5-chloro-7-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile → (+/-)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile

HRID 913969Notes

Reaction equation

HRID 913969 reaction equation
[CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:24]#[N:25]>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH:14]([OH:15])[CH3:1])[CH:13]=1)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[CH:9]=[C:8]2[C:24]#[N:25]

Participants

4

Reactant 2

HCID 575462455-chloro-7-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrileHCID 178418573HCID 178418573, compound2×

Product 1

HCID 57546168(+/-)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrileYield 70.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

Methylmagnesium bromide (0.334 mL, 1.002 mmol) was added to a −20° C. solution of 5-chloro-7-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (305 mg, 0.911 mmol) in THF (10 mL). The reaction was stirred 1 hour at −20° C., and TLC indicated that reaction was about 50% complete and no longer progressing. More methylmagnesium bromide (0.304 mL, 0.911 mmol) was added and the reaction was stirred an additional 1 hour at −20° C. The reaction was quenched by addition of HCL(1N, 10 mL) and then water (30 mL) was added and the reaction was extracted with ethyl acetate (3×20 mL). The organic layers were washed with brine (20 mL), dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 20% ethyl acetate/hexanes to provide (±)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (224 mg, 0.638 mmol, 70.1% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.66 (d, J=2.0 Hz, 1H), 7.62 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 5.83 (d, J=11.3 Hz, 1H), 5.56 (pentet, J=6.3 Hz, 1H), 5.48 (d, J=11.3 Hz, 1H), 3.46 (app t, J=8.5 Hz, 2H), 2.27 (d, J=6.1 Hz, 1H), 1.66 (d, J=6.5 Hz, 3H), 0.86 (app t, J=8.3 Hz, 2H), −0.07 (s, 9H). LC/MS (HPLC method 4): tR=3.57 min, 373.16(MNa)+.

Workup

  1. customTLC indicated that reaction
  2. stirringthe reaction was stirred an additional 1 hour at −20° C
  3. customThe reaction was quenched by addition of HCL(1N, 10 mL)
  4. additionwater (30 mL) was added
  5. extractionthe reaction was extracted with ethyl acetate (3×20 mL)
  6. washThe organic layers were washed with brine (20 mL)
  7. dry with materialdried with MgSO4
  8. customevaporated
  9. customThe residue was purified by chromatography on SiO2 with 20% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-1dd808664f3b442e9f1fe4d8266a03df
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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