Methyl iodide → 1-(Phensulfonyl)-5-chloro-2-methyl-1H-pyrrolo[3,2-B]pyridine

HRID 628447Notes

Reaction equation

HRID 628447 reaction equation
[CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CI>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH3:1])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 7912DiisopropylamineHCID 181764365-Chloro-1-(phenylsulfonyl)-4-azaindoleHCID 178418339Butyllithium

Product 1

HCID 1181598771-(Phensulfonyl)-5-chloro-2-methyl-1H-pyrrolo[3,2-B]pyridineYield 80.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To N,N-diisopropylamine (13 mL, 93 mmol, Aldrich) in tetrahydrofuran (200 mL) at −78° C. was added 1.6 M n-butyllithium in hexanes (55 mL, 88 mmol, Aldrich). The reaction mixture was warmed to 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (17.1 g, 58.4 mmol, from Step 1) in tetrahydrofuran (86 mL) was added dropwise over 30 minutes. The reaction mixture was then stirred for 1 hour at −78° C., and methyl iodide (7.3 mL, 120 mmol, Aldrich) was added dropwise over 5 minutes. The reaction was allowed to warm to 5° C. over 3 hours, then cooled to −20° C. and quenched by the addition of 1 N HCl. EtOAc was added, and the solution was stirred for 15 minutes and left at ambient temperature overnight. The layers were separated and the organic layer was washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a wet orange solid that was then triturated with MeOH (18 mL). The solid was isolated by filtration, washed and dried at 40° C. under high vacuum for 2.2 h to give 14.4 g of product. Additional amount of product was obtained by flash chromatography of the filtrate (eluting with a gradient from 0-40% EtOAc in hexanes) afforded 1.87 g. (Yield: 16.3 g, 91%).

Workup

  1. temperatureThe reaction mixture was cooled to −78° C.
  2. stirringThe reaction mixture was then stirred for 1 hour at −78° C.
  3. temperatureto warm to 5° C. over 3 hours
  4. temperaturecooled to −20° C.
  5. customquenched by the addition of 1 N HCl
  6. additionEtOAc was added
  7. stirringthe solution was stirred for 15 minutes
  8. waitleft at ambient temperature overnight
  9. customThe layers were separated
  10. washthe organic layer was washed sequentially with water and brine
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customto give a wet orange solid that
  15. customwas then triturated with MeOH (18 mL)
  16. customThe solid was isolated by filtration
  17. washwashed
  18. customdried at 40° C. under high vacuum for 2.2 h

Sources & evidence

ORD record
ord-84ed61d4e3f94e66a20dab0590553f72
Source dataset
uspto-grants-2016_04
Patent number
US09309246B2

Reaction notes

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