Potassium Carbonate → (S)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile

HRID 1851122Notes

Reaction equation

HRID 1851122 reaction equation
[Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][C@@H:18]([CH3:23])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>[Cu]I.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[C@H:18]([C:19]([OH:21])([CH3:22])[CH3:20])[CH3:23]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 13387N-methyl-2-pyrrolidoneHCID 51415372(S)-3-Amino-2-methylbutan-2-OLHCID 86709177HCID 86709177, compound

Product 1

HCID 86709178(S)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrileYield 62%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 22728543Water ethylacetateSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile, (0.229 g, 0.91 mmol), (S)-3-amino-2-methylbutan-2-ol (Example 21E) (0.113 g, 1.092 mmol), and K2CO3 (0.252 g, 1.820 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2 for 2 h. CuI (0.017 g; 0.091 mmol) was added and the mixture was subjected to microwave heating (140° C.) for 30 min. The reaction mixture was poured into EtOAc/water and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were filtered (Whatman #2), washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile (0.148 g, 62% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.42-7.39 (m, 1H), 7.39-7.34 (m, 1H), 6.74 (d, J=3.3 Hz, 1H), 4.41 (q, J=7.0 Hz, 1H), 1.60 (d, J=7.1 Hz, 3H), 1.41 (s, 1H), 1.33 (s, 3H), 1.09 (s, 3H); MS (LCMS ES+) m/z 263 ([M+H]+, 88%), 304 ({[M+H]+MeCN}+, 100%).

Workup

  1. temperatureheating (140° C.) for 30 min
  2. filtrationthe whole was filtered through a pad of Celite
  3. customLayers of the filtrate were separated
  4. extractionthe aqueous layer was extracted with EtOAc (×2)
  5. filtrationCombined organics were filtered (Whatman #2)
  6. washwashed (water, brine)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-64336274ff4b4f879c5f8abee53f3311
Source dataset
uspto-grants-2015_02
Patent number
US08957104B2

Reaction notes

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