1-benzyloxymethyl-1H-benzimidazole → (1-benzyloxymethyl-1H-benzimidazol-2-yl)-(3-bromothiophen-2-yl)methanone

HRID 2111157Notes

Reaction equation

HRID 2111157 reaction equation
[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[Br:34])=[O:28].CCOCC.CCCCCCC>O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[Br:34])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 113223751-benzyloxymethyl-1H-benzimidazoleHCID 21897273Diethylether heptaneHCID 576374043-bromo-N-methoxy-N-methylthiophene-2-carboxamideHCID 178418339Butyllithium

Product 1

HCID 57637380(1-benzyloxymethyl-1H-benzimidazol-2-yl)-(3-bromothiophen-2-yl)methanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of 1-benzyloxymethyl-1H-benzimidazole (648 mg, 2.72 mmol, Example 1B) in tetrahydrofuran (15 mL) at −78° C. under nitrogen is added n-butyllithium (1.30 mL of a 2.5 M solution in hexanes, 3.25 mmol) over 5 minutes and the resulting yellow solution is stirred at −78° C. After 25 minutes, a solution of 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide (680 mg, 2.72 mmol, Example 1A) in tetrahydrofuran (10 mL) is added over 15 minutes and the reaction stirred at −78° C. After 1 hour the reaction is warmed to ambient temperature and stirred for an additional 2 hours. The reaction is quenched with saturated ammonium chloride and the mixture extracted with ethyl acetate. The organic layer is washed with water and brine successively, dried over magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The crude material is chromatographed on silica, eluting with 40% ethyl acetate/heptane, to give the product. Trituration with ether/heptane affords (1-benzyloxymethyl-1H-benzimidazol-2-yl)-(3-bromothiophen-2-yl)methanone as an off-white powder; TLC Rƒ0.52 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 427.0, RT=3.84 minutes); 1H NMR[(CD3)2SO), 300 MHz]: δ 8.18 (d, 1H, 5.2 Hz), 7.90-7.82 (m, 2H), 7.55-7.50 (m, 1H), 7.45-7.38 (m, 2H), 7.25-7.17 (m, 5H), 6.13 (s, 2H), 4.58 (s, 2H).

Workup

  1. stirringthe reaction stirred at −78° C
  2. temperatureAfter 1 hour the reaction is warmed to ambient temperature
  3. stirringstirred for an additional 2 hours
  4. customThe reaction is quenched with saturated ammonium chloride
  5. extractionthe mixture extracted with ethyl acetate
  6. washThe organic layer is washed with water and brine successively
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated under reduced pressure to a yellow oil
  9. customThe crude material is chromatographed on silica
  10. washeluting with 40% ethyl acetate/heptane
  11. customto give the product

Sources & evidence

ORD record
ord-8ed046b3fd80491fb2c085520516512d
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

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