Dichloromethane → 3-(Chloromethyl)-5-fluorobenzofuran

HRID 1936613Notes

Reaction equation

HRID 1936613 reaction equation
[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[C:13]([C:16](OC)=O)[C:12]=2[CH:20]=1.C(Cl)[Cl:22]>O1CCCC1>[Cl:22][CH2:16][C:13]1[C:12]2[CH:20]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[O:15][CH:14]=1

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 18184300Methyl 5-fluoro-3-benzofurancarboxylateHCID 21226445Aluminium lithium hydride

Product 1

HCID 181843143-(Chloromethyl)-5-fluorobenzofuran

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
55 °C

Procedure

Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing. A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g). A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 mL) was heated to 80° C. followed by quick addition of a solution of 3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL). The mixture was kept at 80° C. for ½ h and then poured onto ice. Standard work-up with diethyl ether gave a dark crystalline material, 5-fluorobenzofuran-3-ylacetonitrile (8.8 g).

Workup

  1. customwas quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL)
  2. additionFurther tetrahydrofuran (500 mL) was added
  3. stirringthe mixture stirred for 1 h
  4. filtrationThe mixture was filtered
  5. extractionthe precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L)
  6. concentrationThe combined organic phases were concentrated in vacuo
  7. customgiving an oil which
  8. customThe resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing
  9. additionA solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL)
  10. stirringAfter stirring for 16 h at room temperature the reaction
  11. concentrationwas concentrated in vacuo

Sources & evidence

ORD record
ord-64a5b2ac3e5c473cac59410c2e272116
Source dataset
uspto-grants-2002_05
Patent number
US06391882B1

Reaction notes

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