Butyl vinyl ether → tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

HRID 1508290Notes

Reaction equation

HRID 1508290 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2.[CH:21]([O:23]CCCC)=[CH2:22].C([O-])(O)=O.[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)[O:6][CH2:5]2)(=[O:23])[CH3:22]

Participants

7

Reactant 3

HCID 8108Butyl vinyl etherHCID 516892Sodium BicarbonateHCID 66555337tert-Butyl 5'-bromo-3'h-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate2×

Product 1

HCID 70663143tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylateYield 94.2%

Reagents, catalysts & solvents 3

HCID 812191,3-Bis(diphenylphosphino)propaneCatalystHCID 167845palladium(II) acetateCatalystHCID 702EthanolSolvent

Conditions

Temperature
96 °C

Procedure

In 100 mL autoclave vessel a solution of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Intermediate 1, 10 g, 29.4 mmol) in ethanol (35 mL) was degassed with nitrogen gas for 30 minutes. To the resulting reaction mixture was added TEA (7.37 mL, 52.9 mmol), butyl vinyl ether (7.60 mL, 58.8 mmol), dppp (0.727 g, 1.8 mmol) followed by addition of Pd(OAc)2 (0.198 g, 0.9 mmol) at room temperature. Reaction mixture was heated at 96° C. for 16 hours in autoclave. After complete consumption of starting material, reaction mixture was quenched with addition of 1N HCl (10 mL) to adjust pH 2-3 then reaction mixture was stirred for 2 hours. The pH of reaction mixture was adjusted to 7 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with brine (250 mL), dried over sodium sulfate and concentrated under reduced pressure to get crude compound as dark brown sticky oil 12 g as crude material. The crude was purified by column chromatography on silica gel using 230-400 silica mesh. Desired compound was eluted in 30% ethyl acetate in n-hexane to give (8.4 g) compound as off white sticky semi-solid. 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 2.61 (s, 3H), 4.13 (d, J=9.64 Hz, 2H), 4.32 (d, J=9.52 Hz, 2H), 5.14 (s, 2H), 7.54 (d, J=7.96 Hz, 1H), 7.80 (s, 1H), 7.97 (d, J=7.92 Hz, 1H); VETERINARY (m/z): 304.0 (M+H).

Workup

  1. customTo the resulting reaction mixture
  2. customReaction mixture
  3. customAfter complete consumption of starting material, reaction mixture
  4. customwas quenched with addition of 1N HCl (10 mL)
  5. customreaction mixture
  6. customThe pH of reaction mixture
  7. extractionextracted with ethyl acetate (3×100 mL)
  8. washCombined organic layers were washed with brine (250 mL)
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customto get crude compound as dark brown sticky oil 12 g as crude material
  12. customThe crude was purified by column chromatography on silica gel using 230-400 silica mesh
  13. washDesired compound was eluted in 30% ethyl acetate in n-hexane

Sources & evidence

ORD record
ord-bd976e40335c4781b728cec7dc952c54
Source dataset
uspto-grants-2015_12
Patent number
US09221835B2

Reaction notes

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