Hydrochloric Acid → 1-(4-Phenoxyphenyl)ethan-1-amine

HRID 911319Notes

Reaction equation

HRID 911319 reaction equation
[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:23].[Na+].Cl>CO>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([NH2:23])[CH3:1])=[CH:5][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 2367834'-PhenoxyacetophenoneHCID 517165Ammonium AcetateHCID 5003444Sodium cyanoborohydride

Product 1

HCID 592071-(4-Phenoxyphenyl)ethan-1-amineYield 30%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Mix 4-phenoxyacetophenone (5.3 g, 25 mmol), ammonium acetate (14.5 g, 187.5 mmol) and sodium cyanoborohydride (3.2 g, 50 mmol) in anhydrous methanol (200 mL). Stir for 18 h at ambient temperature. Acidify with 1N aqueous HCl (10 mL), dilute, extract with ethyl ether (3×150 mL), dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1, 1:1 and 0:1) and EtOAc/methanol (1:1) to give (±)-1-(4-phenoxyphenyl)-ethylamine (1.6 g, 30%). Dissolve the racemate (1.1 g, 5.2 mmol) in DCM (100 mL), add triethylamine (1.6 mL, 11.4 mmol) followed by di-tert-butyl-dicarbonate (1.7 g, 7.8 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give [α-methyl-(4′-phenoxy)-benzylamino]carbamic acid tert-butyl ester as an off-white solid (1.3 mg, 81%). Separate via chiral chromatography (heptane/isopropanol/DMEA 95:5:0.2, 4.6×250 mm Chiralpak AD, 1 mL/min, UV detector at 260 nm) to give [α-methyl-(4′-phenoxy)benzylamino]carbamic acid tert-butyl ester, isomer 1 (315 mg, chiral HPLC: tR=7.35 min; 99.1% ee) and [α-methyl-(4′-phenoxy)benzyl-aminocarbamic acid tert-butyl ester, isomer 2 (400 mg, chiral HPLC: tR=8.7 min; 97.2% ee). Dissolve [α-methyl-(4′-phenoxy)benzylamino]carbamic acid tert-butyl ester isomer 1 or isomer 2 in DCM/trifluoroacetic acid (1:1, 20 mL) to give, after solvent evaporation and chromatography over SCX column, 1-(4-phenoxyphenyl)-ethylamine, isomer 1 (Preparation 146) and 1-(4-phenoxyphenyl)-ethylamine, isomer 2 (Preparation 147). MS (ES+) m/z: 214 (M+H)+.

Workup

  1. additiondilute
  2. extractionextract with ethyl ether (3×150 mL)
  3. dry with materialdry over MgSO4
  4. filtrationfilter
  5. concentrationconcentrate in vacuo
  6. customPurify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1, 1:1 and 0:1) and EtOAc/methanol (1:1)

Sources & evidence

ORD record
ord-42fea5762fd64edebc88bfcf756ebb46
Source dataset
uspto-grants-2011_09
Patent number
US08022062B2

Reaction notes

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