Methyl iodide → HCID 135400902, compound

HRID 1816410Notes

Reaction equation

HRID 1816410 reaction equation
Br[C:2]1[C:3]([O:21]C)=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[O:10][N:9]=2)[CH:7]=1.[Li][CH2:24]CCC.IC.B(Br)(Br)Br>C1COCC1>[OH:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([CH3:24])[C:3]([OH:21])=[CH:4][C:5]=3[OH:19])=[N:9][O:10][C:11]=2[CH:16]=1

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 25134Boron tribromideHCID 22493719HCID 22493719, compoundHCID 178418339Butyllithium

Product 1

HCID 135400902HCID 135400902, compoundYield 81%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 3-(5-bromo-2,4-dimethoxyphenyl)-6-methoxy-1,2-benzisoxazole (200 mg, 0.55 mmol) in THF (6 mL) at −78° C. was added n-BuLi (0.24 mL, 0.60 mmol, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 30 min and then iodomethane (60 μL, 0.96 mmol) was added dropwise. The cooling bath was switched to an ice bath and the solution was stirred at 0° C. for 2 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was conducted in EtOAc (2×30 mL) with water (20 mL). Flash chromatography with silica gel (gradient to 25% EtOAc/hexanes) provided a mixture of the desired methylated product and the protonated side product (both compounds have the same Rf). The above mixture of compounds was treated with BBr3 according to Example 2, Step i, to produce the title compound as a light orange solid (114 mg, 81% yield for two steps): mp 195° C. (dec.); 1H NMR (300 MHz, acetone-d6) δ 2.25 (s, 3H), 6.59 (s, 1H), 7.04 (dd, 1H, J=8.5, 2.1 Hz), 7.09 (d, 1H, J=1.8 Hz), 7.80 (s, 1H), 8.12 (d, 1H, J=8.8 Hz), 8.88 (broad s, 1H), 9.42 (broad s, 1H), 9.52 (s, 1H); MS m/e 258 (M+H)+.

Workup

  1. customThe cooling bath was switched to an ice bath
  2. stirringthe solution was stirred at 0° C. for 2 h
  3. customThe reaction was quenched with water, most of the solvent
  4. customwas removed in vacuo, and extraction
  5. customFlash chromatography with silica gel (gradient to 25% EtOAc/hexanes) provided
  6. additiona mixture of the
  7. additionThe above mixture of compounds

Sources & evidence

ORD record
ord-76447625c3e74e459c75960ffc92b768
Source dataset
uspto-grants-2005_04
Patent number
US06884814B2

Reaction notes

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