Potassium Phosphate, Tribasic → 1,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylate

HRID 1909923Notes

Reaction equation

HRID 1909923 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:4]([C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]2)#[N:5]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 5227222-Fluoro-6-iodobenzonitrileHCID 18451469tert-butyl 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate

Product 1

HCID 668237921,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylateYield 72.4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-fluoro-6-iodobenzonitrile (2.65 g, 10.73 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (3.78 g, 10.95 mmol, 1.02 equiv), tricyclohexylphosphine (301 mg, 1.07 mmol, 0.1 equiv), Pd2(dba)3 (491 mg, 0.54 mmol, 0.05 equiv) and K3PO4 (3.87 g, 18.24 mmol, 1.7 equiv) in 40 mL of dioxane and 10 mL of water in a 150 mL pressure vessel was bubbled under argon for 10 min. The mixture was capped and heated in an oil bath at 100° C. for 18 h. LCMS showed conversion complete. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (130 mL) and brine (40 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The dark brownish oil was stored in the refrigerator for 20 h, which became a cake. Trituration in DCM/hexane (1:4), breaking up of the cake, filtration, and drying under vacuum at room temperature gave 1,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylate (2.63 g) as a greyish solid. The filtrate was concentrated in vacuo and absorbed onto a dryload cartridge. Purification was done on an RS-120 g silica gel cartridge using gradient elution of 1% EtOAc in hexane to 40% EtOAc in hexane. The product eluted from 29-34% EtOAc in hexane. Concentration in vacuo and drying under vacuum additional 1,1-dimethylethyl 5-(2-cyano-3-fluorophenyl)-2,3-dihydro-1H-indole-1-carboxylate (0.77 g) as a yellow foam.

Workup

  1. customwas bubbled under argon for 10 min
  2. customThe mixture was capped
  3. filtrationThe mixture was filtered through Celite
  4. concentrationThe filtrate was concentrated in vacuo
  5. customThe residue was partitioned between EtOAc (130 mL) and brine (40 mL)
  6. dry with materialThe organic was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. filtrationTrituration in DCM/hexane (1:4), breaking up of the cake, filtration
  10. customdrying under vacuum at room temperature

Sources & evidence

ORD record
ord-8707135c6a1044c58aacd392c56b43d0
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

Loading…