Tetrahydrofuran → 2,4-Dimethoxy-5-thien-2-ylbenzaldehyde

HRID 347332Notes

Reaction equation

HRID 347332 reaction equation
Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C1COCC1.[F-].[K+]>O.CCOC(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 522689Potassium FluorideHCID 6683465-Bromo-2,4-dimethoxybenzaldehydeHCID 27339602-Thiopheneboronic acid

Product 1

HCID 161161832,4-Dimethoxy-5-thien-2-ylbenzaldehydeYield 94%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

Ex-1A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g, 83 mmol), thiophene-2-boronic acid (11.6 g, 91 mmol) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g, 174 mmol), and Pd(tBu3P)2 (0.424 g, 0.83 mmol). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 in Hg) affording 19.32 g (94%) of the desired 2,4-dimethoxy-5-thien-2-ylbenzaldehyde as a light off-white solid, mp 125–126° C. 1H-NMR (300 MHz, CDCl3): 10.34 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J=3.5 and 1.5 Hz), 7.31 (dd, 1 H, J=5.2 and 1.5 Hz), 7.07 (dd, 1 H, J=5.2 and 3.5 Hz), 6.51 (s, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H). HRMS (EI) Calcd. for C13H12O3S: 248.0507 (M+); Found: 248.0504.

Workup

  1. customfitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter
  2. customNitrogen was bubbled into the resulting solution for 20 min
  3. customtransferred to a separatory funnel
  4. extractionthe aqueous layer was extracted with EtOAc (100 mL)
  5. filtrationThe combined organic cuts were filtered through a pre-washed pad of solka floc (5 g)
  6. washwere washed with fresh EtOAc (200 mL)
  7. concentrationThe resultant filtrate was concentrated to dryness
  8. dissolutionThe crude product was dissolved in THF (38 mL)
  9. customcrystallized upon heptane (152 mL) addition
  10. filtrationThe product was filtered
  11. customdried to a constant weight in the vacuum oven (38° C., 20 in Hg)

Sources & evidence

ORD record
ord-15f7157770b74f169dc94629701e98cd
Source dataset
uspto-grants-2007_02
Patent number
US07173129B2

Reaction notes

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