Triethylamine → a-Tosyl-(4-fluorobenzyl) isocyanide

HRID 1871687Notes

Reaction equation

HRID 1871687 reaction equation
[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([NH:18][CH:19]=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([CH:10]([N+:18]#[C-:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 24813Phosphorus oxychlorideHCID 516892Sodium BicarbonateHCID 10828539N-[(4-Fluorophenyl)((4-methylphenyl)sulfonyl)methyl]formamide

Product 1

HCID 10827289a-Tosyl-(4-fluorobenzyl) isocyanideYield 70%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamide produced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5 volumes) was cooled to 0° C. and POCl3 (46 mL, 487 mmoles, 1.5 equiv.) was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., the white slurry was cooled to -5° C. Triethylamine (166 g, 1.62 moles, 5 equiv.) was added dropwise to the slurry over 45 minutes at such a rate to keep the reaction temperature below 0° C. but above -5° C. Caution should be exercised at the beginning of the addition because the reaction has a tendency to exotherm quickly. After complete addition, the yellow slurry was stirred for 30 minutes at 0° C. The reaction slurry has a tendency to darken during the stirring period. The reaction was poured into a mixture of saturated aqueous sodium bicarbonate (1 L) and ethyl acetate (1 L), both pre-cooled to 0° C. The organic phase was subsequently washed with water followed by brine. The organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume remained. i-Propanol (200 mL) was added and concentrated again under vacuum at 35° C. until about 10% of the initial volume remained. This process was repeated with fresh 1-propanol (200 mL). A fine, yellow precipitate was observed. The precipitate was cooled to 0° C. and the product was collected by suction filtration and rinsed with 1-propanol (50 mL). The off-white solid was dried to a constant weight at 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product, affording a 70% yield. 1H NMR (300 MHz, CDCl3) δ 7.62 (2H, d, J=6.7 Hz), 7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1H, s), 2.46 (3H, s).

Workup

  1. customA 1° C. exotherm
  2. temperaturethe white slurry was cooled to -5° C
  3. customthe reaction temperature below 0° C. but above -5° C
  4. additionCaution should be exercised at the beginning of the addition because the reaction
  5. additionAfter complete addition
  6. temperatureboth pre-cooled to 0° C
  7. washThe organic phase was subsequently washed with water
  8. concentrationThe organic phase was concentrated under vacuum via rotary evaporation until about 10% of the initial volume
  9. additioni-Propanol (200 mL) was added
  10. concentrationconcentrated again under vacuum at 35° C. until about 10% of the initial volume
  11. temperatureThe precipitate was cooled to 0° C.
  12. filtrationthe product was collected by suction filtration
  13. washrinsed with 1-propanol (50 mL)
  14. customThe off-white solid was dried to a constant weight at 40° C./<1 mm

Sources & evidence

ORD record
ord-e9fca3b31f254b1aa6a7af0b9de5c375
Source dataset
uspto-grants-2000_08
Patent number
US06103936

Reaction notes

Loading…