Cesium carbonate → HCID 67466652, compound

HRID 593833Notes

Reaction equation

HRID 593833 reaction equation
Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][B-](F)(F)F)=[O:26])([CH3:23])([CH3:22])[CH3:21].[K+].C([O-])([O-])=O.[Cs+].[Cs+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>C1(C)C=CC=CC=1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11])=[O:26])([CH3:23])([CH3:22])[CH3:21]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl2×HCID 42614635potassium tert-butyl N-(2-(trifluoroboranuidyl)ethyl)carbamateHCID 67465593methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate

Product 1

HCID 67466652HCID 67466652, compoundYield 33.7%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalyst2×HCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

To a stirred mixture of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.37 g, 1.074 mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.30 g, 1.195 mmol) and Cs2CO3 (1.0 g, 3.07 mmol) (purged with N2) in toluene (12 mL) and water (4 mL) was added palladium(II) acetate (20 mg, 0.089 mmol) and RuPhos (80 mg, 0.171 mmol). The reaction was heated to 95° C. and stirred for 18 hr under N2. LCMS still showed SM. Another portion of palladium(II) acetate (20 mg, 0.089 mmol) and RuPhos (80 mg, 0.171 mmol) was added and the reaction stirred at 95° C. for another 18 hr. LCMS showed that the reaction was now mostly done. The reaction was diluted with EtOAc and water, and filtered to remove insolubles. The EtOAc phase was removed, dried (MgSO4), filtered, and concentrated under vacuum. The crude was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 25% EtOAc in hexanes). Three fractions were collected. The first fraction contained a significant amount of the desbromo product, the second fraction was a mixture of unknowns, and the last fraction contained product (Note; opposite order from the TLC). The product fractions were combined, evaporated to dryness under vacuum, triturated with hexanes, filtered and dried under vacuum to give the product methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (148 mg, 0.362 mmol, 33.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.81 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.00 (t, J=5.6 Hz, 1H), 3.87 (s, 3H), 3.07 (q, J=6.7 Hz, 2H), 2.97-2.85 (m, 2H), 2.13 (s, 3H), 1.56 (d, J=7.1 Hz, 6H), 1.36 (s, 9H). MS(ES)+ m/e 409.2 [M+H]+.

Workup

  1. stirringthe reaction stirred at 95° C. for another 18 hr
  2. filtrationfiltered
  3. customto remove insolubles
  4. customThe EtOAc phase was removed
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customThe crude was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 25% EtOAc in hexanes)
  9. customThree fractions were collected
  10. additiona mixture of unknowns
  11. customevaporated to dryness under vacuum
  12. customtriturated with hexanes
  13. filtrationfiltered
  14. customdried under vacuum

Sources & evidence

ORD record
ord-c0cf6a2798a842b682350b0291fa3f9c
Source dataset
uspto-grants-2016_01
Patent number
US09242962B2

Reaction notes

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