Reaction #69792

Reaction equation

4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole

barium hydroxide octahydrate

tributylamine

4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane

5-(tert-butyldimethylsilyloxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

→

title compound

(E)-1-(Tetrahydro-2H-pyran-2-yl)-3-(2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazol-5-ol

Solvents

water

DMF

Conditions

Workup

1. 1
   OtherSparge with nitrogen
2. 2
   Otherequipped with magnetic stirring, temperature probe, and condenser with septa for 10 minutes
3. 3
   Othercontinue sparging for 10 minutes
4. 4
   Otherto sparge for an additional 0.5 hours
5. 5
   TemperatureCool the reaction mixture to below 40° C.
6. 6
   Othercontinue sparging for 10 minutes
7. 7
   OtherAdd 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride DCM complex (1.3 g, 1.56 mmol) to the reaction
8. 8
   Othercontinue sparging 0.5 hours
9. 9
   TemperatureHeat the mixture at 95° C. under nitrogen for 3 hours
10. 10
    workup.ADDITIONDilute the mixture with EA
11. 11
    Filtrationfilter through a Celite® pad
12. 12
    WashWash the pad with brine (400 mL)
13. 13
    Otherseparate the filtrate layers
14. 14
    WashWash the organic layer with brine
15. 15
    Extractionextract the combined aqueous layers with EA
16. 16
    Concentrationconcentrate to a brown oil
17. 17
    workup.DISSOLUTIONDissolve the oil in DCM (100 mL)
18. 18
    workup.ADDITIONadd to a silica gel pad
19. 19
    WashElute the pad with eluent (50% EA in hexanes followed by 70% EA in hexanes)
20. 20
    Otherto afford a light brown oil
21. 21
    OtherTriturate with MTBE (100 mL)

Procedure

Sparge with nitrogen a mixture of 5-(tert-butyldimethylsilyloxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (14 g, 30.54 mmol) in DMF (150 mL) in a 500 mL 3-neck round bottom flask equipped with magnetic stirring, temperature probe, and condenser with septa for 10 minutes. To the resulting solution add tributylamine (TBA, 6.7 g, 36.1 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.0 g, 43.18 mmol) and continue sparging for 10 minutes. To the resulting mixture add bis(triphenylphosphine) palladium (II) chloride (0.45 g, 0.63 mmol) and continue to sparge for an additional 0.5 hours. Heat the mixture at 95-100° C. for 18 hours. Cool the reaction mixture to below 40° C. and charge with 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (9.8 g, 30.42 mmol). To the resulting mixture add barium hydroxide octahydrate (19.3 g, 60.3 mmol) and water (13 mL) and continue sparging for 10 minutes. Add 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride DCM complex (1.3 g, 1.56 mmol) to the reaction and continue sparging 0.5 hours. Heat the mixture at 95° C. under nitrogen for 3 hours. Dilute the mixture with EA and filter through a Celite® pad. Wash the pad with brine (400 mL) and separate the filtrate layers. Wash the organic layer with brine and extract the combined aqueous layers with EA. Combine the organic solutions and concentrate to a brown oil. Dissolve the oil in DCM (100 mL) and add to a silica gel pad. Elute the pad with eluent (50% EA in hexanes followed by 70% EA in hexanes) to afford a light brown oil. Triturate with MTBE (100 mL) to afford the title compound as a solid. Yield: 5 g (37%). MS (ES) m/z 439 [M+1]+.

Source