(Trifluoromethyl)benzene → tert-butyl 5'-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

HRID 1508296Notes

Reaction equation

HRID 1508296 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2)(=[O:3])[CH3:2].[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[CH:32]=[C:31]([Cl:33])[C:30](Cl)=[C:29]([Cl:35])[CH:28]=1)=O.C([O-])([O-])=O.[Cs+].[Cs+].[F:44]C(F)(F)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:35][C:29]1[CH:28]=[C:27]([C:25]([C:24]([F:37])([F:36])[F:23])=[CH:2][C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9]2([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[O:8][CH2:7]3)=[O:3])[CH:32]=[C:31]([Cl:33])[C:30]=1[F:44]

Participants

6

Reactant 4

HCID 7368(Trifluoromethyl)benzeneHCID 10796Cesium carbonateHCID 580775942,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-oneHCID 70663143tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate

Product 1

HCID 124000325tert-butyl 5'-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylateYield 80.64%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

In 100 mL two neck RBF equipped with dean-stark apparatus a stirred solution of tert-butyl 5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 1, 4.5 g, 14.851 mmol) in toluene (13.5 mL) and trifluorotoluene (13.5 mL) was added 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)-ethanone (4.44 g, 17.079 mmol) and Cs2CO3 (0.483 g, 1.485 mmol) at room temperature. Resulting reaction mixture was heated at 110° C. for 16 hours. After complete consumption of starting material, reaction mixture was diluted with ter-butylmethyl ether (30 mL) and filtered through celite bed. Filtrate was concentrated under vacuum to afford brown sticky oil (9.01 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 20% ethyl acetate in n-hexane to give light yellow solid (6.54 g, 80.64%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.10 (d, J=9.52 Hz, 2H), 4.32 (d, J=9.36 Hz, 2H), 5.12 (s, 2H), 7.20 (d, J=9.76 Hz, 2H), 7.39 (s, 1H), 7.56 (d, J=7.96 Hz, 1H), 7.67 (s, 1H), 7.84 (d, J=7.96 Hz, 1H). LC-MS (m/z): 374.1 (M+H).

Workup

  1. customResulting
  2. customreaction mixture
  3. customAfter complete consumption of starting material, reaction mixture
  4. additionwas diluted with ter-butylmethyl ether (30 mL)
  5. filtrationfiltered through celite bed
  6. concentrationFiltrate was concentrated under vacuum
  7. customto afford brown sticky oil (9.01 g, crude)
  8. customCrude compound was purified by column chromatography
  9. washDesired compound was eluted in 20% ethyl acetate in n-hexane

Sources & evidence

ORD record
ord-8ff46c8102624d57bd8c78045b98fa21
Source dataset
uspto-grants-2015_12
Patent number
US09221835B2

Reaction notes

Loading…