N-Hydroxyacetamidine → tert-butyl (1R,5R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

HRID 705696Notes

Reaction equation

HRID 705696 reaction equation
[C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].[C@:9]12([C:22](OCC)=O)[CH2:14][C@H:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2>CC1CCCO1>[CH3:2][C:1]1[N:3]=[C:22]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[O:5][N:4]=1

Participants

5

Reactant 3

HCID 30926N-HydroxyacetamidineHCID 10942334Sodium MethoxideHCID 866993163-tert-butyl 1-ethyl (1R,5R)-3-azabicyclo(3.1.0)hexane-1,3-dicarboxylate

Product 1

HCID 86699315tert-butyl (1R,5R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylateYield 56.5%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Procedure

2-Methyl-tetrahydrofuran (40 mL), acetamide oxime (0.93 g, 0.0125 mol) and sodium methoxide (1.1 g, 0.020 mol) were added to (1R,5R)-3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (142) (1.27 g, 0.0050 mol) and the mixture was heated to reflux for 3 hours. Upon cooling the suspension was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic layer was washed with water (25 mL), saturated sodium chloride (25 mL) and dried over Na2SO4. The mixture was concentrated and the residue was chromatographed over 25 g of silica gel with 15-25% ethyl acetate/hexanes, to obtain 0.75 g of clear colorless oil. MS (ESI) m/z 304 [M+K]+. 1H NMR (CDCl3) δ 1.16-1.17 (m, 1H), 1.46 (s, 9H), 1.60 (s, 1H), 1.72-1.75 (m, 1H), 2.36 (s, 3H), 3.49-3.51 (m, 1H), 3.65-3.79 (dd, 1H), 3.91-4.00 (m, 2H).

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux for 3 hours
  3. temperatureUpon cooling the suspension
  4. customwas partitioned between ethyl acetate (100 mL) and water (25 mL)
  5. washThe organic layer was washed with water (25 mL), saturated sodium chloride (25 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationThe mixture was concentrated
  8. customthe residue was chromatographed over 25 g of silica gel with 15-25% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-14f104d9fedb4ba7997001b950d05654
Source dataset
uspto-grants-2015_11
Patent number
US09174972B2

Reaction notes

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