Toluene → ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate

HRID 2402112Notes

Reaction equation

HRID 2402112 reaction equation
Br[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C1(C)C=CC=CC=1.[Cl-].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][Zn+])=[CH:31][CH:30]=1.O1CCCC1>CCOC(C)=O.[NH4+].[Cl-].C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][C:2]2[C:6]([C:7]#[N:8])=[C:5]([C:9]3[CH2:10][CH2:11][O:12][CH2:13][CH:14]=3)[S:4][C:3]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:31][CH:30]=1

Participants

9

Reactant 4

HCID 1140TolueneHCID 8028TetrahydrofuranHCID 66747715ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylateHCID 178478120HCID 178478120, compound

Product 1

HCID 66747497ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylateYield 43.6%

Reagents, catalysts & solvents 4

HCID 178418851HCID 178418851, compoundCatalystHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
60 °C

Procedure

In a sealable reaction vial, ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (180.0 mg, 0.5260 mmol) and a stir pea were azeotroped with toluene 3× and dried under high vacuum overnight. To the vial was added bis(tri-t-butylphosphine)palladium(0) (26.88 mg, 0.05260 mmol). Vial was evacuated and then back-filled with argon 2×, at which time was added via syringe 4-chlorobenzylzinc chloride as a 0.50 M solution in tetrahydrofuran (3.682 mL, 1.841 mmol). The reaction was heated with stirring at 60° C. for 2 h. Reaction was cooled to room temperature and then diluted with EtOAc and sat. aq. NH4Cl. Mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer extracted 2× with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered through a pad of Celite, and concentrated in vacuo to afford a yellow oil. The residue was dissolved in DCM and loaded onto 40 g ISCO column (gradient elution: 0-25% EtOAc/hexanes) to afford ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (92 mg, 43.6%) as a yellow solid. LC/MS: (AA) ES− 386, 388; 1H NMR (400 MHz, DMSO) δ 7.38-7.33 (m, 2H), 7.22 (m, 2H), 6.80-6.76 (m, 1H), 4.40 (s, 2H), 4.34-4.24 (m, 4H), 3.80 (dd, J=5.4, 5.4, 2H), 2.52 (dd, J=2.2, 5.0, 2H), 1.26 (dd, J=7.1, 7.1, 3H).

Workup

  1. customdried under high vacuum overnight
  2. customVial was evacuated
  3. additionback-filled with argon 2×, at which time
  4. temperatureThe reaction was heated
  5. customReaction
  6. temperaturewas cooled to room temperature
  7. customMixture was transferred to a separatory funnel
  8. customthe layers were separated
  9. extractionthe aqueous layer extracted 2× with EtOAc
  10. washThe combined organic layers were washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered through a pad of Celite
  13. concentrationconcentrated in vacuo
  14. customto afford a yellow oil
  15. washloaded onto 40 g ISCO column (gradient elution: 0-25% EtOAc/hexanes)

Sources & evidence

ORD record
ord-3b3b521436e745b9b3ba27d964829cbd
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

Loading…