl-3-[4-(benzyloxy)benzyl]azepan-2-one

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Magnesium sulfate (5.0 g, 41.5 mmol) was added to a solution of commercially available 3-amino-1-benzylazepan-2-one (940 mg, 4.31 mmol), triethylamine (0.60 mL, 4.31 mmol) and benzaldehyde (0.46 mL, 4.52 mmol) in dichloromethane (20 mL). After 18 h, the mixture was filtered and concentrated to give the crude imine. Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran; 1.42 mL, 1.42 mmol) was added to a solution of the crude imine (363 mg, 1.19 mmol) in tetrahydrofuran (4 mL). After 2 h, the mixture was cooled to 0° C. 4-benzyloxybenzyl chloride (290 mg, 1.24 mmol) was added and the mixture was allowed to warm to ambient temperature. After an additional 18 h, the mixture was quenched with 1N hydrochloric acid (10 mL). After 30 min, the mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium carbonate, water, saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→90% dichloromethane/10% methanol (10% ammonium hydroxide/methanol)] gave the title compound. (109 mg) MS 415 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.44–7.36 (m, 4H), 7.34–7.23 (m, 6H), 7.03 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.29 (s, 2H), 4.64–4.52 (m, 2H), 3.31–3.26 (m, 1H), 3.22–3.18 (m, 1H), 3.02 (d, J=13.4 Hz, 1H), 2.86 (d, J=13.7 Hz, 1H), 1.90–1.75 (m, 4H), 1.72–1.60 (m, 2H), 1.49–1.42 (m, 2H).

Workup

  1. filtrationthe mixture was filtered
  2. concentrationconcentrated
  3. customto give the crude imine
  4. waitAfter 2 h
  5. temperatureto warm to ambient temperature
  6. waitAfter an additional 18 h
  7. customthe mixture was quenched with 1N hydrochloric acid (10 mL)
  8. waitAfter 30 min
  9. extractionthe mixture was extracted with ethyl acetate
  10. washthe organic layer was washed with aqueous saturated sodium carbonate, water, saturated brine
  11. dry with materialdried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurification by silica gel chromatography [100% dichloromethane→90% dichloromethane/10% methanol (10% ammonium hydroxide/methanol)]

Sources & evidence

ORD record
ord-006ff5c99a9f4ac99f2fab6c0ac6bdb8
Source dataset
uspto-grants-2007_04
Patent number
US07205292B2

Reaction notes

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