Tetrahydrofuran → Ethyl 3-bromo-4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxylate

HRID 2401871Notes

Reaction equation

HRID 2401871 reaction equation
[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1.O1CCCC1>O>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:25]2[CH2:26][CH2:27][O:28][CH:23]([CH2:22][OH:21])[CH2:24]2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 10796Cesium carbonateHCID 3497988Morpholin-2-ylmethanolHCID 66747477Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate

Product 1

HCID 66747938Ethyl 3-bromo-4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxylateYield 41%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (0.360 g, 1.06 mmol), cesium carbonate (1.05 g, 3.21 mmol), 2-hydroxymethylmorpholine (137 mg, 1.17 mmol), and tetrahydrofuran (4.5 mL, 36 mmol) were combined in a 15 mL pressure vessel equipped with a stir bar. The vessel was sealed, and the r×n was heated @ 90° C. with stirring for 4 hours. The reaction was cooled to rt. The r×n was poured into water/saline. The reaction vessel was washed out with additional water, then ethyl acetate, and these were added to the quench which was then transferred to a separatory funnel. The aqueous layer was extracted 3× with EtOAc. The extracts were combined, washed with saline, dried over Na2SO4, filtered, added Celite, concentrated in vacuo, and dried on high vac 30 min. Purified dry load via silica gel chromatography (gradient elution: 0-60% EtOAc/hexanes) to give 163 mg solid (41% yield). 1H NMR (400 MHz, DMSO) δ 4.91 (t, J=5.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.99-3.92 (m, 3H), 3.69-3.58 (m, 2H), 3.50 (dt, J=10.5, 5.2 Hz, 1H), 3.41 (dt, J=11.5, 5.8 Hz, 1H), 3.37-3.27 (m, 1H, under H2O peak), 3.15-3.08 (m, 1H), 1.26 (t, J=7.1 Hz, 3H).

Workup

  1. customequipped with a stir bar
  2. customThe vessel was sealed
  3. temperatureThe reaction was cooled to rt
  4. washThe reaction vessel was washed out with additional water
  5. additionethyl acetate, and these were added to the
  6. customquench which
  7. customwas then transferred to a separatory funnel
  8. extractionThe aqueous layer was extracted 3× with EtOAc
  9. washwashed with saline
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. additionadded Celite
  13. concentrationconcentrated in vacuo
  14. customdried on high vac 30 min
  15. customPurified
  16. customdry load
  17. washvia silica gel chromatography (gradient elution: 0-60% EtOAc/hexanes)

Sources & evidence

ORD record
ord-358f195456cb486faca29886759ae1b0
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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