Sodium Bicarbonate → 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate

HRID 1910075Notes

Reaction equation

HRID 1910075 reaction equation
Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]3)O1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[NH2:11][C:7]1[C:6]2[C:2]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]4)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 184507953-Bromofuro[3,2-c]pyridin-4-amineHCID 18451469tert-butyl 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate

Product 1

HCID 668240741,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylateYield 77.6%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

3-Bromofuro[3,2-c]pyridin-4-amine (7.23 g, 33.9 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (12.90 g, 37.4 mmol), PdCl2(dppf)-CH2Cl2 adduct (1.39 g, 1.702 mmol), 1,4-Dioxane (300 mL), and saturated aqueous sodium bicarbonate (100 mL, 100 mmol) were added to a 3-neck, 1 L flask equipped with a reflux condenser and a heating mantle. The flask was evacuated and filled with nitrogen 4 times, and then the mixture was stirred at reflux under Nitrogen for 2 hr. HPLC showed complete conversion, so it was cooled and allowed to stir at room temperature overnight. The crude mixture was then filtered through celite, rinsing with EtOAc (500 mL). The filtrate was washed with half-saturated aqueous NaHCO3 (500 mL), and the aqueous phase was back-extracted with ethyl acetate (1×500 mL). The combined organic phases was washed with brine (1×500 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 600 g SiO2, 20%-100% EtOAc in hexanes gradient over 60 minutes, then 100% EtOAc for 30 more minutes). The product fractions were combined and concentrated in vacuo to give 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (9.23 g, 26.3 mmol, 77% yield) as an off-white solid. LC/MS (ES) m/z=352 [M+H]+.

Workup

  1. customequipped with a reflux condenser
  2. customThe flask was evacuated
  3. additionfilled with nitrogen 4 times
  4. temperatureat reflux under Nitrogen for 2 hr
  5. temperatureso it was cooled
  6. stirringto stir at room temperature overnight
  7. filtrationThe crude mixture was then filtered through celite
  8. washrinsing with EtOAc (500 mL)
  9. washThe filtrate was washed with half-saturated aqueous NaHCO3 (500 mL)
  10. extractionthe aqueous phase was back-extracted with ethyl acetate (1×500 mL)
  11. washThe combined organic phases was washed with brine (1×500 mL)
  12. dry with materialdried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by flash chromatography (Analogix, 600 g SiO2, 20%-100% EtOAc in hexanes
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c6027cac9b7a4776b28475baa2da54f1
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

Loading…