Indoline → HCID 49783405, compound

HRID 2095381Notes

Reaction equation

HRID 2095381 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]

Participants

7

Reactant 3

HCID 10328IndolineHCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 23676156Sodium t-butoxide

Product 1

HCID 49783405HCID 49783405, compoundYield 90%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
99 °C

Procedure

To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (70 mg, 0.20 mmol) and indoline (25 μL, 0.22 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (29 mg, 0.3 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (3.7 mg, 4.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 6.9 mg, 12 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC (SiO2, CH2Cl2/EtOAc 4:1, then 1:1). The product (71 mg, 90%) was obtained as a bright yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.91 (s, 1H), 7.20-7.00 (m, 4H), 6.79 (t, 1H, J=6.8 Hz), 4.11 (m, 2H), 3.90-3.86 (m, 3H), 3.41 (m, 2H), 3.13 (t, 2H, J=8.4 Hz), 2.02 (m, 3H), 1.86 (m, 1H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 155.6, 146.0, 141.4, 132.1, 131.5, 130.1, 129.1, 127.3, 125.3, 120.0, 109.4, 108.7, 68.5, 56.1, 51.9, 47.1, 46.8, 28.9, 28.6, 28.2, 24.0.

Workup

  1. customThe mixture was degassed
  2. custompurged with Ar (3 cycles)
  3. temperatureAfter cooling to room temperature
  4. additionthe mixture was diluted with EtOAc
  5. washthe solution was washed with brine
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customThe residue was purified by CC (SiO2, CH2Cl2/EtOAc 4:1

Sources & evidence

ORD record
ord-300448fac1744cba89f7b8b51c934473
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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