Water → tert-Butyl 3-(4-((dimethylamino)methyl)-3-methylphenoxy)azetidine-1-carboxylate

HRID 1035185Notes

Reaction equation

HRID 1035185 reaction equation
[H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[CH:9][C:8]=1[CH3:14])[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 580431044-((Dimethylamino)methyl)-3-methylphenol

Product 1

HCID 58043102tert-Butyl 3-(4-((dimethylamino)methyl)-3-methylphenoxy)azetidine-1-carboxylateYield 55%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
80 °C

Procedure

A mixture of NaH (55-65% disp. in oil, 1.0 g, 23 mmol) in dry DMF (25 mL) under nitrogen was cooled by an ice-bath. A solution of 20A (2.9 g, 18 mmol) in DMF (20 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (5.3 g, 21 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (200 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic phases were dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by column chromatography on SiO2 using 5-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 3.1 g (55%) of 20B as a semi-solid. 1H NMR (600 MHz, CDCl3): δ 1.44 (s, 9H), 2.21 (s, 6H), 2.32 (s, 3H), 3.29 (s, 2H), 3.93-4.02 (m, 2H), 4.21-4.32 (m, 2H), 4.79-4.89 (m, 1H), 6.48 (d, 1H), 6.55 (s, 1H), 7.12 (d, 1H).

Workup

  1. temperaturewas cooled by an ice-bath
  2. temperaturecooled to RT
  3. extractionthe mixture was extracted three times with EtOAc (100 mL)
  4. dry with materialThe combined organic phases were dried (MgSO4)
  5. customthe solvent was removed by evaporation
  6. customThe residue was purified by column chromatography on SiO2 using 5-75% EtOAc/heptane as eluent
  7. customThe product was further purified

Sources & evidence

ORD record
ord-21c74f6d04864ce98378bc7314cd75cd
Source dataset
uspto-grants-2013_10
Patent number
US08546375B2

Reaction notes

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