Potassium Phosphate, Tribasic → methyl 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylate

HRID 593830Notes

Reaction equation

HRID 593830 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].[CH3:20][N:21]([CH2:23][B-](F)(F)F)[CH3:22].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH2:20][N:21]([CH3:23])[CH3:22])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 45588179Potassium dimethylaminomethyl trifluoroboronateHCID 67465593methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate

Product 1

HCID 67468936methyl 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylateYield 48.1%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred mixture of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (1.0 g, 2.90 mmol), potassium ((dimethylamino)methyl)trifluoroborate (0.5 g, 3.03 mmol) and Potassium phosphate (1.9 g, 8.95 mmol) (purged with N2)) in dioxane (3 mL) and water (3 mL) was added palladium(II) acetate (25 mg, 0.111 mmol) and sPhos (90 mg, 0.219 mmol). The reaction was heated to 100° C. and stirred for 18 hr under N2. LCMS showed that the reaction was complete. The reaction was diluted with EtOAc and water, and filtered to remove insolubles. The EtOAc phase was removed, dried (Na2SO4), filtered, and concentrated under vacuum. The crude was purified by silica gel chromatography (Analogix, SF25-40g, 0 to 2% (5% NH4OH/MeOH) in CH2Cl2). The product fractions were combined, evaporated to dryness under vacuum to give the product methyl 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.45 g, 1.394 mmol, 48.0% yield) as a light yellow oil (Only 84% pure by LCMS). This was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ=7.82 (d, J=1.8 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.96 (dt, J=7.1, 14.1 Hz, 1H), 3.88 (s, 3H), 3.52 (s, 2H), 2.17 (s, 3H), 2.16 (s, 6H), 1.53 (d, J=7.1 Hz, 6H). MS(ES)+ m/e 323.2 [M+H]+, 278.1 [M+H]+ −45 (HNMe2).

Workup

  1. filtrationfiltered
  2. customto remove insolubles
  3. customThe EtOAc phase was removed
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe crude was purified by silica gel chromatography (Analogix, SF25-40g, 0 to 2% (5% NH4OH/MeOH) in CH2Cl2)
  8. customevaporated to dryness under vacuum

Sources & evidence

ORD record
ord-31099fd2b7c546d88e5652395617f403
Source dataset
uspto-grants-2016_01
Patent number
US09242962B2

Reaction notes

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