Water → Tert-butyl 3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidine-1-carboxylate

HRID 1035164Notes

Reaction equation

HRID 1035164 reaction equation
[H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CS(O[CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)(=O)=O.O>CN(C=O)C>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:21]3[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]3)=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 187719784-(Pyrrolidin-1-ylmethyl)phenol

Product 1

HCID 58043117Tert-butyl 3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidine-1-carboxylateYield 64%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
80 °C

Procedure

A mixture of NaH (55-65% disp. in oil, 0.62 g, 14.3 mmol) in dry DMF (20 mL) under nitrogen was cooled by an ice-bath. A solution of 4-(pyrrolidin-1-ylmethyl)phenol—see e.g. Bioorganic & Medicinal Chemistry Letters, 15, 3834-3837 (2005)—(2.1 g, 11.9 mmol) in DMF (20 mL) was added drop-wise. The mixture was stirred for one h and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.9 g, 15.5 mmol) in DMF (10.0 mL) was added. The mixture was heated to 80° C. overnight and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The combined organic solutions were washed with brine, dried (MgSO4) and evaporated. The residue was purified twice by column chromatography on SiO2 using 10-100% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.5 g (64%) of 1A. 1H NMR (600 MHz, CDCl3): δ 1.43 (s, 9H), 1.77 (s, 4H), 2.47 (s, 4H), 3.54 (s, 2H), 3.95-4.02 (m, 2H), 4.24-4.30 (m, 2H), 4.82-4.88 (m, 1H), 6.67 (d, 2H), 7.23 (d, 2H).

Workup

  1. temperaturewas cooled by an ice-bath
  2. additionwas added drop-wise
  3. temperaturecooled to RT
  4. extractionthe mixture was extracted three times with EtOAc (100 mL)
  5. washThe combined organic solutions were washed with brine
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe residue was purified twice by column chromatography on SiO2 using 10-100% EtOAc/heptane as eluent
  9. customThe product was further purified

Sources & evidence

ORD record
ord-51481224c8224f2c9c81a18ecc591d81
Source dataset
uspto-grants-2013_10
Patent number
US08546375B2

Reaction notes

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