Reaction #1702378

Reaction equation

NH4Cl

NH4Cl

s-BuLi

THF

6-bromo-1H-indazole

THF

NaH

THF

→

title compound

Yield 58.0%

1H-indazole-6-carbaldehyde

Yield 58.0%

Solvents

DMF

DMF

Conditions

Workup

1. 1
   workup.ADDITIONwas added
2. 2
   workup.ADDITIONAfter addition
3. 3
   Otherto give a dark red clear solution which
4. 4
   workup.ADDITIONwas added dropwsie over 1 h
5. 5
   workup.ADDITIONwas added
6. 6
   workup.STIRRINGstirring
7. 7
   workup.ADDITIONAfter the addition
8. 8
   workup.STIRRINGthe resulting mixture was stirred for 75 min at −78° C.
9. 9
   Otherreaction
10. 10
    Temperatureoccasional warming
11. 11
    workup.STIRRINGstirring)
12. 12
    workup.STIRRINGThe resulting mixture was stirred at rt overnight
13. 13
    Temperaturecooled to 0° C
14. 14
    Otherto quench
15. 15
    Otherthe reaction
16. 16
    ExtractionThe product was extracted with EtOAc (800 mL+200 mL+300 mL, 1.3 L in total)
17. 17
    Washthe combined extracts were washed with H2O (300 mL×3)
18. 18
    Dryingdried (Na2SO4)
19. 19
    OtherEvaporation of the solvent
20. 20
    Othergave a dark red solid which
21. 21
    Otherwas triturated by EtOAc (4 times
22. 22
    Otherthe last filtrate was purified by flash chromatography)

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.

Source