Potassium Fluoride → 4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzo [2,1,3]thiadiazole

HRID 751284Notes

Reaction equation

HRID 751284 reaction equation
I[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[C:10]3[C:6](=[N:7][S:8][N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1

Participants

7

Reactant 4

HCID 522689Potassium FluorideHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 27762874-Iodo-2,1,3-benzothiadiazoleHCID 59710031(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid

Product 1

HCID 104486384-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzo [2,1,3]thiadiazoleYield 11.1%

Reagents, catalysts & solvents 2

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
45 °C

Procedure

Add 4-iodo-[2,1,3]-benzothiadiazole (Maybridge; 350 mg, 1.3 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 300 mg, 1.3 mmol), potassium fluoride (250 mg, 4.3 mmol), and THF (6.0 mL) to a flask under nitrogen. Purge the system with nitrogen for 10 min and add tris(dibenzylideneacetone) dipalladium(0) (120 mg, 0.13 mmol) and tri-tert-butylphosphonium tetrafluoroborate (Strem; 100 mg, 0.039 mmol). Purge the system with nitrogen for 2 min and stir for 48 h at 45° C. Filter the reaction through Celite®, rinse with chloroform/methanol, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Collect the pure fractions from the HPLC, concentrate in vacuo, take up the residue in methanol, and treat with MP-carbonate beads. Filter and concentrate in vacuo to provide the title compound (46 mg, 11%) as a pale yellow solid. Melting Range: 140-142° C. MS APCI m/e 320 (M+1). 1H NMR (CDCl3): δ 8.44-8.37 (m, 1H), 7.95-7.89 (m, 1H), 7.60-7.49 (m, 3H), 7.48-7.41 (m, 1H), 7.12-7.02 (m, 1H), 4.37-4.28 (m, 2H), 3.09-2.99 (m, 2H), 2.72-2.60 (m, 2H). HPLC: 98.3%, Rt=15.03 min. TLC (SiO2): Rf0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).

Workup

  1. customPurge the system with nitrogen for 10 min
  2. customPurge the system with nitrogen for 2 min
  3. filtrationFilter
  4. customthe reaction through Celite®
  5. washrinse with chloroform/methanol
  6. concentrationconcentrate in vacuo
  7. customPurify by flash column chromatography
  8. customCollect the pure fractions from the HPLC
  9. concentrationconcentrate in vacuo
  10. additiontreat with MP-carbonate beads
  11. filtrationFilter
  12. concentrationconcentrate in vacuo

Sources & evidence

ORD record
ord-51be9830e9834a1684f24ba8eea71af2
Source dataset
uspto-grants-2008_07
Patent number
US07405299B2

Reaction notes

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