N-Phenyl-2-benzyloxyethylamine → 9-(2-Benzyloxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide

HRID 1753958Notes

Reaction equation

HRID 1753958 reaction equation
[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8](Br)[C:7]=1O)=[O:5])[CH3:2].[CH2:17]([O:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[C:7]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:26][CH2:25][O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH2:9][CH:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 571665N-Phenyl-2-benzyloxyethylamineHCID 666795353-Bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide

Product 1

HCID 666788489-(2-Benzyloxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamideYield 8%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 3-bromo-2-hydroxy-5-methyl-cyclohex-1-enecarboxylic acid diethylamide (47) (4.0 g, 14 mmol) and (2-benzyloxy-ethyl)-phenyl-amine (21; prepared according to Example 3(c)) (6.3 g, 28 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (14 mL) and dry zinc chloride (5.72 g, 42 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL) then dried and concentrated in vacuo. The crude mixture was purified by SCX cartridge (40 mL) and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10-50% B, 100 g, 12 CV, 85 mL/min) to afford 467 mg (8%) of 9-(2-Benzyloxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (48) as a white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.20-1.40 (9H, m, CH3 and N(CH2CH3)2), 1.90-2.20 (3H, m, 2-CH and 3-CH2), 2.35-2.45 (1H, m, 1-CH2), 2.85-2.95 (1H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 3.70-3.80 (1H, m, 4-CH), 4.10-4.30 (4H, m, NCH2CH2OBn), 4.43 (2H, s, OCH2Ph), and 7.00-7.30 (9H, m, CHCHCHCH and Ph).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux under N2 for 16 h
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue was dissolved in ethyl acetate (200 mL)
  5. washwashed with 2 N HCl (50 mL), water (2×50 mL) and aqueous potassium carbonate solution (2×50 mL)
  6. customthen dried
  7. concentrationconcentrated in vacuo
  8. customThe crude mixture was purified by SCX cartridge (40 mL)
  9. washsilica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10-50% B, 100 g, 12 CV, 85 mL/min)

Sources & evidence

ORD record
ord-aae0b1f27d9c43aaa61f05b623e3b82d
Source dataset
uspto-grants-2015_10
Patent number
US09168317B2

Reaction notes

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