Tetrahydrofuran → 1H-Indazole-6-carbaldehyde

HRID 1615196Notes

Reaction equation

HRID 1615196 reaction equation
[H-].[Na+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.[Li]C(CC)C.[NH4+].[Cl-].C1C[O:23][CH2:22]C1>CN(C=O)C>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH:22]=[O:23])[CH:12]=2)[CH:8]=[N:9]1

Participants

7

Reactant 5

HCID 8028Tetrahydrofuran3×HCID 24758Sodium hydrideHCID 25517Ammonium Chloride2×HCID 178424716-Bromo-1H-indazoleHCID 178418400CID 53628100

Product 1

HCID 185383681H-Indazole-6-carbaldehydeYield 58%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a suspension of 60% NaH (10.0 g, 0.24 mol) in THF (240 mL) was added a suspension of 6-bromo-1H-indazole (39.4 g, 0.2 mol) in THF (280 mL) dropwise over 45 min. After addition, the resulting mixture was stirred for 1 h at rt to give a dark red clear solution which was cooled to −78° C. s-BuLi (1.4 M in hexane, 300 mL, 0.42 mol) was added dropwsie over 1 h. During this addition, additional THF (130 mL) was added to keep the mixture stirring. After the addition, the resulting mixture was stirred for 75 min at −78° C.; DMF (90 mL) was added dropwise (note: reaction solidified upon addition of DMF, occasional warming was needed to keep the mixture stirring). The resulting mixture was stirred at rt overnight and cooled to 0° C. Solid NH4Cl and saturated NH4Cl were added to quench the reaction and bring the pH to about 7. The product was extracted with EtOAc (800 mL+200 mL+300 mL, 1.3 L in total) and the combined extracts were washed with H2O (300 mL×3) and dried (Na2SO4). Evaporation of the solvent gave a dark red solid which was triturated by EtOAc (4 times, the last filtrate was purified by flash chromatography) to give the title compound (16.96 g in total, 58%) as yellow brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H, NH), 10.12 (s, 1H, CHO), 8.23 (s, 1H), 8.17 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H); MS ESI 147.0 [M+H]+, calcd for [C8H6N2O+H]+ 147.0.

Workup

  1. additionwas added
  2. additionAfter addition
  3. customto give a dark red clear solution which
  4. additionwas added dropwsie over 1 h
  5. additionwas added
  6. stirringstirring
  7. additionAfter the addition
  8. stirringthe resulting mixture was stirred for 75 min at −78° C.
  9. customreaction
  10. temperatureoccasional warming
  11. stirringstirring)
  12. stirringThe resulting mixture was stirred at rt overnight
  13. temperaturecooled to 0° C
  14. customto quench
  15. customthe reaction
  16. extractionThe product was extracted with EtOAc (800 mL+200 mL+300 mL, 1.3 L in total)
  17. washthe combined extracts were washed with H2O (300 mL×3)
  18. dry with materialdried (Na2SO4)
  19. customEvaporation of the solvent
  20. customgave a dark red solid which
  21. customwas triturated by EtOAc (4 times
  22. customthe last filtrate was purified by flash chromatography)

Sources & evidence

ORD record
ord-a24af2fce184435791e985490958b755
Source dataset
uspto-grants-2014_07
Patent number
US08765748B2

Reaction notes

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