3-(Bromomethyl)-5-methylisoxazole → Ammonium Hydroxide

HRID 593497Notes

Reaction equation

HRID 593497 reaction equation
Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[O:32][N:31]=1>C1COCC1>[NH4+:5].[OH-:32].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:29][C:30]2[CH:34]=[C:33]([CH3:35])[O:32][N:31]=2)[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1

Participants

6

Reactant 3

HCID 27763043-(Bromomethyl)-5-methylisoxazoleHCID 3251421Potassium bis(trimethylsilyl)amideHCID 445539613-Methyl-2-(3-pyridyl)indole hydrochloride

Product 2

HCID 14923Ammonium HydroxideYield 0.1%HCID 445541373-methyl-1-(5-methyl-isoxazol-3-ylmethyl)-2-pyridin-3-yl-1H-indole

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A flask is charged with 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1, 0.100 g, 0.408 mmol) in THF (2.5 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 1.8 mL, 0.898 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of 3-bromomethyl-5-methyl-isoxazole (0.144 g, 0.817 mmol). The reaction mixture is stirred for 0.5 h, then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH4OH in acetonitrile gradientto afford 3-methyl-1-(5-methyl-isoxazol-3-ylmethyl)-2-pyridin-3-yl-1H-indole product as a colorless oil. The oil is dissolved in diethyl ether and few drops of concentrated HCl are added. The volatiles are removed in vacuo and the reside is lyophilized to afford the product as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 2.30 (s, 3H), 2.31 (s, 3H), 5.30 (s, 2H), 5.67 (s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.27 (ddd, J=7.6, 1.1 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.56-7.69 (m, 2H), 7.99 (dt, J=8.0, 1.9, 1.8 Hz, 1H), 8.56-8.68 (m, 2H). HRMS (ESI) m/z 304.1440 [(M+H)+ Calcd for C19H18N30, 304.1450].

Workup

  1. stirringThe reaction mixture is stirred for 0.5 h
  2. customquenched with saturated ammonium chloride solution
  3. extractionextracted with ethyl acetate
  4. dry with materialThe organic layer is dried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by reverse phase HPLC with Xbridge Shield RP18 column

Sources & evidence

ORD record
ord-b8b880c76e0a4773b9d83fe2c0ebb9e7
Source dataset
uspto-grants-2016_01
Patent number
US09242963B2

Reaction notes

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